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Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS Honolulu, Hawaii Friday, February 18, 2011, 2:45 pm – 4:45 pm Co-Chair: Angela Dispenzieri, MD, Mayo Clinic Transplant Center, Rochester, MN Telephone: 507-284-2479; Fax: 507-266-4972; E-mail:[email protected] Co-Chair: Sagar Lonial, MD, Emory University Hospital, Atlanta, GA Telephone: 404-778-1900; Fax: 404- 727-3520; E-mail: [email protected] Co-Chair: Gustavo Milone, MD, Angelica Ocampo-Fundaleu, Buenos Aires, Argentina Telephone: 54-11-4807-1313; Fax: 54-11-4805-1703;E-mail: [email protected] Statisticians: Peigang Li, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0647; Fax: 414-805-0714; E-mail: [email protected] Tony X. Zhong, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0567; Fax: 414-805-0714; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Scientific Director: Parameswaran Hari, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-4604; Fax: 414-805-4606; E-mail: [email protected] 1. Introduction

a. Minutes of February, 2010 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers

a. MM05-01 Reece DE, Vesole DH, Shrestha S, Zhang MJ, Pérez WS, Dispenzieri A, Milone GA, Abidi M, Atkins H, Baskey A, Bredeson CN, Boza WB, Freytes CO, Gale RP, Gajewski JL, Gibson J, Hale GA, Kumar S, Kyle RA, Lazarus HM, McCarthy PL, Pavlovsky S, Roy V, Weisdorf DJ, Winernik PH, Hari P. Outcome of patients with IgD and IgM multiple myeloma undergoing autologous hematopoietic stem cell transplantation: a retrospective CIBMTR study. Clinical Lymphoma, Myeloma & Leukemia 10: 458-463, 2010.

b. MM02-03/MM03-01 Ringdén O, Shrestha S, Silva GT, Zhang M-J, Dispenzieri A, Remberger M, Kamble R, Freytes CO, Gale RP, Gibson J, Gupta V, Holmberg L, Lazarus H, McCarthy P, Meehan K, Schouten H, Milone GA, Lonial S, Hari P. Influence of acute and chronic graft-versus-host disease on relapse and survival after reduced intensity conditioning allogeneic transplantation for myeloma. Submitted.

c. MM05-02 Vogl DT, Wang T, Pérez WS, Stadtmauer EA, Heitjan DF, Lazarus HM, Kyle

RA, Kamble R, Weisdorf D, Roy V. Gibson J, Ballen K, Holmberg L, Bashey A, McCarthy PL, Freytes C, Maharaj D, Maiolino A, Vesole D, Hari P. Effect of obesity on outcomes after autologous Hematopoietic stem cell transplantation for multiple myeloma. Submitted.

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d. MM08-01 Kumar S, Zhang M-J, Li P, Dispenzieri A, Milone GA, Lonial S, Krishnan A, Maiolino A, Wirk B, Weiss B, Freytes CO, Vogl DT, Vesole DH, Lazarus HM, Meehan KR, Hamadani M, Lill M, Callander NS, Majhail NS, Wiernik PH, Nath R, Kamble RT, Vij R, Kyle, RA, Gale RP, Hari P. Time trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. Submitted.

e. MM09-01 Mahindra A, Kalaycio ME, Vela-Ojeda J, Vesole DH, Zhang M-J, Li P, Berenson

JR, Bird JM, Dispenzieri A, Gajewski, JL, Gale RP, Holmberg L, Kumar S, Kyle R, Lazarus HM, Lonial S, Mikhael J, Milone GA, Munker R, Math R, Saccaro S, To LB, Vogl DT, Wirk B, Hari P. Hematopoietic stem cell transplantation for primary plasma cell leukemia: Results from the Center for International Blood and Marrow Transplant Registry. Submitted.

4. Studies in progress (Attachment 3)

a. MM02-01/D01-117 MM in pts <55/unrelated NST for MM (C Freytes/D Vesole)

Data File Preparation

b.

MM06-04 Outcomes-auto post PR with induct vs. salvage therapy in MM (R Vij/S Kumar/D Reece)

Data File Preparation

c.

MM08-02 Human histocompatibility Ag-multiple myeloma association (M Beksac)

Manuscript Preparation

d. MM09-02 Outcome of salvage 2nd auto HCT in relapsed MM (A Saad/L Michaelis/D Vesole) (Attachment 4)

Protocol Development

e. MM09-03 Delayed auto transplant in MM (L Holmberg/S Vesole) (Attachment 5)


f. MM10-01 Late complications/malignancies post HCT for MM (P Mehta/A Mahindra/G Raval) (Attachment 6)


g. MM10-02 Effect of comorbidities on post HCT complications in MM (A Saad/A Mahindra) (Attachment 7)


h. MM10-03 Full 1st allo vs. tandem auto/NMA allo for MM (L Costa) (Attachment 8)


i. MM08-03 Effect of renal failure before auto HCT for myeloma (B Wirk)

Discontinued

j. MM09-04 DLI for relapse/persistent MM post allo HCT (B Wirk) Discontinued 5. Future/ Proposed studies

a. PROP 0810-03 Do patients above 65 years old attain the same benefit from an autologous progenitor cell transplant as younger patients? (M Sharma) (Attachment 9)

b. PROP 1210-05 Waldenstrom’s macroglobulinemia (WM): retrospective analysis with hematopoietic stem cell transplantation (R Cornell) (Attachment 10)

c. PROP 1210-06 A comparison of the outcome and prognostic characteristics of patients who have myeloablative sibling and unrelated donor transplants for multiple myeloma who are alive and disease free at 10 years post transplant with those who relapse between 5 and 10 years post transplant (D Marks) and PROP 1210-38 Development of a prognostic scoring system to predict relapse of multiple myeloma after allogeneic hematopoietic stem cell transplant (N Hardy) (Attachment 11)

d. PROP 0910-02 High-dose therapy for patients with primary systemic amyloidosis (L Maramattom) and PROP 1210-12 Outcomes of allogeneic hematopoietic cell transplantation for AL amyloidosis (B Wirk) (Attachment 12)

e. PROP 1210-48 Comparison of the efficacy of conditioning regimens in autologous hematopoietic cell transplantation for plasma cell myeloma (B Wirk) (Attachment 13)

f. PROP 1210-61 High dose intravenous busulfan and melphalan followed by bortezomib vs.

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high dose melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation for patients with multiple myeloma (T Rodriguez) (Attachment 14)

6. Other business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS Orlando, Florida Saturday, February 27, 2010, 2:45 pm – 4:45 pm Co-Chair: Angela Dispenzieri, MD, Mayo Clinic Transplant Center, Rochester, MN Telephone: 507-284-2479; Fax: 507-266-4972; E-mail:[email protected] Co-Chair: Gustavo Milone, MD, Angelica Ocampo-Fundaleu, Buenos Aires, Argentina Telephone: 54-11-4807-1313; Fax: 54-11-4805-1703; E-mail: [email protected] Co-Chair: Sagar Lonial, MD, Emory University Hospital, Atlanta, GA Telephone: 404-778-1900; Fax: 404-727-3520; E-mail: [email protected] Statisticians: Peigang Li, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0647; Fax: 414-805-0714; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Scientific Director: Parameswaran Hari, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-4604; Fax: 414-805-4606; E-mail: [email protected] 1. Introduction

Minutes of February, 2009 meeting Dr. Lonial opened the meeting at 2:45pm. He asked the audience to get voting sheets and participate in prioritizing the studies in progress and proposals. The voting guidelines were presented. He introduced the new team member, Peigang Li, Biostatistician at the CIBMTR; email: [email protected]. He asked for approval of last year’s Tandem minutes. The minutes were approved without objections.

2. Accrual summary Dr. Lonial briefly presented the accrual summary that provides information about the number of patients available in the registry for potential studies and depth of this committee has used for analysis. Details of the characteristics were not presented to the committee but were available as part of the Working Committee attachments.

3. Presentations, published or submitted papers Dr. Lonial shared with the committee that over the past year 3 manuscripts were published or submitted for publication, and three abstracts were presented at the 2009 ASH. A number of new ideas and comments were incorporated into last year’s proposals. a. MM04-01 Hari P, Zhang M-J, Roy V, Pérez WS, Bashey A, Bik To L, Elfenbein G, Freytes

CO, Gale RP, Gibson J, Kyle RA, Lazarus HM, McCarthy PL, Milone GA, Pavlovsky S, Reece DE, Schiller G, Vela-Ojeda J, Weisdorf D, Vesole D. Is the International staging system superior to the Durie Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia 23:1528-1534, 2009.

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b. MM06-03/ HS06-01 Hari PN, Majhail NS, Zhang M-J, Hassebroek A, Siddiqui F, Ballen K, Bashey A, Bird J, Freytes CO, Gibson J, Hale G, Holmberg L, Kamble R, Kyle RA, Lazarus HM, LeMaistre CF, Loberiza FR, Maiolino A, McCarthy PL, Milone G, Omondi N, Reece DE, Seftel M, Trigg M, Vesole D, Weiss B, Wiernik P, Lee SJ, Rizzo JD, Mehta P. Race and Outcomes of Autologous Hematopoietic Cell Transplantation for Multiple Myeloma. In Press, Biol Blood Marrow Transplant.

c. MM05-01 Reece DE, Vesole DH, Shrestha S, Zhang M-J, Pérez WS, Dispenzieri A, Milone

GA, Abidi M, Atkins H, Bashey A, Bredeson CN, Bujan-Boza W, Freytes CO, Gale RP, Gajewski JL, Gibson J, Hale GA, Kumar S, Kyle RA, Lazarus HM, Lohar PV, McCarthy PL, Pavlovsky S, Roy V, Weisdorf DJ, Wiernik PH, Hari PN. Outcomes of autotransplant for IgD and IgM Multiple Myeloma. Submitted.

d. MM02-03/MM03-01 Hari PN, Barrett J, Shrestha S, da Silva GT, Zhang M-J, Dispenzieri

A, Milone GA, Lonial S and Ringdén O on behalf of the Plasma Cell Disorders Working Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HSCT) for Myeloma (MM) - Chronic Graft versus Host Disease (GVHD) is associated with lower risk of relapse and superior progression free survival (PFS) – A CIBMTR analysis. Presented at the American Society of Hematology in New Orleans, Louisiana, December 2009.

e. MM08-01 Kumar S, Shrestha S, Zhang M-J, Dispenzieri A, Milone GA, Lonial S and Hari

PN on behalf of the Plasma Cell Disorders Working Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Allogeneic Stem Cell Transplantation (SCT) for Multiple Myeloma (MM) - What has changed? : A CIBMTR Analysis from 1989 - 2005. Presented at the American Society of Hematology in New Orleans, Louisiana, December 2009.

f. MM09-01 Mahindra A, Vesole D, Kalaycio ME, Vela-Ojeda J, Shrestha S, Zhang M-J,

Dispenzieri A, Milone GA, Lonial S, and Hari PN on behalf of the Plasma Cell Disorders Working Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Autologous Hematopoietic Stem Cell Transplantation (HCT) is a Safe and Effective Treatment for Primary Plasma Cell Leukemia: the CIBMTR Experience. Presented at the American Society of Hematology in New Orleans, Louisiana, December 2009.

4. Studies in progress

Dr. Milone led the discussion on studies in progress. Those studies which had been selected for statistical hours last year were not presented in order to allow time for prioritization of other proposals. A summary of the progress was provided as an attachment to the committee members. These studies were as follows: a. MM02-03/MM03-01 Related NST/GVL in MM (O Ringdén)

The study’s objectives are to (a) identify a graft-versus-myeloma effect after allogeneic BMT for Multiple Myeloma by comparing myeloma recurrence in patients with and without acute and/or chronic GVHD after non-myeloablative transplants; and (b) to determine the competing effects of GVHD and relapse on disease-free survival in these patient groups. A draft manuscript is underway and it is expected to be submitted by July 2010.

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b. MM05-02 Effect of obesity on SCT outcome in MM (D Vogl) The specific aims of the study are: (a) to compare the outcomes in patients who are normal weight, overweight, obese and severely obese; (b) to assess the frequency at which obese patients receive a reduced dose of melphalan; and (c) to compare outcomes in obese patients who receive full doses of melphalan or reduced doses of melphalan. A draft manuscript is underway and it is expected to be submitted by July 2010.

c. MM06-04 Post PR with induction vs salvage therapy in autoHCT for MM (R Vij/D Reece/S Kumar) This study proposes (a) to examine the relationship between disease status at transplant and outcomes after stem cell transplantation (b) to compare the response rates, traditional outcomes such as disease free survival and overall survival of patients achieving less than a partial response or complete response; and (c) to examine the relationship between the degrees of reduction in M-protein prior to transplant the outcomes after stem cell transplantation. There are about 2300 adult patients who underwent autologous transplant within one year of diagnosis receiving one or more lines of therapy. The protocol is available for review.

d. MM08-01 Time trends in allo HCT for MM (S Kumar) The specific aim is to study the trend of the demographic characteristics of the patients who have undergone allogeneic transplantation for Multiple Myeloma between 1989 and 2005 and their baseline clinical features and transplant outcomes among patients. A draft manuscript is underway and it is expected to be submitted by July 2010.

e. MM08-02 HLA specificities and predisposition to the development of MM (M Beksac) This purpose of this study is to compare HLA-A,-B and -DRB1 2-digit allele and haplotype frequencies in patients with MM to the normal population in order to define HLA specificities associated with the risk of developing MM. A draft manuscript is underway and it is expected to be submitted by July 2010.

f. MM09-01 Plasma Cell Leukemia: Outcomes with auto or allo HCT (A Mahindra) The objectives of the study are to compare traditional outcomes (TRM, PFS, and OS) after autologous and allogeneic transplantation for patients with primary and secondary plasma cell leukemia (PCL), outcomes in patients receiving bortezomib based induction compared to other induction regimens, and genetic aberrations in patients undergoing transplantation for PCL. A draft manuscript is underway and it is expected to be submitted by July 2010.

Previously accepted studies but with little progress during the past year were as follows. These studies were presented and voted on.

g. MM02-01/D01-117 Second autologous HCT vs. NST after relapsed autologous HCT for

MM (C Freytes/D Vesole) Dr. Freytes presented this study. The basic objective is to compare the outcome of second autologous HCT vs. the outcome of related or unrelated RIC allo HCT for MM. There are renewed interests in transplants after first transplantation and salvage allo, and a relative large cohort of 80 patients were presented at ASH 2009 by Dr. Donna Reece. A multi-institution study in Germany had a projected five year survival of ~20%. There are 355 eligible patients who underwent second auto transplants in the CIBMTR registry before 2006. Note that the disease status for second transplants from most unrelated donors is not available but sensitive/resistant information prior to transplant is collected. There could be surrogate

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markers useful for this study. It was suggested to include time from first to salvage transplants and powerful markers of prognosis. The committee recommended to proceeds the study with the existing data.

h. MM08-03 Effect of renal failure after auto HCT for MM (B Wirk) Dr. Wirk presented this study. Renal failures occur in 30-55% of MM patients with up to 10% undergoing dialysis at some point, with median survival of only 4-28 months. Single institution studies have indicated that renal failure is not an exclusion criterion for auto transplant. However conflicting results were reported. The optimal conditioning regimen is unknown. For example, a study showed that melphalan dose 140 mg/m2 patients have greater toxicity. These studies did not provide consistent and independent predictors impacting the primary endpoints such as TRM, PFS and OS. Better understand of the predictors would allow better selection of patients in the high risk group and help guide clinical practice in the community at large. Secondary endpoints include kinetics of engraftment, reversibility of dialysis dependence and optimal conditioning regimen. The current study could potentially be the largest study in the literature involving over 3000 patients with renal insufficiency and about 150 patients underwent tandem auto transplant: (1) Normal or mild (n=2228); (2) Moderate (n=864); (3) Severe (n=199). Renal insufficiency was defined based on the calculated rate of creatinine clearance. The SSN for patients having dialysis are not available in the registry so it is not known how many transplant patients came off dialysis. The draft protocol was available for review.

i. MM09-02 Outcome of salvage 2nd auto HCT in relapsed MM (A Saad/L Michaelis/D Vesole) Dr. Vesole briefly discussed this study. The purpose of the study is to evaluate the outcome of patients with MM who undergo second auto HCT as a salvage treatment and subsequently relapse. There are 144 eligible patients. Based on the voting results, the committee will decide whether it should be a free-standing study or merged with study #MM02-01.

j. MM09-03 Early vs delayed HCT in MM pts treated w/novel induction (L Holmberg/D Vesole) Dr. Holmberg presented this study. The objective of the study is to describe clinical outcomes after initial upfront or delayed auto PBSC in MM patients. Conventional chemotherapies are the standard for initial treatments. With introduction of novel therapy, there is a trend to delay undergoing autologous transplants. This study will determine if upfront transplant still has superior outcome for disease control, time to progression and overall survival. If approved, a supplemental form will be needed to collect data for patients transplanted in recent years since this information was not captured in the former CIBMTR forms (before 2009).

k. MM09-04 DLI for relapse/persistent MM post allo HCT (B Wirk/J Wingard) Dr. Wirk presented this study. The purpose of the study is to look at the clinical outcomes of DLI for persistent or relapsed MM after allo HCT. Allo HCT is associated with longer progression free survival (PFS) in comparison with auto HCT likely due to graft-versus-myeloma (GvM) effect. There are 144 patients receiving DLI after allogeneic transplant for MM, potentially the largest dataset to be undertaken to evaluate the primary endpoints of the response rate of DLI, PFS, and OS. The secondary endpoints are to understand the impact of prognostic factors’ response to DLI, induction of chemotherapy prior to DLI, the impact of the response and severity of the current GVHD. The relevant information is found on CIBMTR’s Forms 2100, 2200, and 2300, and transplant centers will be contacted by the PIs if there is missing information. DLI study requires complicated information. Newer information was collected by the CIBMTR beginning in 2007. There are 74 patients who will

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need further review to determine if they have received a DLI infusion. If approved, a supplemental form will be needed to collect detailed DLI information which was not captured in the former CIBMTR forms. The draft protocol was available for review.

5. Future/ Proposed studies Dr. Dispenzieri announced that the following new proposals are to be presented and voted on. a. PROP 1109-07 Role of stem cell transplantation as salvage therapy for multiple myeloma (S

Giralt/ M Qazilbash) Dr. Giralt presented this proposal. The PIs have been looking at salvage therapy for transplant of MM, especially primary refractory MM where less than 5-10% of the patients failed to achieve PR with novel induction of therapies. The median survival is 10 months before novel induction. The hypothesis is that with new therapies patients could have a better outcome, specifically transplant naïve patients. He mentioned the type of clinical trials and ongoing study at the MD Anderson. The original idea was to look at descriptive factor showing which therapies will predict longer event for survival, treatment before and post transplants, whether patients get maintenance or not, and how they will respond. Now there are enough patients (n=340) to look at how effective consolidation with transplant as part of the salvage therapy is. No extra data are needed and overall outcomes will be enough. The study overlaps with an ongoing study from last year, MM09-02, which looks at delay vs. early relapse. Another study (MM09-03) looks at novel induction. It was agreed upon that these studies would be merged.

b. PROP 1109-08 Long term complications after stem cell transplantation for multiple myeloma (P Mehta/G Raval) Dr. Raval presented this proposal. The objective of the study is to look at the incidence of long term complications patients after SCT. The rate and type of complications with tandem upfront SCT are not well studied, and MM patients after transplant have a high risk of developing long term complications such as organ failure, secondary malignancies and MDS. There are about 5000 patients selected from the registry before 2008. A total of 199 patients had secondary malignancies (13 MDS; 65 no MDS; 121 Unknown). This will be merged with PORP 1209-15.

c. PROP 1209-15 Second malignancies after autologous stem cell transplantation for multiple myeloma: analysis of risk factors and outcome (A Mahindra) Dr. Mahindra presented this proposal. The purpose is to look at risks of second malignancies after auto transplant for MM and to evaluate prognostic factors. There are over 5000 patients in the registry while 75% of them having first transplant and 25% having tandem transplants. The data is slight different from the AK data. This may help understand the difference between single vs. two transplants. Although there are only 199 patients who had secondary malignancies, but the prevalence is higher if missing data were excluded. Secondary malignancies account for 30 cases (1%) of the cause of death. It is worth of looking into how different the mortality of these patients from those where secondary malignancies are not the cause of death. Comments were made to recommend merging with PROP 1109-08.

d. PROP 1209-23 The impact of pre-transplant co-morbidities on the outcome of autologous hematopoietic cell transplantation in multiple myeloma (A Saad/P Hari) Dr. Saad presented this proposal. It is aimed to look at the impact of pre-transplant co-morbidities on the outcome of autologous transplants only. The decision on transplant is rather objective, depending on physician’s assessment of patients eligibility involving factors

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like co-morbidities, age, etc. There exists co-morbidity index in the transplant studies but it has not been applied in MM. The goal here is to create a similar model of co-morbidity index which is unique to the MM population. The eligible patients undergo either upfront or salvage transplants between 1995 and 2007, and conditioning regimen is restricted to melphalan. Patients who had previous allogeneic are excluded to eliminate confounding factors. None of the patients have co-morbidity index scores. There are enough events in this large dataset to say that the NRM rate is lower in autologous transplant patients which is not shown in institutional settings with smaller dataset. It is question whether the NRM rate will impact the clinical practice. It is suggested that tandem transplant plants be included to have a fair assessment of the co-morbidity index. Almost 70% of eligible patients have co-existing diseases prior to conditioning (n=1622/2351). If approved, a supplemental data form is needed to collect the co-morbidity information.

e. PROP 1209-30 Non-relapse mortality after autologous stem cell transplantation for multiple myeloma: analysis of risk factors and outcome (A Mahindra) Dr. Mahindra presented this proposal. The purpose is to evaluate the incidence and causes of NRM after auto transplant for MM as well as prognostic factors for NRM. A number of causes of death are the focus of this study, such as IpN, ARDS, organ failure, etc. Questions can be asked whether these complications happen early or late, and what are the predictive factors in terms of patient characteristics. This proposal might need more information from the CIBMTR to split it into two parts, NRM and secondary malignancies. It was suggested to combine with PROP 1209-23 to look at whether co-morbidities can predict mortality.

f. PROP 1209-41 Outcomes of a first fully myeloablative allogeneic transplant compared with an autologous followed by a non-myeloablative allogeneic transplant for the treatment of multiple myeloma (L Costa) Dr. Costa presented this proposal. The hypothesis is that more recent NRM rate estimate is needed to reflect current standard of care. The aims are to compare 3-year PDF for a full allo vs. tandem auto-allo, and the cumulative incidence for NRM vs. relapse. Eligible patients are restricted to have HLA-id sibs or URD well-matched donors between 1995 and 2007. Graft sources are BM or PB, not T-cell depleted. Melphalan doses must be at least 140 mg/m2. Variables to be measured include traditional outcomes, incidence and grade of aGVHD, incidence and severity of cGVHD, rate of complete response post transplant, incidence of relapse, and median follow-up of survivors. Data may focus on the 2000-2006 cohort to avoid selection bias where clinical practice was different for early years. The reviewers will be picky on this as well. It’s worth of finding a similar dataset in EBMT to evaluate whether full ablative regimen plays a role in the allogeneic transplants.

6. Other business Marcelo Pasquini gave an update on CTN 0702 for MM. The meeting adjourned at 4:40pm. Based on the current status and voting results, the following studies/proposals will move forward or defer (next page).

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Studies, Free-standing or Combined Priority

MM06-04 Outcomes-Auto post PR with induct vs salvage therapy in post MM (Vij/Reece/Kumar)

X

MM02-01/D01-117 Second autologous HCT vs. NST after relapsed autologous HCT for MM (C Freytes/D Vesole)

X

MM09-02 Outcome of salvage 2nd auto HCT in relapsed MM (A Saad/L Michaelis/D Vesole)

X

MM09-03 Early vs delayed HCT in MM pts treated w/novel induction (L Holmberg/D Vesole) PROP 1109-07 Role of stem cell transplantation as salvage therapy for multiple myeloma (A Giralt/ M Qazilbash)

PROP 1109-08 Long term complications after stem cell transplantation for multiple myeloma (P Mehta/G Raval) PROP 1209-15 Second malignancies after autologous stem cell transplantation for multiple myeloma: analysis of risk factors and outcome (A Mahindra)

MM08-03 Effect of renal failure after auto HCT for MM (B Wirk) DeferredPROP 1209-41 Outcomes of a first fully myeloablative allogeneic transplant compared with an autologous followed by a non-myeloablative allogeneic transplant for the treatment of multiple myeloma (L Costa)

MM09-04 DLI for relapse/persistent MM post allo HCT (B Wirk/J Wingard) DeferredPROP 1209-23 The impact of pre-transplant co-morbidities on the outcome of autologous hematopoietic cell transplantation in multiple myeloma (A Saad/P Hari) PROP 1209-30 Non-relapse mortality after autologous stem cell transplantation for multiple myeloma: analysis of risk factors and outcome (A Mahindra)

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Accrual Summary for Plasma Cell Disorders Working Committee Characteristics of patients who underwent autologous transplant for Plasma Cell Disorders reported to the

CIBMTR between 1990 and 2010 Characteristics of patients Registration only ResearchNumber of patients 32044 8761Number of centers 410 263Age at transplant, median (range), years 57 (<1 - 74) 57 (<1 - 74)Gender Male 18743 (58) 5204 (59) Female 13207 (41) 3538 (40) Missing 94 (<1) 19 (<1)Graf type Bone marrow 342 ( 1) 103 ( 1) Peripheral blood 30226 (95) 8527 (98) Umbilical cord blood 2 (<1) 0 Missing 1434 ( 4) 131 ( 1)Year of transplant 1990-1991 212 (<1) 46 (<1) 1992-1993 322 ( 1) 79 (<1) 1994-1995 601 ( 2) 277 ( 3) 1996-1997 1188 ( 4) 619 ( 7) 1998-1999 2349 ( 7) 749 ( 9) 2000-2001 3506 (11) 993 (11) 2002-2003 4620 (14) 932 (11) 2004-2005 4950 (15) 1611 (18) 2006-2007 5142 (16) 1552 (18) 2008-2009a 5495 (17) 1665 (19) 2010a 3659 (11) 238 ( 3) Other Plasma Cell Disorders Plasma cell leukemia 268 (<1) 81 (<1) Waldenstrom macroglobulinemiab 104 (<1) 32 (<1) Amyloidosis 1055 ( 3) 546 ( 6) Solitary plasmacytoma 158 (<1) 36 (<1) Other plasma cell disorder 438 ( 1) 179 ( 2) Median follow-up of survivors (range), months 33 (<1-242) 48 (<1-216)a Cases continue to be reported in this interval b Small lymphoplasmacytic lymphoma cases were not included

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Accrual Summary for Plasma Cell Disorders Working Committee Characteristics of patients who underwent allogeneic transplant for Plasma Cell Disorders reported to the

CIBMTR between 1990 and 2010 Characteristics of patients Registration only ResearchNumber of patients 1803 1259Number of centers 253 215Age at transplant, median (range), years 48 (10 - 69) 47 (<1 - 67)Gender Male 1085 (60) 759 (60) Female 714 (40) 499 (40) Missing 4 (<1) 1 (<1)Graf type Bone marrow 812 (45) 674 (54) Peripheral blood 912 (51) 579 (46) Umbilical cord blood 1 (<1) 2 (<1) Missing 78 ( 4) 4 (<1)Year of transplant 1990-1991 47 ( 3) 114 ( 9) 1992-1993 146 ( 8) 166 (13) 1994-1995 233 (13) 183 (15) 1996-1997 281 (16) 184 (15) 1998-1999 276 (15) 112 ( 9) 2000-2001 294 (16) 184 (15) 2002-2003 203 (11) 129 (10) 2004-2005 98 ( 5) 71 ( 6) 2006-2007 116 ( 6) 37 ( 3) 2008-2009a 61 ( 3) 73 ( 6) 2010a 48 ( 3) 6 (<1) Other Plasma Cell Disorders Plasma cell leukemia 53 ( 3) 66 ( 5) Waldenstrom macroglobulinemiab 50 ( 3) 69 ( 5) Amyloidosis 14 (<1) 6 (<1) Solitary plasmacytoma 16 (<1) 4 (<1) Other plasma cell disorder 41 ( 2) 19 ( 2) Median follow-up of survivors (range), months 48 (<1-228) 85 (<1-228)a Cases continue to be reported in this interval b Small lymphoplasmacytic lymphoma cases were not included

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TO: Plasma Cell Disorders Working Committee FROM: Parameswaran Hari, MD, MS, Scientific Director for Plasma Cell Disorders WC RE: Studies in Progress Summary

MM02-01/D01-117: Comparison Of Second Autologous Transplant Versus Related or Unrelated Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Multiple Myeloma Who Relapse After Autologous Transplantation (C Freytes/ D Vesole): This study proposes to compare the outcome of second autologous transplantation versus the outcome of related or unrelated reduced intensity allogeneic stem cell transplantation of patients with Multiple Myeloma who fail to respond or progress after autologous transplantation. The data file preparation is underway. MM06-04: Impact of Pre-Transplant Therapy and Depth of Disease Response Prior To Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma (R Vij/ S Kumar/ D Reece): This study proposes to (1) measure the outcomes of patients who failed to achieve CR after autologous transplantation for multiple myeloma comparing the patients with 1st line vs. more than one lines of therapy and compare the response rates, disease free survival and overall survival of patients of these two cohorts of patients; (2) examine the relationship between disease status at transplant (CR/PR/NR/SD) and outcomes after stem cell transplantation; (3) compare the outcomes between patients who were in a complete response at the time of SCT to those who obtained a CR after their SCT; (4) examine the relationship between the degrees of reduction (% reduction divided into groups by deciles) in the M-protein (urine and serum) prior to transplant and the outcomes after stem cell transplantation. The data file preparation is underway. MM08-02: HLA Specificities and Predisposition to the Development of Multiple Myeloma (M Beksac): This study proposes to compare HLA-A,-B and -DRB1 2-digit allele and haplotype frequencies in patients with MM to the normal population in order to define HLA specificities associated with the risk of developing MM. A revised manuscript is being reviewed and to be submitted to NEJM by July 2011. MM09-02: Outcome of Salvage Second Autologous Stem Cell Transplantation (HCT) in Relapse Multiple Myeloma (A Saad/L Michaelis): This study proposes to evaluate the outcome of patients with MM who undergo second auto HCT as a salvage treatment and subsequently relapse. The draft protocol is available for review. Studies previously proposed, but not initiated MM09-03: Comparison of Outcome After Initial Upfront Autologous Peripheral Blood Stem Cell (PBSC) Transplant with Delayed Initial Autologous PBSC Transplant in Multiple Myeloma Patients (L Holmberg/D Vesole/S Giralt): This study proposes to describe clinical outcomes after initial upfront or delayed auto PBSC in MM patients. Dr. Giralt’s proposal (Role of stem cell transplantation as salvage therapy for multiple myeloma) was merged with this study. Information will continue to be collected on patients treated w/novel induction until sufficient number is reached. The draft protocol is available for review.

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MM10-01: Long Term Complications After Stem Cell Transplantation For Multiple Myeloma (P Mehta/ A Mahindra/G Raval): This study proposes to look at the incidence of long term complications patients after SCT and risks of second malignancies after auto transplant for MM and evaluate prognostic factors. A preliminary assessment of the data shows that 199/5000 patients developed a secondary malignancy (13 MDS; 65 no MDS; 121 unknown). The draft protocol is available for review. MM10-02: The Impact Of Pre-Transplant Co-morbidities on The Outcome of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma (A Saad/ A Mahindra): This study aims to look at the impact of pre-transplant co-morbidities on the outcome of autologous transplants only and evaluate the incidence and causes of NRM after auto transplant for MM as well as prognostic factors for NRM. The hematopoietic cell transplantation comorbidity index (HCT-CI) was proposed to capture information on 17 different organ-specific comorbidities that are available for patients who transplanted after December 2007. One year follow-up is needed. The draft protocol is available for review. MM10-03: Outcomes of a First Fully Myeloablative Allogeneic Transplant (Full Allo) Compared With an Autologous Followed By a Non-Myeloablative Allogeneic Transplant (Tandem Auto-Allo) for The Treatment Of Multiple Myeloma (L Costa): This study aims to compare 3-year PFS for a full allo vs. tandem auto-allo, and the cumulative incidence for NRM vs. relapse. Preliminary data from the registry shows eligible patients who underwent HLA-id or URD well-matched full-allo myeloablative (n=232) and auto-allo NST/RIC (n=194) transplants for myeloma between 1995 and 2007. The draft protocol is available for review. Studies previously discontinued MM08-03: Effect Of Renal Failure On Outcomes Of Autologous Stem Cell Transplant In Multiple Myeloma (B Wirk): This study proposes to analyze the impact of renal failure on the outcomes of autologous stem cell transplant (first and tandem) in multiple myeloma patients and prognostic factors affecting recovery from dialysis. The study was discontinued (Low interest/prior publication on this subject). MM09-04: Clinical Outcomes Of Donor Lymphocyte Infusions For Relapsed, Persistent Or Progressive Multiple Myeloma After Allogeneic Hematopoietic Stem Cell Transplantation (B Wirk/J Wingard): This study proposes to analyze the clinical outcomes of donor lymphocyte infusions (DLI) for relapsed or persistent multiple myeloma after myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). The study was discontinued (incomplete data).

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CIBMTR MM09-02

OUTCOME OF SALVAGE SECOND AUTOLOGOUS STEM CELL TRANSPLANTATION (HCT) IN RELAPSE MULTIPLE MYELOMA

DRAFT PROTOCOL

Study Chair: Ayman Saad, MD Assistant Professor

Division of Hematology/Oncology Froedtert Memorial Lutheran Hospital

9200 W. Wisconsin Ave. Milwaukee, WI 53226 USA

Telephone: 414-805-4600 Fax number: 414-805-4606 E-mail address: [email protected]

Study Co-Chairs: Laura C. Michaelis, MD

Loyola University Chicago Maywood, IL 60153 Telephone: 708-327-2316 Fax number: 708-327-3219 E-mail address: [email protected] David H. Vesole, MD, PhD Hackensack University Medical Center 360 Essex St., Suite 302 Hackensack, NJ 07601 Telephone: 201-336-8133 Fax: 201-336-8706 E-mail address: [email protected]

Study Statisticians: Tony X. Zhong, MS CIBMTR Statistical Center Medical College of Wisconsin

9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 USA

Telephone: 414-805-0756 Fax: 414-805-0714 E-mail: [email protected]

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Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA


Working Committee Chairs: Gustavo Milone, MD Angelica Ocampo-Hospital and Research Center-Fundaleu Uirburu 1450 Buenos Aires C1114AAN Argentina Phone: 54-11-4877-1050 Fax: 54-11-4805-1703 E-mail: [email protected]

Angela Dispenzieri, MD

Associate Professor of Medicine Mayo Clinic Transplant Center Rochester, Minnesota Telephone: 507-284-2479 Fax: 507-266-4972;

Email: [email protected]

Sagar Lonial, MD Emory University Hospital 1365-C Clifton Road NE Atlanta, GA 30322 Telephone: 404-778-3933 Fax: 404-778-5530 Email: [email protected] Scientific Director: Parameswaran Hari, MD, MS

Associate Professor Division of Hematology/Oncology Froedtert Memorial Lutheran Hospital



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1.0 SPECIFIC AIMS: The current proposal aims at evaluation of the outcome of patients with multiple myeloma who undergo second auto HCT as a salvage treatment when they relapse after an initial auto HCT. This proposal also aims at identifying specific prognostic factors that can predict the outcome of this patients’ population.

− Comparison of response rate after second salvage auto HCT and first auto HCT Treatment-related mortality

− Identification of the median overall survival and disease-free survival following second salvage auto HCT

− Identification of the rate and type of complications after second salvage auto HCT versus first auto HCT

− Identification of prognostic factors that predict the response or durable remission following second salvage auto HCT

− Identification prognostic factors associated with treatment-related mortality and failure to achieve response or durable remission following the second salvage auto HCT Overall survival

2.0 SCIENTIFIC JUSTIFICATION:

Following the initial induction chemotherapy of multiple myeloma, potential stem cell transplantation candidates undergo a stem cell harvest typically collecting stem cells enough for two transplants. These patients are anticipated to undergo either a tandem auto HCT or a second salvage auto HCT with relapsed disease. The improvement of overall response rate and overall survival following an upfront (early) auto HCT in multiple myeloma was first shown in randomized trial in 19961 and again in 2003.2 In both trials the auto HCT was compared to standard chemotherapy. auto HCT can successfully salvage patients with chemotherapy-refractory disease. A study has compared the outcome of auto HCT in patients with primary progressive disease and patients with responsive disease. In this study, the one-year progression-free survival was 70% and 83% respectively.3 The benefit of tandem autologous stem cell transplantation (two sequential auto HCT with a maximum of 6 months interval) was shown in the IFM94 trial.4 This trial also showed that the benefit of a second transplant was primarily seen in patients with partial response or stable disease after the first transplant.4 Accordingly, patients with complete response or very good response are managed conservatively after the first transplant. Those patients can typically be salvaged by second auto HCT when they relapse or develop progressive disease.5 Conditioning regimen including total body irradiation was shown to be inferior to melphalan-alone conditioning regimens.6 This finding may, at least partially, explain the unexpected equivalent outcome of auto HCT and standard therapy by the Arkansas group.7 It should be noted that all randomized studies of auto HCT following induction therapy were done prior to the availability of thalidomide, lenalidomide or bortezomib.

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3.0 PREVIOUS WORK: There is less data on the outcome of the population of patients who receive second salvage auto HCT compared to patients who receive upfront AUTO HCT for responsive or primary progressive disease. A systemic review of this population reported that some of these patients can achieve durable complete or partial remission.8 The National Cancer Comprehensive Network (NCCN) guidelines currently endorse two indications for repeated salvage auto HCT in relapse multiple myeloma. The first is following “lone” initial induction standard chemotherapy followed by auto HCT. The second is following upfront auto HCT.

4.0 PATIENT ELIGIBILITY CRITERIA:

This study will include all patients with age > 18 who underwent auto HCT for Multiple Myeloma from 1995 to 2006 and had upfront auto HCT followed by second salvage auto HCT with relapsed or progressive disease reported to the CIBMTR. All patients with allogeneic stem cell transplantation and/or donor lymphocyte infusion will be excluded.

5.0 VARIABLES TO BE ANALYZED:

− Age, gender and race of the patients − Co-morbidities − Type of monoclonal disease − The interval between the 2 auto HCT − Type of the transplant conditioning regimen (names and doses of therapeutic agents) − Type of stem cells (bone marrow or peripheral blood) − Conditioning regimen used in both transplants − The type of stem cells (peripheral versus bone marrow) − Engraftment day of the transplant

6.0 STUDY DESIGN:

CIBMTR database will be used to create descriptive tables of the following: Patients’ demographic data: age, gender, race and co-morbidities. Disease-related factors: type of monoclonal abnormality, renal dysfunction, bone and soft tissue disease, cytogenetic abnormalities, type of chemotherapy used prior to transplant, response to initial chemotherapy, response to first auto HCT, disease burden during the second salvage auto HCT [monoclonal protein level, plasma cell percent in the bone marrow and extent of lytic lesions], and interval between the 2 auto HCT. Transplant-related factors: conditioning regimen used in both transplants, the type of stem cells (peripheral versus bone marrow), engraftment day of the transplant. These tables will list median and range for continuous variables and percent of total for categorical variables. Probability of progression-free survival and overall survival will be calculated using the Kaplan-Meier product limit method, with the confidence intervals estimated using Greenwood’s formula. Comparison of survival curves will be done using the log-rank test.

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7.0 REFERENCES: 1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous

bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.

2. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883.

3. Kumar S, Lacy MQ, Dispenzieri A, et al. High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant. 2004;34:161-167.

4. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502.

5. 5. Stadtmauer EA. Multiple myeloma, 2004--one or two transplants? N Engl J Med. 2003;349:2551-2553.

6. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99:731-735.

7. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24:929-936.

8. Hahn T, Wingard JR, Anderson KC, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003;9:4-37.

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Table 1. Characteristics of adult patients who underwent second autologous transplantation for Multiple Myeloma following relapse or progression after first autologous transplant between 1995 and 2006, reported to the CIBMTR

Characteristics of patients N (%) Number of patients 144 Number of centers 58 Age, median (range), years 57 (28-74) Age at transplant, years <30 2 ( 1) 30-39 4 ( 3) 40-49 31 (22) 50-59 49 (34) 60-69 51 (35) ≥70 7 ( 5) Male sex 85 (59) Karnofsky score prior to transplant <90% 62 (90) ≥90% 7 (10) Missing 75 Durie-Salmon stage at diagnosis I 8 ( 6) II 29 (23) III 89 (71) Missing 18 Disease status prior to transplant Complete remission 10 (10) Partial remission 46 (45) Minimal response 8 ( 8) No response/stable disease 17 (17) Progression/Relapse 21 (20) Missing 42 Graft type Peripheral blood stem cell ± bone marrow 144 (100) Year of transplant 1995-1996 3 ( 2) 1997-1998 6 ( 4) 1999-2000 15 (10) 2001-2002 24 (17) 2003-2004 41 (29) 2005-2006 55 (38) Median follow-up of survivors, median (range), months 28 (3 - 88)

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CIBMTR MM09-03

COMPARISON OF OUTCOME AFTER INITIAL UPFRONT AUTOLOGOUS PERIPHERAL BLOOD STEM CELL (PBSC) TRANSPLANT WITH DELAYED INITIAL AUTOLOGOUS

PBSC TRANSPLANT IN MULTIPLE MYELOMA PATIENTS

DRAFT PROTOCOL

Study Chair: Leona Holmberg, MD, PhD Fred Hutchinson Cancer Research Center

1100 Fairview Ave. N. P.O. Box 19024, MS D5-390 Seattle, WA 98109

Telephone: 206-667-6447 Fax number: 206-667-4937 E-mail address: [email protected]

Study Co-Chair: David H. Vesole, MD, PhD Hackensack University Medical Center 360 Essex St., Suite 302 Hackensack, NJ 07601 Telephone: 201-336-8133 Fax: 201-336-8706 E-mail address: [email protected]



Telephone: 414-805-0756 Fax: 414-805-0714 E-mail: [email protected] Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA


21







Associate Professor Division of Hematology/Oncology Froedtert Memorial Lutheran Hospital



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1.0 SPECIFIC AIMS: 1.1 To describe clinical outcome after initial upfront or delayed autologous PBSC transplant in

patient with multiple myeloma. Outcomes to be assessed include: 1.1.1 Rate of engraftment of neutrophils (ANC ≥ 500 cells/μl) and platelets (≥ 20,000

cells/μl and ≥ 50,000 cells/μl) 1.1.2 Treatment-related mortality 1.1.3 Complete remission (CR), near CR, very good partial remission (PR), PR, and

overall response rates 1.1.4 Progression-free survival rates 1.1.5 Overall survival 1.1.6 Causes of death

1.2 To determine in era of new novel agents if upfront autologous stem cell transplant still has

superior outcome for disease control, time to progression, and overall survival


Randomized studies have clearly established that ASCT prolongs the survival of patients with multiple myeloma in an upfront setting [Attal M, et al. NEJM 335 (2): 91-7, 1996; Child JA, et al. NEJM: 348, 2003]. Typically, newly-diagnosed patients with myeloma are given initial induction therapy prior to proceeding to ASCT as most studies were done as part of upfront treatment. There was an original study, published a number of years ago, that showed more benefit to upfront transplant than delaying transplant [Fermand J, et al. Blood 92: 3131, 1998]. Median EFS was 40 versus 12 months for early versus late transplant. Over the years, induction regimens have evolved as more active agents have become available, such as Thalidomide, Lenalidomide (Revlimid®), and Bortezomib (Velcade®). There has been a drift both in the general oncology community and in patients to delay undergoing autologous ASCT and not use as part of upfront therapy. There are no published data that readdresses this issue in the era of the new novel agents. I propose a study with you to compare the outcome of patients who underwent upfront initial ASCT to patients who delayed initial ASCT.

3.0 PATIENT ELIGIBILITY CRITERIA:

This study will include all adult patients who underwent autologous ASCT for Multiple Myeloma from 1995 to 2005 reported to the CIBMTR.

4.0 OUTCOMES:

4.1 Hematopoietic recovery: time to neutrophils (ANC) > 0.5 x 109/L and to untransfused platelets > 20 and > 50 x 109/L sustained for three consecutive days

4.2 Transplant-related mortality: deaths occur within first 28 days after ASCT 4.3 Initial response to ASCT therapy: according to standard CIBMTR/EBMT criteria 4.4 Time to relapse or progression from ASCT: start at time of stem cell infusion to first

laboratory evidence of reoccurrence or progression by standard CIBMTR/EBMT criteria 4.5 Relapse: first evidence of laboratory recurrence or progression of multiple myeloma

according to standard CIBMTR/EBMT criteria 4.6 Progression-free survival: time from transplant to death, disease progression, or relapse after

complete response. Patients who are alive and in continuous complete remission, partial response, minimal response or stable disease are censored at time of last contact

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4.7 Overall survival: events are death by any cause. Surviving patients are censored at the time of last contact, regardless of ongoing treatment

5.0 VARIABLES TO BE ANALYZED:

Patient-related variables:

− Age: continuous − Gender: male versus female − Transplant Karnofsky performance status: ≤ 80% vs > 80% − Ethnicity

Disease-related variables:

− Durie-Salmon stage at diagnosis: I vs. II vs. III − Number of cycles of therapy − Number of regimens − Radiation therapy − Prior regimens of

− Thalidomide-based − VAD/DAD − Lenalidomide (Revlimid®)-based − Bortezomib (Velcade®)-based − Corticosteroids or other

− Stage of disease at ASCT − Durie Salmon − International staging system

− Beta 2 microglobulin at ASCT − Albumin at ASCT − Cytogenetics of disease − Immunochemical subtype − IgG versus IgA versus IgD versus light chain versus non-secretory − Mobilzation regimen − Disease state prior to transplant

− CR − (VGPR)/near CR − PR − minimal − No response versus relapse versus progression

Transplant-related variables: − Time from diagnosis to transplant

− < 6 months − 6-12 months − 12-18 months − 18-24 months − > 24 months, continuous

− Sensitivity to chemotherapy prior to transplant

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− Total number of transplant − 1 versus 2 − Planned 1st transplant, no 2nd − Planned 2nd following 1st

− CD 34 cells/kg per transplant, continuous − TNC kg per transplant, continuous − Purging yes or no − Year of transplant, continuous − Maintenance therapy after transplant and regimens − Conditioning transplant regimen − Response to transplants

6.0 STUDY DESIGN:

Patient-, disease-, and transplant-related factors will be compared between groups using the Chi-square test for categorical variables and the Wilcoxan two-sample test for continuous variables. The product-limit estimator proposed by the Kaplan-Meier will be used to estimate the median and range of the follow-up time. Univariate probabilities of PFS and survival will be calculated using the Kaplan-Meier estimator. Probabilities of hematopoietic recovery, transplant-related mortality, and progression/relapse will be calculated using cumulative incidence curves to accommodate competing risks. Ninety-five percent confidence intervals for all probabilities and p-value of pairwise comparisons will be derived from pointwise estimates and calculated using standard techniques at a predetermined time point. The response rate and patients who died without achieving a response rate by 100 days will be described. The outcome events (TRM, relapse/progression, PFS, and survival) between two treatment groups will be compared using proportional hazards regression models. A stepwise forward method will be used to identify the variables associated with the outcomes. The variable listed will be considered in model building. The risk factors with significant level of p < 0.05 will be included in the model. The potential interaction between main treatment effect and all significant risk factors will be examined. Adjusted probability of time to progression, disease-free survival, and overall survival will be computed based on final Cox regression models, stratified by treatment groups, and weighed by the pooled sample proportion value for all populations with similar prognostic factors.

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Table 1. Characteristic of patients who underwent autologous transplant for Multiple Myeloma by time from diagnosis to transplant between 1995 and 2005, reported to the CIBMTR

Characteristics of patients < 6 Months 6 -12 Months 12-18 Months > 18 MonthsNumber of patients 859 1981 429 633Number of centers 132 180 126 134Gender

Male 523 (61) 1168 (59) 236 (55) 378 (60)Female 336 (39) 813 (41) 193 (45) 255 (40)

Age, median(range), years 56 (30 - 76) 56 (22 - 80) 58 (31 - 77) 59 (35 - 76)Age at transplant, years

18-30 1 (<1) 12 ( 1) 30-39 26 ( 3) 110 ( 6) 15 ( 3) 16 ( 3)40-49 169 (20) 400 (20) 87 (20) 95 (15)50-59 362 (42) 756 (38) 169 (39) 236 (37)60-69 267 (31) 614 (31) 137 (32) 236 (37)≥70 34 ( 4) 89 ( 4) 21 ( 5) 50 ( 8)

Karnofsky score pre-transplant ≤80% 310 (36) 692 (35) 149 (35) 221 (35)>80% 502 (58) 1214 (61) 266 (62) 387 (61)Missing 47 ( 5) 75 ( 4) 14 ( 3) 25 ( 4)

Durie-salmon stage at diagnosis Stage I 48 ( 6) 145 ( 7) 37 ( 9) 100 (16)Stage II 224 (26) 536 (27) 130 (30) 190 (30)Stage III 552 (64) 1219 (62) 231 (54) 283 (45)Missing 35 ( 4) 81 ( 4) 31 ( 7) 60 ( 9)

International Staging System at diagnosis Stage I 152 (18) 382 (19) 69 (16) 113 (18)Stage II 166 (19) 377 (19) 79 (18) 73 (12)Stage III 112 (13) 232 (12) 27 ( 6) 25 ( 4)Missing 429 (50) 990 (50) 254 (59) 422 (67)

Immunochemical subtype of myeloma IgG 450 (52) 1038 (52) 223 (52) 348 (55)IgA 153 (18) 371 (19) 76 (18) 89 (14)IgD 6 ( 1) 19 ( 1) 7 ( 2) 4 ( 1)Light chain 152 (18) 363 (18) 59 (14) 94 (15)Non-secretory 50 ( 6) 91 ( 5) 27 ( 6) 35 ( 6)Secretory, not specified 5 ( 1) 13 ( 1) 4 ( 1) 9 ( 1)Missing 43 ( 5) 86 ( 4) 33 ( 8) 54 ( 9)

Albumin at diagnosis, g/dL <3.5 257 (30) 601 (30) 121 (28) 111 (18)≥3.5 371 (43) 846 (43) 162 (38) 234 (37)

Beta 2 microglobulin level at diagnosis, mg/L ≤3.5 274 (32) 679 (34) 146 (34) 190 (30)3.5-5.5 87 (10) 179 ( 9) 31 ( 7) 30 ( 5)≤5.5 112 (13) 232 (12) 27 ( 6) 25 ( 4)Missing 386 (45) 891 (45) 225 (52) 388 (61)

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Table 1. Continued. Characteristics of patients < 6 Months 6 -12 Months 12-18 Months > 18 MonthsSensitivity to chemotherapy prior to transplant

Sensitive 717 (83) 1614 (81) 311 (72) 409 (65)Resistant 104 (12) 275 (14) 83 (19) 156 (25)Unknown/not applicable 11 ( 1) 19 ( 1) 10 ( 2) 30 ( 5)Missing 27 ( 3) 73 ( 4) 25 ( 6) 38 ( 6)

Disease status prior to transplant Complete remission 148 (17) 334 (17) 78 (18) 87 (14)Partial remission 505 (59) 1133 (57) 209 (49) 275 (43)Minimal response 56 ( 7) 134 ( 7) 34 ( 8) 44 ( 7)No response/Stable disease 89 (10) 215 (11) 48 (11) 84 (13)Relapse 5 (<1) 3 ( 1) 12 ( 2)Progressive 5 ( 1) 33 ( 2) 12 ( 3) 29 ( 5)Others 38 ( 4) 88 ( 4) 31 ( 7) 55 ( 9)Missing 18 ( 2) 39 ( 2) 14 ( 3) 47 ( 7)

International Staging System prior to transplant

I 278 (32) 769 (39) 141 (33) 216 (34)II 152 (18) 321 (16) 51 (12) 101 (16)III 27 ( 3) 76 ( 4) 21 ( 5) 28 ( 4)Missing 402 (47) 815 (41) 216 (50) 288 (45)

Time from diagnosis to transplant, median(range), months

5 (0 - 6) 8 (6 - 12) 14 (12 - 18) 32 (18 - 249)

Conditioning regimen None 2 (<1) 3 (<1) 2 (<1) 1 (<1)Melphalan alone 638 (74) 1407 (71) 278 (65) 467 (74)Melphalan+tbi 56 ( 7) 155 ( 8) 30 ( 7) 37 ( 6)Melphalan+-others 99 (12) 229 (12) 45 (10) 69 (11)Others 64 ( 7) 187 ( 9) 74 (17) 59 ( 9)

Graft type Bone marrow 1 (<1) 12 ( 1) 5 ( 1) 3 (<1)Peripheral blood±bone marrow 858 (100) 1969 (99) 424 (99) 630 (100)

Induction Therapies Bortezomib (Velcade R) only ± Others 3 (<1) 27 ( 1) 11 ( 3) 11 ( 2)Lenalidomide(Revlimid R) only ± Others 5 ( 1) 5 (<1) 0 1 (<1)Thalidomide only ± Others 144 (17) 384 (19) 86 (20) 128 (20)Lenalidomide and Thalidomide ± Others 1 (<1) 2 (<1) 0 0Bortezomib and Thalidomide ± Others 21 ( 2) 55 ( 3) 15 ( 3) 30 ( 5)Others 685 (80) 1508 (76) 317 (74) 463 (73)

Year of transplant 1995-1996 52 ( 6) 149 ( 8) 56 (13) 48 ( 8)1997-1998 123 (14) 291 (15) 68 (16) 114 (18)1999-2000 133 (15) 326 (16) 70 (16) 126 (20)2001-2002 219 (25) 453 (23) 89 (21) 149 (24)2003-2004 179 (21) 448 (23) 83 (19) 101 (16)2005 153 (18) 314 (16) 63 (15) 95 (15)

Median follow-up of survivors, range, months 46 (1 - 123) 47 (1 - 146) 53 (1 - 144) 49 (1 - 144)

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CIBMTR MM10-01

LONG TERM COMPLICATIONS AFTER STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA

DRAFT PROTOCOL

Study Chair: Girindra Raval, MD Jefferson Regional Medical Center Internal Medicine

1600 42nd Avenue Pine Bluff, AR 71603

Telephone: 501-766-0539 E-mail: [email protected]

Study Co-Chairs: Anuj Mahindra, MD

Massachusetts General Hospital Hematology/Oncology 55 Fruit St., POB 236 Boston, MA 02114 Telephone: 617-643-3415 Fax: 617-724-3166 E-mail: [email protected]

Paulette Mehta, MD, MPH University of Arkansas for Medical Sciences Division of Hematology/Oncology 4301 West 7th Street, Slot 111K Little Rock, AR 72205 Telephone: 501-247-9263 Fax: 501-257-4925 E-mail: [email protected]

Study Statistician: Tony X. Zhong, MS CIBMTR Statistical Center Medical College of Wisconsin



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Study Statistician: Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA







Associate Professor Froedtert Memorial Lutheran Hospital



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1.0 GENERAL AIMS: The aims of this project are to describe the long term complications after stem cell transplantation for patients with multiple myeloma with specific attention to the development of secondary malignancies (including MDS). Patients with multiple myeloma receive high dose alklyator (melphalan) therapy, known to be associated with myelodysplasia [1, 2]. Whether patients who receive a single versus a tandem transplant have different rates of this complication or not is not known. Also, patients with other hematologic malignancies such as non-Hodgkin lymphoma have a higher than expected rate of leukemia and other secondary cancers after transplant [3]; whether this is true for patients with myeloma has not been well studied. This information is critical to know since there is controversy in the field as to whether tandem upfront stem cell transplants with high dose chemotherapy (melphalan) should be done or whether single transplants should be done upfront with second transplants for salvage treatment unresponsive to novel therapies [4-8]. If myelodysplasia, second malignancies and other complications are significantly more frequent with double versus single transplants, then these adverse effects will have to weigh against the advantage derived from tandem transplant, and treatment guidelines may need to be changed to indicate the true risk of complications.

2.0 SPECIFIC AIMS:

2.1 To determine long term complications after stem cell transplantation (SCT) for patients

with multiple myeloma, including organ failure, relapse, interstitial pneumoniti and secondary malignancy (including MDS)

2.2 To determine if long term complications (organ failure, interstitial pneumonitis, secondary malignancy (including MDS) are more frequent in patients who undergo more than one SCT compared to those who undergo a single SCT.

2.3 To develop a predictive model for secondary malignancy after SCT for MM in relation to the following variables: patient disease and treatment characteristics as listed below.

2.4 To develop a predictive model for myelodysplasia after SCT for MM in relation to the following variables: patient disease and treatment characteristics, as listed below


Patients who undergo autologous stem cell transplantation at are risk of many complications, especially relapse of underlying malignancy, myelodysplasia (MDS), secondary malignancy, organ dysfunction and death [3, 9-12]. These risks may be greater in patients who have undergone more than one stem cell transplantation. In addition, certain chemotherapy regimens, such as high dose melphalan, may predispose to MDS more than other regimens. Patients with multiple myeloma receive undergo high dose chemotherapy with melphalan as part of their preparative regimen for autologous stem cell transplantation. Many patients receive more than one transplantation either up-front as part of a tandem transplant regimen or subsequently at the time of molecular or clinical relapse. We hypothesize that patients who receive more than one course of high dose melphalan and more than one stem cell transplant would have higher risks for organ dysfunction, myelodysplasia (MDS), and death than those who receive a single transplant. We also seek to describe the overall incidence of myelodysplasia, organ dysfunction, relapse and death in patients with myeloma after autologous stem cell transplantation. There are few reports of long term complications in patients with multiple myeloma. Some studies however have indicated that patients with multiple myeloma have a high risk for

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developing second cancers or myelodysplasia (MDS) [1]. Whether the incidence of MDS is higher for patients who have undergone a second transplantation compared to those who undergo a single SCT has not been documented. In a recent study, Barlogie et al reported on myelodysplasia after stem cell transplant for patients with myeloma and found that predictive factors included low CD34 counts at stem cell harvests, longer time from diagnosis to high dose therapy, older age and delayed platelet recovery after transplantation. In another study, Leone et al evaluated therapy related MDS and AML in patients who underwent either radiotherapy or chemotherapy and found that alkylating agents, radiotherapy, chemotherapy, and g-csf played roles [2, 13]. Hake has hypothesized that treatment prior to transplantation as well as the transplant itself which involves conditioning regimen and extensive cellular proliferation during engraftment could play a role in predisposing to treatment related AML and/or MDS in patients with lymphoma who undergo SCT [3]. Patients with myeloma also may be at high risk for long term renal complications, since many patients with myeloma present with renal insufficiency, many receive renal toxic drugs used during the time of treatment and SCT, and many suffer form hypocalcaemia and other complications that may affect renal function. Other potential side effects not yet studied may include deep vein thrombosis, bone disease, early death, early relapse, second malignancies and MDS. In this study we propose to study the overall incidence of secondary malignancies, treatment related MDS and other complications in patients with myeloma who undergo one or more courses of high dose chemotherapy with stem cell transplantations.

4.0 STUDY POPULATION: Patients with the diagnosis of multiple myeloma over the age of 18 years of age who underwent autologous stem cell transplantation reported to the CIBMTR between 1990 and 2009.

5.0 OUTCOMES: 5.1 100-day mortality: time to death from any cause within 100 days post transplant 5.2 Length of hospital stay: from first day of conditioning to first hospital discharge 5.3 Treatment-related mortality (TRM): Any death within the first 28 days of transplant or

any death occurring after day 28 post transplant in the absence of overt disease progression.

5.4 Relapse of myeloma 5.5 Secondary malignancy ( including MDS ) 5.6 Myelodysplasia 5.7 Renal insufficiency/failure. Organ failure 5.8 Interstitial pneumonitis 5.9 Death

6.0 VARIABLES TO BE DESCRIBED OR ANALYZED:

Patient-related: − Age at transplant − Gender: male vs. female − Karnofsky performance at transplant: > 90% vs. < 90%

31


− Race: CC vs. AA vs. HP vs. other − Hypertension − Diabetes − Body mass index: underweight/normal (< 25) vs. overweight (25-29.9) vs.

obese/morbidly obese (>30) − Cause of Death

Disease-related: − Durie Salmon Disease stage at diagnosis: I vs. II vs. III − ISS stage at diagnosis: 1 vs. 2 vs. 3 − Immunoglobulin isotype: IgG vs. IgA vs. light chain vs. others/unknown − Beta-2 microglobulin at diagnosis: < 3.5 mg/L vs. > 3.5 mg/L (if available) − Albumin at diagnosis: < upper limits of normal (ULN) vs. > ULN − Creatinine at diagnosis: > 1.5 mg/dL vs. <1.5 mg/dL − Hemoglobin at diagnosis: < 10 g/dL vs. > 10 g/dL − Sensitivity to chemotherapy prior to transplant: sensitive vs. not sensitive − Disease status at the time of transplant: complete vs. partial remission − Cytogenetics pre Stem cell transplant ( conventional and FISH )

Treatment-related: − Time from diagnosis to transplant (median, range) − Number of previous chemotherapy: 1 vs. 2. vs. > 2 − Time from diagnosis to transplant < 12 months vs. > 12 months − Conditioning regimen: To be determined − Year of transplantation 1997-2000 vs. 2001-2007 − Number of auto-transplants − Prior chemotherapy regimens: MP ± others vs. VAD ± others vs. cyclophosphamide ±

others vs. corticosteroid ± others vs. novel agents (thalidomide, lenalidomide, bortezomib) based regimens used prior to autoHCT in patients transplanted from 2001-2006

− Type of medication used for harvesting stem cells

The required study data is available through existing data collection forms. 7.0 STUDY DESIGN:

The goal of the study is to describe long term complications after high dose chemotherapy with melphalan with autologous stem cell transplantation in patients with multiple myeloma, with emphasis on secondary malignancies (including MDS), with respect to patient , disease and treatment characteristics and time to development of complications post transplant. With respect to time to development of complications post transplant, person-years of observation will start 1 year post transplant, considering that long term complications are unlikely to develop within the first year of treatment. Descriptive analysis of late term complications after high dose chemotherapy after stem cell transplantation will be done. Other analysis will include difference in outcome after single versus tandem transplants.

32


The incidence rates of development of these complications will be compared to that expected in similar age and gender cohort from the SEER database , after accounting for person-years of observation. Absolute and relative risk will be calculated for the development of each long term complication and also with regards to single versus tandem transplants. Patient, disease and treatment related factors will be tested for significance in development of long term complications by univariate log rank testing and by proportional hazards models. Regression analysis will be used for development of predictive models for the long term complications taking into account above described patient, disease and treatment characteristics.

8.0 REFERENCES:

1. Barlogie, B., et al., Cytogenetically defined myelodysplasia after melphalan-based auto transplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989. Blood, 2008. 111(1): p. 94-100.

2. Sevilla, J., et al., Secondary acute myeloid leukemia and myelodysplasia after autologous peripheral blood progenitor cell transplantation. Ann Hematol, 2002. 81(1): p. 11-5.

3. Hake, C.R., T.A. Graubert, and T.S. Fenske, Does autologous transplantation directly increase the risk of secondary leukemia in lymphoma patients? Bone Marrow Transplant, 2007. 39(2): p. 59-70.

4. Terpos, E., et al., Management of complications in multiple myeloma. Semin Hematol, 2009. 46(2): p. 176-89.

5. Jain, P., S. Gupta, and P.M. Parikh, Newer therapeutic molecules for multiple myeloma. Indian J Cancer, 2008. 45(4): p. 142-8.

6. Schwartz, R.N. and M. Vozniak, Current and emerging treatments for multiple myeloma. J Manag Care Pharm, 2008. 14(7 Suppl): p. 12-9.

7. Ballester, O., The emperor's new clothes or the current practice of clinical trials for multiple myeloma in the USA. Cancer Invest, 2008. 26(5): p. 445-7.

8. Jagannath, S., Current standards for first-line therapy of multiple myeloma. Clin Lymphoma Myeloma, 2007. 7 Suppl 5: p. S207-14.

9. Harousseau, J.L. and P. Moreau, Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med, 2009. 360(25): p. 2645-54.

10. Bourhis, J.H., et al., Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study. Haematologica, 2007. 92(8): p. 1083-90.

11. Leone, G., et al., Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica, 2007. 92(10): p. 1389-98.

12. Mileshkin, L.R., et al., Cardiovascular toxicity is increased, but manageable, during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients aged 60 years and older. Leuk Lymphoma, 2005. 46(11): p. 1575-9.

13. Ke, X., et al., Autologous peripheral blood stem cell transplantation in the patients with hematologic malignancies and solid tumors. Chin Med J (Engl), 2001. 114(2): p. 196-9.

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Table 1. Characteristic of patients who underwent autologous transplant for Multiple Myeloma before 2008, reported to the CIBMTR.

Characteristics of patients: N (%)Number of patients 5003Number of centers 199Age at transplant, median (range), years 57 (22-83)Age at transplant, years

18-29 22 (<1)30-39 210 ( 4)40-49 949 (19)50-59 1946 (39)60-69 1614 (32)>=70 262 ( 5)

Gender Male 2953 (59)Female 2034 (41)Missing 16 (<1)

Karnofsky score <90% 1750 (35)>=90% 2976 (59)Missing 277 ( 6)

Immunochemical subtype of MM IgG 2662 (53)IgA 898 (18)IgD 44 ( 1)Light chain 856 (17)Non-secretory 253 ( 5)Secretory, not spec 43 ( 1)Missing 247 ( 5)

Durie-Salmon stage at diagnosis Stage I 436 ( 9)Stage II 1342 (27)Stage III 2945 (59)Missing 280 ( 6)

Sensitivity to chemotherapy prior to transplant Sensitive 3939 (79)Resistant 766 (15)Not applicable 85 ( 2)Missing 213 ( 4)

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Table 1. Continued. Characteristics of patients: N (%)Disease status prior to transplant

Complete remission 770 (15)Partial remission 2869 (57)Minimal response 320 ( 6)No response/stable disease 509 (10)Relapse 24 (<1)Progressive 94 ( 2)Missing 417 ( 8)

Time from diagnosis to transplant, months < 6 months 1120 (22)6-12 months 2528 (51)12-18 months 552 (11)> 18 months 803 (16)

Lines of chemotherapy 0 94 ( 2)1 2715 (54)2 1348 (27)>2 711 (14)Missing 135 ( 3)

Total number of transplant 1 tx, no planned 2nd 3390 (68)>=2 tx, no planned 2nd 455 ( 9)1 tx, planned 2nd 258 ( 5)>=2 tx, planned 2nd 833 (17)1 tx, planned unknown 59 ( 1)>=2 tx, planned unknown 8 (<1)

Graft type Bone marrow 81 ( 2)Peripheral blood 4922 (98)

Year of HCT <1995 166 ( 3)1995-1996 305 ( 6)1997-1998 597 (12)1999-2000 656 (13)2001-2002 927 (19)2003-2004 859 (17)2005-2006 1248 (25)2007 245 ( 5)

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Table 1. Continued. Characteristics of patients: N (%)Interstitial pneumonitis after transplant

No 4760 (95)Yes 233 ( 5)Missing 10 (<1)

Veno-occlusive disease after transplant No 4900 (98)Yes 59 ( 1)Missing 44 ( 1)

New malignancy No 4774 (95)Yes 199 ( 4)Missing 30 ( 1)

Median follow-up of survivors (range), months 49 (3- 227)

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CIBMTR MM10-02

THE IMPACT OF PRE-TRANSPLANT CO-MORBIDITIES ON THE OUTCOME OF HEMATOPOIETIC CELL TRANSPLANTATION IN MULTIPLE MYELOMA

DRAFT PROTOCOL

Study Chair: Ayman Saad, MD Assistant Professor

Division of Hematology/Oncology Froedtert Memorial Lutheran Hospital

9200 W. Wisconsin Ave. Milwaukee, WI 53226 USA

Telephone: 414-805-4600 Fax number: 414-805-4606 E-mail: [email protected]

Study Co-Chairs: Anuj Mahindra, MD

Massachusetts General Hospital Hematology/Oncology 55 Fruit St. POB 236 Boston, MA 02114 Telephone: 617-643-3415 Fax: 617-724-3166 E-mail: [email protected] Parameswaran Hari, MD, MS Associate Professor Froedtert Memorial Lutheran Hospital






37


Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA










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1.0 SPECIFIC AIMS: The primary purpose of this proposal is to identify how pre-transplant co-morbidities influence the treatment-related mortality (TRM) after autologous and allogeneic hematopoietic progenitor cell transplant (AHCT) in patients with multiple myeloma.


High-dose melphalan followed by AHCT is widely used for patients with multiple myeloma as an upfront and salvage therapy.1 The decision to perform transplant depends on the physician assessment of patients’ eligibility, which typically involves evaluating the co-morbidities, performance status and age of the patient.2 The uncertainty of tolerability of older patients to aggressive therapy has resulted in inconsistent arbitrary cutoff age limit for performing this treatment. The discrepancy between chronological and physiological age is likely influenced by the co-morbidities. Moreover, despite the few absolute contraindications for performing high-dose therapy, there are numerous relative contraindications, which often times impose a challenge for decision making. Co-morbidities indices have been implemented to assess the tolerability of the allogeneic and autologous transplant in patients with leukemia and lymphoma respectively. The Charlson Co-morbidity Index (CCI) was developed in 1987 based on 1-year mortality data of internal medicine patients admitted to a single New York Hospital3 and was subsequently validated as a predictor for mortality in cancer patients.4 CCI has been used to assess pre-transplantation comorbidities in patients with hematological malignancy undergoing allogeniec transplantation, where higher comorbidity scores resulted in increased toxicity and mortality.5,6 However, due to paucity of some co-morbidities among transplant patients, CCI has been modified by Sorror to exclude unusual morbidities and include more relevant morbidities.7 This modified co-morbidity index has actually been validated in patients receiving allogeneic transplant for hematological malignancies.8-10 No data exist for myeloma patients receiving AHCT or allogeneic transplant. Unlike other hematological malignancies, multiple myeloma may be associated with a variety of end-organ compromise such as renal dysfunction, bone disease, neuropathy, and anemia and repeated infectionsstate.11 Thus, it is likely that the tolerance of myeloma patients to high-dose therapy with AHCT is different from patients with other hematological malignancies. With the advent of minimally toxic conditioning regimens and higher quality supportive care, AHCT choice is now available to myeloma patients with end-stage renal disease. In USA, there is no specific age limit for AHSCT, while in Europe the general maximum age limit is 65 years.2 Identifying co-morbidity index for tolerability of AHCT in myeloma patients may resolve this age cutoff discrepancy.

3.0 PATIENT ELIGIBILITY: Eligibility criteria - Patients (≥ 18 years old) diagnosed with multiple myeloma (all stages) undergoing AHCT or

allogeneic transplant as an upfront (including tandem transplant) or salvage treatment. - Conditioning regimen of high-dose melphalan 140-200 mg/m2 with or without total body

irradiation (TBI). - Transplant using peripheral progenitor cells. - Transplant done at least 2 years prior to data collection.

39


Exclusion Criteria: - Conditioning regimens that were not melphalan- or TBI-based. - Bone marrow progenitor cells as a source of transplant - Incomplete the pre-Transplant Essential Data (TED) form.

4.0 VARIABLES TO BE ANALYZED: - Age, gender and race of the patients - Co-morbidities - Type of monoclonal disease - The interval between the 2 auto HCT - Type of the transplant conditioning regimen (names and doses of therapeutic agents) - Type of stem cells (bone marrow or peripheral blood) - Conditioning regimen used in both transplants - The type of stem cells (peripheral versus bone marrow) - Engraftment day of the transplant

5.0 DATA COLLECTION:

We will collect the following variables for the selected group of patients. These variables will include all the co-morbid conditions captured by the pre-Transplant Essential Data (TED) form of the CIBMTR registry. The following is a list of these variables. All variables will be assessed as categorical or dichotomous (YES/NO).

- Age: grouped into ≤ 65 years and 5-year incremental age groups (65-70, 70-75, and > 75). - Gender. - ISS (International Staging System) and Durie Salmon stage. - Cytogenetic features (FISH and karyotyping): high versus low (if available) - Induction regimen used in case of upfront transplant. - Prior hematopoietic transplant. − Performance status: Karnofsky performance score (KPS) ≥ 80, or less. − Arrhythmia: (atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias) − Cardiac disease (coronary artery disease, congestive heart failure, myocardial infarction, or

EF ≤ 50%) − Cerebrovascular disease (transient ischemic attack or cerebrovascular accident) − Diabetes: requiring treatment with insulin or oral hypoglycemics but not diet alone − Heart valve disease (except mitral valve prolapsed) − Hepatic dysfunction: bilirubin > ULN to 1.5 × ULN, or AST/ALT > ULN to 2.5 × ULN − Infection: active infection requiring continuation of antimicrobial treatment after day 0,

HIV test, and CMV status. − Inflammatory bowel disease (Crohn's disease or ulcerative colitis) − Obesity: body mass index > 35 − Peptic ulcer (requiring treatment) − Psychiatric disturbance (depression or anxiety requiring psychiatric consult or treatment) − Pulmonary dysfunction: mild (DLco and/or FEV1 < normal but > 80% or no dyspnea on

activity), moderate (DLco and/or FEV1 66-80% or dyspnea on slight activity), severe (DLco and/or FEV1 ≤ 65% or dyspnea at rest or requiring oxygen).

− Renal dysfunction: serum creatinine < 2, ≥ 2-5, ≥ 5, on hemodialysis. − Rheumatologic disease (SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatic). − Solid tumor: diagnosed prior to transplant.

40


6.0 STUDY DESIGN: The CIBMTR database will be used to collect information on eligible patients. The patients sample will be divided into 2 groups, two-thirds of the patients will be assigned to a “training” group and one-third to a “validation” group. For the “training” group, adjusted hazard ratio (HR) from Cox proportional hazard models of TRM (at 30 days, 100 days and > 100 days) will be calculated for each co-morbidity. The adjusted HR (only with statistically significant confidence interval) will be converted to integer “weights” according to the following: HR of up to 2.0 will be assigned a weight of 1 HR of 2.1 to 3.0 will be assigned a weight of 2 HR of 3.1 or more will be assigned a weight of 3, and so forth. The co-morbidity index will be the sum of these weights. It is tentatively planned to divide risk stratification into 3 categories (high, intermediate, and low risk for TRM) provided that the total sum of weights is at least 3 [If the total sum is 2, risk will be stratified into 2 categories. If the total sum is only 1, this co-morbidity will be assigned the only risk factor. If no statistically significant HR was encountered, then the study will conclude failure to identify any co-morbidity that can increase the TRM in this setting. No further validation group testing will be done]. A sub-analysis will be done for different cohorts, single upfront, single salvage, and tandem autologous transplant, and allogeneic transplant. The variables will be evaluated for each transplant for those patients who had > one transplant. The impact of age, gender, KPS, and individual co-morbidities on TRM will be analyzed. We will attempt to construct an index predictive of TRM for (both or each of) autologous and allogeneic transplant. For the “validation” group, the constructed index will be calculated for all patients. This group will be stratified into risk groups (e.g. high, intermediate and low). Kaplan-Meier survival curves will test the difference in TRM among the three groups using log rank test for statistical significance among these groups.

7.0 REFERENCES:

1. Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med. 2009;360:2645-2654.

2. Rajkumar SV, Sonneveld P. Front-line treatment in younger patients with multiple myeloma. Semin Hematol. 2009;46:118-126.

3. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383.

4. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer. 2000;36:453-471.

5. Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood. 2004;104:961-968.

6. Diaconescu R, Flowers CR, Storer B, et al. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004;104:1550-1558.

41


7. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919.

8. Sorror ML, Giralt S, Sandmaier BM, et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood. 2007;110:4606-4613.

9. Sorror M, Storer B, Sandmaier BM, et al. Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer. 2008;112:1992-2001.

10. Sorror M, Storer B, Gopal A. Comorbidity, lactate dehydrogenase (LDH), and chemosensitivity are independent predictors of mortality after autologous hematopoietic cell transplantation (HCT) for patients (pts) with lymphoma Blood. 2007 110 (Part 1) #616 (abstract).

11. Terpos E, Cibeira MT, Blade J, Ludwig H. Management of complications in multiple myeloma. Semin Hematol. 2009;46:176-189.

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Table 1. Characteristic of patients who underwent a melphalan based conditioning regimen (140-200 mg/m2) autologous transplant for Multiple Myeloma, reported to the CIBMTR from 1995 and 2007

Characteristics of patients: N (%)Number of patients 2351Number of centers 172Age at transplant, median (range), years 58 (27-77)Age at transplant, years

18-29 9 (<1)30-39 68 ( 3)40-49 387 (16)50-59 860 (37)60-69 886 (38)>=70 141 ( 6)

Gender Male 1378 (59)Female 973 (41)

Karnofsky score <90% 827 (35)>=90% 1384 (59)Missing 140 ( 6)

Immunochemical subtype of MM IgG 1280 (54)IgA 413 (18)IgD 18 ( 1)Light chain 400 (17)Non-secretory 130 ( 6)Secretory, unknown type 19 ( 1)Missing 91 ( 4)

Durie-Salmon stage at diagnosis Stage I 221 ( 9)Stage II 645 (27)Stage III 1376 (59)Missing 109 ( 5)

Co-existing disease prior to conditioning No 723 (31)Yes 1622 (69)Missing 6 (<1)Disease status prior to transplant Complete remission 345 (15)Partial remission 1351 (57)Minimal response 151 ( 6)No response/stable disease 241 (10)Relapse 10 (<1)Progressive 30 ( 1)Missing 223 ( 9)

Graft type Bone marrow 12 ( 1)Peripheral blood 2339 (99)

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Table 1. Continued Characteristics of patients: N (%)Co-existing disease diagnosis

Hemorrhage 30 ( 2 )History of other malignancy 147 ( 9 )Autoimmune disease 48 ( 3 )Cardiovascular 387 ( 24 )Chromosomal 251 ( 15 )CNS/Psychiatric 3 ( <1)Endocrine 479 ( 30 )Gastriontestinal 304 ( 19 )Genitourinary 227 ( 14 )Hematologic 90 ( 6 )Liver disease 68 ( 4 )Pulmonary 237 ( 15 )Other 639 ( 39 )

Sensitivity to chemotherapy prior to transplant Sensitive 1860 (79)Resistant 344 (15)Not applicable 40 ( 2)Missing 107 ( 5)

Time from diagnosis to transplant < 6 months 511 (22)6-12 months 1201 (51)12-18 months 244 (10)> 18 months 395 (17)

Lines of chemotherapy 0 43 ( 2)1 1270 (54)2 640 (27)>2 350 (15)Missing 48 ( 2)

Total number of transplant 1 tx, no planned 2nd 1834 (78)>=2 tx, no planned 2nd 298 (13)1 tx, planned 2nd 188 ( 8)1 tx, planned unknown 27 ( 1)>=2 tx, planned unknown 4 (<1)

Year of HCT 1995-1996 76 ( 3)1997-1998 185 ( 8)1999-2000 302 (13)2001-2002 559 (24)2003-2004 474 (20)2005-2006 616 (26)2007 139 ( 6)

Median follow-up of survivors (range), months 48 (3- 170)

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Exclusions: a. 2 tx, planned 2nd transplant (tandem tx) b. Melphalan < 140 mg/m2 (n= 726) c. Melphalan > 200 mg/m2 (n= 456) d. Melphalan, missing (n= 100)

Crosstab of KPS by co-existing disease

kps

coexisting organ prior to tx

Total No Yes Missing

<90% 222 605 0 827

>=90% 477 902 5 1384

Missing 24 115 1 140

Total 723 1622 6 2351

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CIBMTR MM10-03

OUTCOMES OF A FIRST FULLY MYELOABLATIVE ALLOGENEIC TRANSPLANT COMPARED WITH AN AUTOLOGOUS FOLLOWED BY A NON-MYELOABLATIVE ALLOGENEIC TRANSPLANT FOR THE TREATMENT OF MULTIPLE MYELOMA

DRAFT PROTOCOL

Study Chair: Luciano J. Costa, MD, PhD Medical University of South Carolina Division of Hematology/Oncology Transplant Program 96 Jonathan Lucas St. 903 CSB MSC 635 Charleston, SC 29425 Telephone: 843-792-5283 Fax: 843-792-0644

E-mail: [email protected] Study Statisticians: Tony X. Zhong, MS CIBMTR Statistical Center Medical College of Wisconsin


Telephone: 414-805-0756 Fax: 414-805-0714 E-mail: [email protected] Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA


46










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1.0 OBJECTIVES: 1.1 Primary:

To compare overall survival and progression free survival between single myeloablative HSCT (SM) and tandem autologous/ reduced intensity allogeneic HSCT (AR) as upfront transplant strategies for patients with multiple myeloma.

1.2 Secondary: To compare cumulative incidence of relapse and non-relapse mortality between SM and AR To obtain updated safety data on SM employing modern standards for HLA matching and supportive care.


Autologous hematopoietic stem cell transplantation (HSCT) is considered part of upfront treatment for patients with standard risk multiple myeloma1,2 aiming at increasing the duration of the initial response. Relapses eventually occur in near all patients. Patients with high-risk multiple myeloma present an even bigger challenge since their benefit from autologous transplantation is marginal3-5. Allogeneic HSCT has been proposed as an alternative transplant strategy by promoting not only aggressive and fast cytoreduction but also graft-versus-myeloma (GVM) effect, potentially eradicating malignant plasma cells and allowing long term disease control (ref). Initial reports of outcomes of a single fully myeloablative regimens in MM (SM) corroborated the relevance o GVM6,7, but also the excessive treatment related mortality (TRM) rate of this procedure. In a multiinstitutional report from 26 centers in the United Kingdon7 on 139 young patients receiving a myeloablative transplant for MM, one year TRM was unacceptably high at 37.9%. Interestingly, 40 % of patients were alive after 4 years with a possible plateau in the survival and progression free survival curves. Excessive 1 year TRM (53%) was also seen in the SWOG 9321 trial, with most deaths occurring in the first three months after transplantation. This finding caused the early closure of the allogeneic transplantation arm after only 36 patients had been accrued. Recent update of this trial shows that at median follow up of 7 years 39% of the patients undergoing allogeneic transplantation remain alive and 22% free of progression8. It is also relevant to mention that not all early series report the same magnitude of TRM associated with SM. Indeed, a long term follow up report from the British Columbia Cancer Agency on 44 patients undergoing fully myeloablative allogeneic transplant for MM showed a 1 year TRM of only 22%6. Even though most of the excessive e toxicity in the early series can be directly attributable to the intensity of the conditioning regimen, it is also possible that they reflect outdated standards for HLA matching and supportive care. In the largest series published to date on allogeneic transplantation for multiple myeloma, investigators of the European Group for Blood and Marrow Transplant Centers report a retrospective analysis of 690 transplants performed in two different eras, 1983-1993 and 1994-1999. There was a substantial reduction in 2 year-TRM, from 46% to 30%, allowing for a more robust 4 years survival rate of 50% in the most recent cohort9. With the intent to avoid the excessive mortality of a fully myeloablative transplant and still keep the GVM effect, many groups have developed a strategy where a cytoreductive autologous transplant is followed by a reduced-intensity allograft (AR). Bruno et al10, reported on 162 patients genetically randomized to receive a tandem autologous transplant or one autologous transplant followed by a non-myeloablative matched sibling donor transplant. This study found

48


low 2-year rate of TRM in the allogeneic arm (10%) with superior overall survival over tandem autologous.

In another study, The Intergroupe Francophone du Myélome genetically randomized patients with high risk MM to receive a tandem autologous (IFM99-04, n=219) or autologous followed by reduced intensity allogeneic transplantation (IFM99-03, n=65) after induction chemotherapy. Despite the low incidence of TRM in the allogeneic study (10.9%), there was no significant difference between studies in overall survival or event free survival11,12. In the U.S., a trial comparing tandem autologous with autologous followed by reduced intensity allograft has completed accrual (BMT-CTN 0102), and results are expected soon. As discussed, the AR approach has been compared with tandem autologous transplantation but not with SM. We intend to compare the outcomes of SM performed in more recent years, therefore reflecting more current supportive care, with the outcomes of AR in multiple myeloma. He hypothesize that “modern” SM may lead to similar, or even superior outcomes than AR, avoiding the increased complexity and cost of two distinct transplant procedures.

3.0 STUDY POPULATION: There are general and group specific eligibility criteria for this protocol. 3.1 General

3.1.1 No age, gender or ethnic restrictions. 3.1.2 Diagnosis of multiple myeloma. 3.1.3 First transplant occurring between 1995 and 2007. 3.1.4 Donor for the allogeneic transplant must have been a full HLA match sibling or well

matched unrelated donor. 3.1.5 Grafts must have been unmanipulated bone marrow or mobilized peripheral blood.

3.2 Myeloablative allogeneic (MA)

3.2.1 Conditioning regimen containing Melphalan >=140mg/m2 and/or TBI >500cGy (single fraction) or 800cGY (multiple fractions) and/or Busulfan > 8mg/kg (oral or intravenous equivalent).

3.2.2 No prior autologous transplantation.

3.3 Tandem autologous/reduced intensity allogeneic (AR) 3.3.1 Conditioning regimen for autologous transplant containing Melphalan >=140mg/m2

with or without total body irradiation or the use of a second chemotherapy agent. 3.3.2 No HSCT of any modality prior to first autologous transplant for the auto-allo tandem. 3.3.3 Interval between autologous transplantation and reduced intensity allogeneic transplant

< 6 months. 3.3.4 Allogeneic transplant conditioning regimen not meeting criteria for myeloablative

(section 3.2.1). 3.3.5 No evidence of disease progression between autologous and allogeneic transplant.

4.0 OUTCOMES:

4.1 Overall survival: events are death due to any cause. Surviving individuals will be censored at

the time of last follow up regardless of disease status.

49


4.2 Progression free survival: events are death from any cause (toxicity, disease progression, not disease or treatment related) or disease progression. Individuals surviving without disease progression will be censored at the time of last follow up.

4.3 Non-relapse mortality (NRM): defined as death in absence of disease progression. 4.4 Relapse mortality (RM): defined as death occurring after disease progression. RM and NRM

will be analyzed as competing risks. 4.5 Best response after transplant: as defined by EBMT-CIBMTR criteria (CR vs. not in CR) 4.6 Incidence and severity of aGVHD and cGVHD

5.0 VARIABLES TO BE DESCRIBED/ANALYZED:

No supplementary forms will be necessary. All the variables to be measure should be obtainable by inquiring existing CIBMTR forms. Patient related:

- Age at the time of first transplant, continuous and in categories (<30 years, 30-39, 40-49, 50-59, 60 or higher).

- Gender - Karnofsky score at the time of first transplant.

Disease related:

- Immunochemical subtype of MM (IgG, IgA, IgD, non-secretory, unknow, missing) - Durie-Salmon stage at diagnosis. - Sensitivity to conventional therapy prior to first transplant (sensitive, resistant, missing). - Disease status prior to transplant (CR, PR, MR, no response, missing). - Number of lines of therapy prior to first transplant. - Time from diagnosis to first transplant, continuous and in categories (<6 months, 6-12

months, 12-18 months, >18 months).

Transplant related: - Calendar year of the first transplant. - Conditioning used in the autologous transplant (Mel 200 mg/m2, Mel <200mg/m2, Mel +

second chemotherapy agent, TBI containing, other). - Conditioning used in the allogeneic transplant. - Graft type (bone marrow or mobilized peripheral blood). - Donor type (matched sibling, volunteer unrelated) - GVHD prophylaxis regimen - Donor/Recipient CMV status (neg/neg vs other) - Donor/Recipient gender (Fem/male vs. other)

Outcome related:

- Survival status and date of death or last follow up. - Cause of death. - Progression status and date the progression was documented or last follow up. - Incidence and highest severity of aGVHD. - Incidence of cGVHD

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6.0 STUDY DESIGN:

Patient and transplant characteristics Patient, disease and transplant related variables will be displayed (table 1) and compared between SM and AR. Categorical variables will be compared using chi-square test and continuous variables will be compared using a non parametric approach, i.e. Mann-Whitney test.

Survival and PFS Survival (from the time of diagnosis) and progression free survival will be calculated using the method of Kaplan-Meier and will be compared using the log-rank test.

Relapse and non-relapse mortality Incidence of relapse and non-relapse mortality for each group (SM and AR) will be described using competing risks analysis.

Graft versus host disease

- Incidence and severity of aGVHD will be described for the two groups and compared using chi-square.

- Incidence of cGVHD among the subjects who survived 100+ days in both approaches will be described and compared using chi-square.

Multivariate analysis There are evidently major differences in patients, disease and transplant characteristics between the two groups. In an attempt to minimize the effect of these differences in the outcomes, multivariate analysis using a regression model will be employed to assess the effect of treatment approach and patient, disease and transplant characteristics in overall survival, progression free survival, relapse mortality and non-relapse mortality13. Variables to enter the final model would be selected by a stepwise approach (forward or backward), but treatment approach (SM or AR) would be kept in the model since its impact in the outcomes of interest is the main purpose of the study. Variables to enter the analysis are:

- Treatment approach (SM or AR) – categorical - Patient age at the time of first transplant- continuous - Patient gender – categorical - Karnofsky score (>=90 or <90) – categorical - Immunochemical subtype of multiple myeloma (IgG vs others) – categorical - Durie-Salmon stage at diagnosis (III vs others) – categorical - Sensitivity to conventional therapy prior to first transplant (sensitive vs. others)-

categorical - Disease status prior to transplant (CR vs others)- categorical - Number of lines of therapy prior to first transplant (0 or 1 vs. >1)- categorical - Time from diagnosis to first transplant – continouos - Calendar year of the first transplant (1995-2000 vs 2001-2007) – categorical - Graft type (bone marrow vs. mobilized peripheral blood) - categorical - Donor type (matched sibling vs. volunteer unrelated) - categorical - Donor/Recipient CMV status (neg/neg vs other) - categorical - Donor/Recipient gender (Fem/male vs. other) - categorical

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7.0 REFERENCES:

1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-2972. 2. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials

for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol;28:1209-1214.

3. Chang H, Sloan S, Li D, et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004;125:64-68.

4. Facon T, Avet-Loiseau H, Guillerm G, et al. Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood. 2001;97:1566-1571.

5. Rajkumar S, Fonseca R, Lacy M, et al. Abnormal cytogenetics predict poor survival after high-dose therapy and autologous blood cell transplantation in multiple myeloma. Bone Marrow Transplant. 1999;24:497-503.

6. Kuruvilla J, Shepherd JD, Sutherland HJ, et al. Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2007;13:925-931.

7. Hunter HM, Peggs K, Powles R, et al. Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation. Br J Haematol. 2005;128:496-502.

8. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24:929-936.

9. Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983--93 and 1994--8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol. 2001;113:209-216.

10. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356:1110-1120.

11. Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006;107:3474-3480.

12. Moreau P, Garban F, Attal M, et al. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008;112:3914-3915.

13. Logan BR, Zhang MJ, Klein JP. Regression models for hazard rates versus cumulative incidence probabilities in hematopoietic cell transplantation data. Biol Blood Marrow Transplant. 2006;12:107-112.

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Table1: Characteristic of patients who underwent a first allogeneic myeloablative transplant (SM) vs patients who underwent an autologous transplant followed by an NST/RIC allograft (AR) for Multiple Myeloma between 1995 and 2007, reported to the CIBMTR

Characteristics of patients SM AR Number of patients 232 190Number of centers 86 58Age at transplant, median (range), years 46 (27-67) 52 (30-68)Gender

Male 138 (59) 109 (57)Female 94 (41) 73 (38)

Karnofsky score <90% 88 (38) 51 (27)>=90% 141 (61) 128 (67)Missing 3 ( 1) 11 ( 6)

Durie-Salmon stage at diagnosis Stage I 27 (12) 15 ( 8)Stage II 63 (27) 47 (25)Stage III 128 (55) 111 (58)

Sensitivity to chemotherapy prior to transplant Sensitive 151 (65) 148 (78)Resistant 56 (24) 22 (12)Not applicable 11 ( 5) 10 ( 5)Missing 14 ( 6) 10 ( 5)

Diseases status prior to transplant Complete remission 39 (17) 33 (17)Partial remission 89 (38) 89 (46)Minimal response 16 (7) 12 ( 6)Other 51 (23) 12 ( 6)Missing 37 (16) 44 (25)

Lines of therapy 0 3 (1) 2 ( 1) 1 120 (52) 74 (38) 2 42 (18) 50 (26) >2 38 (16) 14 ( 7) Missing 29 (13) 50 (28)

Time from diagnosis to transplant, months (range) 8 (1-120) 11 (5-125)Conditioning regimen

Myeloablative 232 N.A. RIC N.A. 16 (10) Non-myeloablative N.A. 174 (90)Type of donor

HLA-id sibling 222 (96) 158 (81) URD well-matched 10 ( 4) 32 (19)

Graft type Bone marrow 110 (47) 2 (2) Peripheral blood 122 (53) 188 (98)

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Table1. Continued. Characteristics of patients SM N (%) AR N (%)CMV status

+/+ 84 (36) 50 (26)+/- 33 (14) 30 (16)-/+ 40 (17) 38 (20)-/- 66 (28) 62 (33)Missing 9 ( 4) 10 ( 5)

Donor /recipient gender M-M 80 (34) 63 (33)M-F 45 (19) 30 (16)F-M 58 (25) 46 (24)F-F 49 (21) 43 (23)Missing 0 8 ( 4)

GVHD prophylaxis None 4 ( 2) 5 ( 3) FK506+MTX+-other 12 ( 5) 21 (11) FK506+-other 10 ( 4) 20 (11) CsA+MTX+-other 175 (75) 7 ( 4) CsA+-other 29 (13) 130 (68) Other 2 ( 1) 4 ( 2)

Missing 0 (0) 3 ( 2)Year of transplant

1995-1996 70 (30) 0 (0)1997-1998 55 (24) 0 (0)1999-2000 36 (16) 6 (3)2001-2002 41 (18) 20 (12)2003-2004 15 ( 6) 51 (27)2005-2006 12 (5) 83 (43)2007 3 ( 1) 30 (15)

Median follow-up of survivors (range), months 76 (3- 168) 36 (3-84)Abbreviations: BM=Bone marrow, PBSC=Peripheral blood stem cells, CMV=Cytomegalovirus, TBI=Total body irradiation, LPAM=Melphalan, Flud=Fludarabine, Bu=Busulfan, Cy=CsA=Cyclosporine, MTX=Methotrexate, FK506=Tacrolimus, MMF=Mycophenolate, Arac=Cytarabine, Ida=Idarubicin. * Exclusions

Interval between auto and allo transplant N 6-12 months 33 12-18 months 28 > 18 months 103

* Missing conditioning regimen: n=4

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Study Proposal 0810-03 Study Title: Do patients above 65 years old attain the same benefit from an autologous progenitor cell transplant as younger patients? Manish Sharma, MD, Patricia R. Kropf, MD, Mary Ellen Martin, MD, Robert V. B. Emmons, MD, Thomas R. Klumpp, MD, FACP, Kenneth F. Mangan, MD, FACP from Temple University Bone Marrow Transplant, Philadelphia, PA Contact: Manish.Sharma @tuhs.temple.edu Specific Aims:

1. Evaluate TRM (treatment related mortality), PFS (progression-free survival) and OS (overall survival) following autologous stem cell transplant (auto-SCT) between a cohort of patients above the age of 65 years (study group) and a cohort of patients under the age of 65 years (control group).

2. Evaluate if older patients (>65 years) have a disease which is “high-risk” (as define by cytogenetics and FISH results) as compared to younger patients.

Background: Multiple myeloma (MM) is the second most common hematological malignancy and is responsible for approximately 1 percent of all cancer-related deaths in Western Countries. The median age at diagnosis is in the middle 70th decade of life and only 10% are diagnosed earlier than age 50 (1). Following diagnosis of the disease, standard therapy is initiated with an induction regimen followed by consolidation therapy. Consolidation therapy can include an autologous stem cell transplant (auto-SCT) or continuation of the induction regimen. Compared to consolidation with chemotherapy, high dose melphalan followed by an auto-SCT result in a significantly prolonged progression-free survival (PFS) and overall survival (OS) of patients with newly diagnosed MM (2-6). However, it should be noted that the median patient age in these clinical studies which now define standard treatment is well below the median age of disease presentation. In fact, there is no prospective study which identifies older patients as having a benefit from auto-SCT. Recently, unsuccessful attempts were made to reduce the dose of melphalan conditioning in this population, however no prospective results are available for full dose melphalan (140 – 200 mg/m2) which was utilized in the younger patients (7). Therefore, it has been generally taught that patients above the age of 65 are not candidates for auto-SCT and are thus restricted to other options. High dose therapy with autologous transplantation is safe and has a low transplant-related mortality (TRM) (<1-2%), and can be done in most patients as an outpatient therapy. The TRM in the older patients is also low in smaller retrospective reviews (8). There is a substantial population that is above the age of 65 years that can benefit from auto-SCT, however we need to demystify the erroneous suggestion that it is of no value in the older population. The hypothesis that auto-SCT is not beneficial in the older population can be justifiable if the disease is more aggressive in these patients as compared to younger patients. This is the case in transplantation for the acute leukemia, in that the older patient population has additional “high-risk’ cytogenetic abnormalities which are responsible for the poor response to both chemotherapy and the transplant approach (9). Is this the case in myeloma as well? It is now well recognized that myeloma is a heterogeneous disease and there exists a “high-risk’ population (10). Do older patients have a disease which is “high-risk” as compared to younger patients and does this make auto-SCT less useful in this population? These are unanswered questions which we look to resolve in this study proposal.

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Methods: We propose to the CIBMTR myeloma committee to review the results of auto-SCT in non-relapsed patients with myeloma above the age of 65 year using collection form 2116. Also, the cytogenetic and FISH results in this population should be reviewed using collection form 2016, to underscore that the benefit in the “standard risk” population is similar to that of younger patients and that an older age is not associated with “high-risk” cytogenetics and FISH results. The endpoint should be to evaluate TRM, PFS and OS following auto-SCT between a cohort of patients above the age of 65 years (study group) and a cohort of patients under the age of 65 years (control group). References:

1. Rajkumar, SV et al. Clinical features, laboratory manifestations and diagnosis of multiple myeloma. Uptodate 2010.

2. Fermand, JP et al. High-dose therapy and autologous transplantation compared with convestional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. JCO 2005: 9227-9233.

3. Barlogie B et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. JCO 2006;24:929-36.

4. Blade, J et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005 106: 3755-3759.

5. Attal, M et al. Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma. NEJM 2003; 349: 2495-2502.

6. Child, AJ et al. High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma. NEJM 2003; 348:1875-1883.

7. Facon, T et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18.

8. Qazilbash, MH et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. BMT 2007; 39: 279-83.

9. McClune, BL et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. JCO 2010 ; 28: 1878-87.

10. Fonseca, R et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009 23, 2210-2221.

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Characteristics of patients who underwent a first autologous transplant for multiple myeloma, reported to the CIBMTR between 1995 and 2008, by age at transplant

Characteristics of patients < 65 years ≥ 65 yearsNumber of patients 4678 973Number of centers 209 140Sex Male 2977 (59) 586 (60) Female 2046 (41) 396 (40) Missing 17 (<1) 2 (<1)Age at transplant, years ≤ 29 31 (<1) -- 30-39 267 ( 5) -- 40-49 1185 (24) -- 50-59 2365 (47) -- 60-64 1192 (24) -- 65-69 -- 670 (68) ≥ 70 -- 314 (32)Karnofsky score prior to transplant, % ≥ 90 4419 (88) 856 (87) < 90 446 ( 9) 84 ( 9) Unknown 175 ( 3) 44 ( 4)Durie-Salmon stage at diagnosis Stage I 408 ( 8) 94 (10) Stage II 1252 (25) 261 (27) Stage III 2791 (55) 491 (50) Unknown 589 (12) 138 (14)Immunochemical subtype of myeloma IgG 2255 (45) 440 (45) IgA 726 (14) 163 (17) IgD 39 (<1) 8 (<1) Light chain 763 (15) 114 (12) Non-secretory 287 ( 6) 50 ( 5) Secretory, not specified 738 (15) 161 (16) Missing 232 ( 5) 48 ( 5)Time from diagnosis to transplant, median (range), months 8 (2 - 295) 9 (3 -218) < 6 months 1100 (24) 164 (17) 6-12 months 2375 (51) 472 (49) 12-18 months 517 (11) 116 (12) > 18 months 677 (14) 220 (23)Sensitivity to chemotherapy prior to transplant Sensitive 3334 (66) 634 (64) Resistant 665 (13) 124 (13) Not applicable/unknown 1041 (20) 226 (23)

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Continued. Characteristics of patients < 65 years ≥ 65 yearsConditioning regimen Melphalan alone 3915 (78) 893 (91) Melphalan + total body irradiation(TBI) ± others 332 ( 7) 21 ( 2) Melphalan ± others, not TBI 261 ( 5) 27 ( 3) Total body irradiation ± others, not Melphalan 137 ( 3) 6 (<1) Busulfan + cyclophosphamide ± others 304 ( 6) 28 ( 3) Others 81 ( 1) 9 (<1)Prior chemotherapy regimens MP ± others 517 (10) 101 (10) VAD ± others 1773 (35) 301 (31) Cy ± others 846 (17) 161 (16) Corticosteroids ± others 260 ( 5) 61 ( 6) Thal ± others 960 (19) 212 (22) Others/unknown 684 (13) 148 (15)Disease status prior to transplant Complete response 779 (15) 135 (14) Partial response 2553 (51) 514 (52) Minimal response 653 (13) 142 (14) No response/Stable disease 557 (11) 102 (10) Relapse from complete response 24 (<1) 3 (<1) Progressive disease 74 ( 1) 13 ( 1) Missing 400 ( 8) 75 ( 8)Year of Transplant 1995 139 ( 3) 3 (<1) 1996 185 ( 4) 11 ( 1) 1997 298 ( 6) 16 ( 2) 1998 294 ( 6) 20 ( 2) 1999 295 ( 6) 36 ( 4) 2000 332 ( 7) 59 ( 6) 2001 415 ( 8) 103 (10) 2002 378 ( 8) 93 ( 9) 2003 264 ( 5) 86 ( 9) 2004 469 ( 9) 78 ( 8) 2005 556 (11) 132 (13) 2006 467 ( 9) 137 (14) 2007 299 ( 6) 59 ( 6) 2008 649 (13) 151 (15)Median follow-up of survivors, median (range), months 51 (<1 - 181) 49 (<1 - 144)Bone marrow only were excluded

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Study Proposal 1210-05 Study Title: Waldenstrom’s macroglobulinemia (WM): Retrospective analysis with hematopoietic stem cell transplantation (HCT). Robert Frank Cornell, MD and Sara Torgerson, DO from The Medical College of Wisconsin, Milwaukee, WI. Specific Aims: The primary purpose of this study is to evaluate the outcomes of patients with WM who have received either autologous, allogenic or syngenetic HCT. There is data available which suggests that HCT is beneficial, however limited because this is a rare condition. Specifically the benefit of allogenic verses autogenic transplant will be evaluated. Optimal transplant conditioning regimens, myeloablative or reduced intensity, will be evaluated. Outcome after transplant based on disease risk using the IPSS for WM, chemorefractory disease, lines of chemotherapy and patient age will be determined. The effect of GVHD, both acute and chronic, on outcome will be assessed as an indirect measure of the immune effect and graft versus leukemia effect. Scientific Justification: WM is a rare lymphoproliferative disorder which accounts for 1 to 2% of all hematological malignancies1,2. It is characterized by bone marrow clonal lymphoplasmacytoid infiltration and an IgM monoclonal gammopathy3. Approximately three-quarters of patients are symptomatic at time of diagnosis and require treatment4. Treatment is reserved for symptomatic patients. Indications for treatment include symptomatic anemia, thrombocytopenia, hyperviscosity, severe neuropathy, organomegaly, cryoglobulinemia or evidence of disease transformation. Determination of disease risk is made via the International Prognostic Scoring System (IPSS)5. Risk is assigned based on age greater than 65, B2-microglobulin level greater than 3 mg/L, IgM greater than 7.0 g/dl, hemoglobin less than 11.5 g/dl and platelet count less than 100 x 109/L. High risk disease is characterized as more than two adverse risk factors. The mainstay of treatment includes purine analogous, alkylating agents, rituximab and combination regimens. Single agent use the of purine analogs cladribine and fludarabine have demonstrated response rates ranging from 40 to 90%6,7. Use of single agent chlorambucil achieves a response rate of approximately 50%8. Monoclonal antibody Rituximab induced remission in about one-third of patients9. In one study, the addition of Rituximab to CHOP demonstrated significant response rate advantage with 94 versus 69% respectively10. Other agents and combinations including R-CHOP, Thalidomide, Lenalidomide, Imatinib mesylate, Pentostatin and Bortezomib have been employed and are being evaluated for treatment of WM. Response rates to chemotherapy is high, but WM is not considered a curable disease and the majority of patients eventually relapse. The role of transplantation at time of relapse versus administration of multiple lines of chemotherapy is not well defined. In addition, early transplantation is patients with high-risk disease warrants further investigation. Recently, the Lymphoma working party of the European group for blood and marrow transplantation (EBMT) published a report investigating high-dose therapy and autologous HCT. In this study data from the EBMT registry was used for analysis. From their initial cohort of 202 eligible patients, 158 had adequate clinical data for analysis. Autologous HCT resulted in 22% CRs and 50% VGPRs. With median follow-up of 4.2 years, the projected five-year PFS was 41% and OS 68%. These data were similar to previously published reports. Statistical analysis showed that chemorefractory disease and administration of at least three lines of chemotherapy resulted in statically significant shorter PFS and OS. In addition,

59


male sex and age >50 were associated with inferior OS. Conclusions from the study included consideration for early autogenic HCT in young patients. In addition, the authors concluded that transplant should not be offered to patients with chemotherapy refractory disease or those who received three or more lines of therapy11. In 2006, data collected from the CIBMTR was published evaluating autologous or allogenic stem cell transplantation in patient with Waldenstrom’s macroglobulinemia. Data from 10 autologous and 26 allogenic patients was analyzed. In this study about three-quarters of patients had received two or more lines of chemotherapy and 52% were considered to have chemorefractory disease. In general the outcomes from the autologous group were more favorable compared to the allogenic group with relapse at 3 years 24% vs. 29%, PFS 65% vs 31%, OS 70% vs. 46% and NRM 11% vs. 40% respectively. The median age for autologous transplant was 56. Importantly, in the 10 patients who received autologus HCT, a 60% progressive free survival was reported at three year follow-up. Conclusions from this study included that autogenic HCT is a reasonable treatment option in high risk patients. It also concluded that allogenic transplant carries significantly higher risk and should only be used in the context of a clinical trial12. Patient Eligibility Population: Given that WM is a rare condition, eligible patients would include any adult patient (>18 years old) that received a HCT for WM between 1986 to date. Data Requirements: Study Design: Analysis of patients registered as having received a HCT for WM between 1986 to date will be performed. Patients included in the study will fulfill two criteria:

– Demonstration of an IgM monoclonal gammopathy of any concentration by serum protein electrophoresis, serum immunoglobulins and immunofixation

– Bone marrow infiltration by lymphoplasmacytic cells via bone marrow biopsy and aspirate. Other parameters analyzed will include age, Karnofsky score, presenting symptoms, albumin level, LDH, Albumin, IgM level, B2-microblogulin,hemoglobin, hyperviscosity, disease risk, stem cell source, CD34+ cells infused in peripheral blood transplants and percentage of bone marrow infiltration. Regarding transplant the number of lines of chemotherapy prior to transplant, conditioning regimen, transplant type, response to chemotherapy (CR, VGPR, PR, progressive disease), disease status at time of transplant, mobilization technique, follow-up and outcome will be assessed. Response after transplant at day 100 and every 3 months thereafter will be evaluated to determine overall survival, progression free survival, relapse, non-relapse mortality and death. Those without comprehensive data will be excluded. Multivariate analysis for outcome after transplant between those excluded and included in the study will be performed to ensure those included are representative of the population. Statistical analysis: Estimates of overall survival and PFS will be calculated using the Kaplan-Meier estimator, with SE estimated by the Greenwood formula. Ninety-five percent confidence intervals will be calculated using log-transformed intervals. Should sample size be adequate, potential prognostic factors for OS, PFS, relapse rate and NRM will be evaluated in multivariate analyses by using Cox proportional hazards regression.

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References: 1. Herrinton LJ, Weiss NS: Incidence of Waldenstrom’s Marcoglobulinemia. Blood 82: 3148-50,

1993 2. Groves FD, Travis LB, Devesa SS, et al: Waldenstrom’s Macroglobulinemia. Incidence patterns

in the United States, 1988-1994. Cancer 82: 1078-81, 1998. 3. Owen RG, Treon SP, Al-Katib A, et al: Clinicopathological definition of Waldenstrom’s

macroglobulinemia: Concensus panel recommendation from the Second International Workshop on Waldenstrom’s Mecroglobulinemia. Semin Oncol 30:110-115, 2003.

4. Dimopoulos MA, Kyle RA, Anagnostopoulus A, et al: Diagnosis and management of Waldenstrom’s macroglobulinemia. J Clin Onc 23: 1564-77, 2005.

5. Morel P, Duhamel A, Gobbi P, et al: Internaltional prognostic scoring system (IPSS) for Waldenstrom’s macroglobulinemia (WM) [abstract]. Blood 2006; 108: Abstract 127.

6. Thalhammer-Scherrer R, Geissler K, Schwarzinger I, et al: Fludarabine therapy in Waldenstrom’s macroglobulinemia. Ann Hematol. 79: 546-59, 2000.

7. Fridrik MA, Jager G, Baldinger C, et al: First-line treatment of Waldenstrom’s disease with Cladribine. Ann Hematol. 74:7-10, 1997.

8. Kyle RA, Greipp PR, Gertz MA, et al: Waldenstrom’s macroglobulinemia: A prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol. 108: 737-42, 2000.

9. Gertz MA, Rue M, Blood E, et al: Multicenter phase 2 trial of rituximab for Waldenstrom’s macroglobulinemia (WM): An Eastern Coorperative Oncology Group Stydu (E3A98). Leuk Lymphoma. 45: 2047-55, 2004.

10. Buske C, Martin H, Dreyling MH, et al: Combined immune-chemotherapy (R-CHOP) results in significantly superior response rates and time to treatment failure in first line treatment of patients with lymphomplascomytoid/ic immunocytoma (LP-IC) – results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). ASH Annu Meet Abstracts. 104: 162. 2004.

11. Kyriakou C, Canals C, Sobin A, et al: High-dose therapy and autologous stem-cell transplantation in of Waldenstrom’s macroglobulinemia: The lymphoma working party of the European group for blood and marrow transplantation. 28: 2227-32. 2010.

12. Anagnostopoulos A, Hari P, Perez W, et al: Autologous or Allogeneic stem cell transplantation in patients with of Waldenstrom’s macroglobulinemia. Biology of blood and marrow transplantation. 12: 845-54. 2006.

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Characteristics of patients ≥18 years old who underwent a first transplant for waldenstrom macroglobulinemia, reported to the CIBMTR between 1986 and 2008, by type of transplant

Characteristics of patients Allogeneic AutologousNumber of patients 92 42Number of centers 53 30Sex Male 61 (66) 32 (76) Female 31 (34) 10 (24)Age at transplant, years ≤ 29 2 ( 2) 1 ( 2) 30-40 8 ( 9) 3 ( 7) 40-50 40 (43) 6 (14) 50-60 36 (39) 20 (48) 60-70 5 ( 5) 12 (19) ≥ 70 1 ( 1) 0Karnofsky score prior to transplant, % ≥ 80 77 (84) 37 (88) < 80 11 (12) 2 ( 5) Missing 4 ( 4) 3 ( 7)Time from diagnosis to transplant, median (range), months 30 (<1-198) 19 (5-169) < 6 months 3 ( 3) 1 ( 2) 6-12onths 14 (15) 11 (26)

12-18 months 10 (11) 7 (17) >18 months 44 (48) 22 (52) Missing 21 (23) 1 ( 2)Disease NHL(small lymphoplasmacytic lymphoma) 47 (51) 18 (43) Waldenstrom macroglobulinemia 45 (49) 24 (57)Sensitivity to chemotherapy prior to transplant Sensitive 29 (32) 23 (55) Resistant 25 (27) 7 (17) Not applicable/unknown 38 (41) 12 (28)Graft type Bone marrow 30 (33) 5 (12) Peripheral blood 62 (67) 37 (88)Year of Transplant 1986-1987 1 ( 1) 0 1988-1989 0 0 1990-1991 3 ( 3) 2 ( 5) 1992-1993 0 1 ( 2) 1994-1995 4 ( 4) 1 ( 2) 1996-1997 11 (12) 7 (16) 1998-1999 12 (13) 4 (10) 2000-2001 12 (14) 5 (12) 2002-2003 17 (19) 5 (17) 2004-2005 20 (22) 7 ( 7) 2006-2007 8 ( 8) 3 ( 7) 2008 4 ( 4) 5 (12)Median follow-up of survivors, median (range) months 72 (<1-229) 50 (<1-146)

NHL=Non-Hodgkin lymphoma

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Not for publication or presentation Attachment 11-1

Study Proposal 1210-06 Study Title: A comparison of the outcome and prognostic characteristics of patients who have myeloablative sibling and unrelated donor transplants for multiple myeloma who are alive and disease free at 10 years post transplant with those who relapse between 5 and 10 years post transplant. These 2 groups will be compared with a reference group of patients who die in the first 5 years of myeloma or transplant related causes David I. Marks, MD, PhD, University Hospitals Bristol NHS Foundation Trust, Bristol, UK Gordon Cook Leeds, MD and Jenny M. Bird Bristol, MBBS, MD, NCRI Myeloma working group, UK Specific Aims:

1. To determine the factors that predispose to 10 year disease free survival after myeloablative allogeneic transplants for myeloma

2. To determine the factors that predispose to late relapse after allografts for myeloma 3. To examine the factors associated with survival of patients who have late relapse after

allogeneic SCT for myeloma Scientific Justification: Allogeneic SCT has a controversial role in the management of patients with myeloma (Lokhorst et al, 2010). Modern therapy including aggressive induction therapy, autologous SCT and the use of novel agents for relapse results in almost 50% of patients surviving 5 years and a smaller proportion surviving 10 years. Recently published data have demonstrated markedly improved survival of myeloma patients over the last decade (Brenner et al, 2009; Kumar et al, 2008). The NRM of conventional (non-allograft) therapy is low but this therapy is not curative. Myeloablative allogeneic SCT for myeloma in first response, in contrast has curative potential, but has a high TRM (20% upwards) and is only applicable to only a small percentage of patients. The allogeneic anti-myeloma effect is prolonged and may be evident >4 years from transplant. Five year survival rates exceed 50% in patients in CR or near CR but ten year survival rates are lower. The major reasons for death between 5 and 10 years are chronic GVHD and late relapse. Late relapse is not uncommon but is poorly understood at a biological level and the risk factors are not known and the outcome and optimum therapy have not been defined. This study will aim to define the factors associated with 10 year survival and relapse between 5 and 10 years and the outcome of the latter group. The goal is to define patients who have the best chance of being cured by allogeneic SCT and to identify potentially modifiable risk factors for late relapse. The comparator group for both these groups will be patients who do not survive the first 5 years after transplant. This study has potential weaknesses and limitations. Before 1995 the CIBMTR database contains limited information about conventional prognostic factors for myeloma and important data such as ISS stage, bone marrow cytogenetic and FISH analysis, response to initial therapy using current response criteria and number of lines of previous chemotherapy. In addition the therapy of patients who relapse is poorly documented. Other potential issues include the definition of myeloablative conditioning, numbers in each group and heterogeneity of transplant technique. Patient Eligibility Population: Adult patients with myeloma in first response who have had a myeloablative sibling or unrelated donor stem cell transplant and have survived 5 years disease free. Patients who are disease free at 10 years post transplant will be compared with patients who relapse between 5 and 10 years post transplant and those who die of disease- and transplant-related reasons in the first 5 years. (The CIBMTR database has data about 700 myeloablative allografts but 40% relapse within the first 5 years and TRM is about 30%)

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Outcomes: – Incidence of acute and chronic GVHD: grade II-IV, grade III-IV acute GVHD and

limited and extensive chronic GVHD. – Myeloma recurrence: time to first myeloma recurrence and site of relapse. – Disease free survival: defined as survival in continuous CR, as defined by the

International myeloma working group. Disease relapse and death in CR are events. Censoring at last contact for survivors.

– Overall survival: Events are death from any cause with censoring at last contact. – Cause of death: disease related vs other – Received DLI: timing and maximum dose (if reported)

Variables to be Analyzed: Patient related:

– Age (by decades, or as a continuous variable) – Gender (M vs F) – Karnofsky PS (<90% vs 90% or more)

Disease related: – Cytogenetic abnormalities: normal vs adverse (t4;14), deletion 13, del 17p – Ig subtype: G vs A vs D vs light chain vs non-secretory – Beta 2 microglobulin at diagnosis: <3, 3-6, >6 – Serum albumin at diagnosis – Maximum response prior to transplant – Durie Salmon Stage – Extramedullary disease at diagnosis – ISS: I vs II vs III – Renal function at diagnosis and at transplant – Prior autologous transplant – Disease management after disease progression

Transplant-related: – Time from diagnosis to transplant – TBI (yes/no), dose as continuous variable and <12 Gy, 12-13 Gy, >13 Gy – Bu/Cy vs Mel/TBI vs Cy/TBI vs other – Alemtuzamab vs ATG (dose to be collected) – GVHD prophylaxis for UD transplants: ex vivo T cell depletion vs CsA+MTX vs

tacrolimus and methotrexate – Steroids as GVHD prophylaxis (yes/no) – Donor age (continuous variable) – Gender match (F-M vs M-F vs M-M vs F-F) – CMV status: -/- vs +/- vs _/+ vs +/+ – Year of transplant, define dividing line – Matching of unrelated donors: well matched vs partly matched vs mismatched (CIBMTR

criteria) – Post-transplant therapy: DLI (yes/no); chemotherapy (yes/no); PBSC vs BM – DLI (yes vs no) – Karnofsky score <90 vs 90 or 100

Patients to be excluded:

– Reduced intensity regimens (CIBMTR definitions) – Cord blood transplants – Second (allogeneic) transplants (prior autograft permitted) – Mismatched unrelated donor transplants

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Study Design (Scientific Plan): Patient-, disease- and transplant-related variables will be analysed in all patients, with the Chi-square test for categorical and Mann-Whitney test for continuous variables. Survival and disease free survival will be calculated using the Kaplan-Meier method and survival curves will be compared using the log rank test. Data will be analyzed using a proportional hazards model This section will be further developed by Dr Hari and colleagues References:

1. Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Pérez-Simon JA, Kröger N, Moreau P, Gahrton G, Gasparetto C, Giralt S, Bensinger W; International Myeloma Working Group. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.J Clin Oncol. 2010;28:4521-30.

2. Byrne JL, Fairbairn J, Davy B, Carter IG, Bessell EM, Russell NH. Allogeneic transplantation for multiple myeloma: late relapse may occur as localised lytic lesion/plasmacytoma despite ongoing molecular remission. Bone Marrow Transplant. 2003;31:157-61.

3. Cook G, Bird JM, Marks DI. In pursuit of the allo-immune response in multiple myeloma: where do we go from here? Bone Marrow Transplant. 2009;43:91-9.

4. Kröger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A, Nagler A, Binder T, Eiermann T, Madrigal A, Schwerdtfeger R, Kiehl M, Sayer HG, Beyer J, Bornhäuser M, Ayuk F, Zander AR, Marks DI; Clinical Trial Committee of the British Society of Blood and Marrow Transplantation and the German Cooperative Transplant Group. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haem. 2005;129:631-43.

5. Brenner, H., Gondos, A. & Pulte, D. (2009) Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010. Haematologica, 94, 270-275

6. Kumar, S.K., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Zeldenrust, S.R., Dingli, D., Russell, S.J., Lust, J.A., Greipp, P.R., Kyle, R.A. & Gertz, M.A. (2008c) Improved survival in multiple myeloma and the impact of novel therapies. Blood, 111, 2516-2520.

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Characteristics of patients who underwent a first allogeneic transplant for multiple myeloma, reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%) Number of patients 583Number of centers 146Sex Male 352 (60) Female 231 (40)Age at transplant, years ≤ 29 12 ( 2) 30-39 85 (15) 40-49 247 (42) 50-59 196 (34) 60-69 40 ( 7) ≥ 70 3 (<1)Karnofsky score prior to transplant, % ≥ 90 485 (83) < 90 91 (16) Unknown 7 ( 1)Durie-Salmon stage at diagnosis Stage I 57 (10) Stage II 159 (27) Stage III 332 (57) Unknown 35 ( 6)Immunochemical subtype of myeloma IgG 239 (41) IgA 67 (11) IgD 4 (<1) Light chain 97 (17) Non-secretory 38 ( 7) Secretory, not specified 113 (19) Missing 25 ( 4)Time from diagnosis to transplant, median (range), months 9 (1 - 216) < 6 months 124 (21) 6-12 months 233 (40) 12-18 months 81 (14) >18 months 145 (25)Graft type Bone marrow 210 (36) Peripheral blood 274 (64)Sensitivity to chemotherapy prior to transplant Sensitive 306 (52) Resistant 115 (20) Not applicable/unknown 162 (28)

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Continued. Characteristics of patients N (%) Conditioning regimen Melphalan alone 127 (22) Melphalan + total body irradiation(TBI) ± others 105 (18) Melphalan ± others, not TBI 46 ( 8) Total body irradiation ± others, not Melphalan 154 (26) Busulfan + cyclophosphamide ± others 98 (17) Others 53 ( 9)Prior chemotherapy regimens MP ± others 122 (21) VAD ± others 177 (30) Cy ± others 67 (11) Corticosteroids ± others 44 ( 8) Thal ± others 22 ( 4) Other/unknown 51 (26)Disease status prior to transplant Complete response 77 (13) Partial response 199 (34) Minimal response 49 ( 8) No response/Stable disease 86 (15) Relapse from complete response 6 ( 1) Progressive disease 166 ( 4) Missing 145 (25)Year of transplant 1995 47 ( 8) 1996 77 (13) 1997 61 (10) 1998 43 ( 7) 1999 42 ( 7) 2000 61 (10) 2001 82 (14) 2002 48 ( 8) 2003 33 ( 6) 2004 23 ( 4) 2005 20 ( 3) 2006 11 ( 2) 2007 9 ( 2) 2008 26 ( 5)Median follow-up of survivors, median (range), months 15 (<1 - 171)Progressive free at various time period <5 years 195 5-10 years 62 >10 years 34

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Study Proposal 1210-38 Study Title: Development of a Prognostic Scoring System to predict relapse of multiple myeloma after allogeneic hematopoietic stem cell transplantation Nancy M. Hardy, MD, National Cancer Institute, Bethesda, MD Ola Landgren, MD, PhD, National Cancer Institute, Bethesda, MD Sergio A. Giralt, MD, Heather J. Landau, MD, David J. Chung, MD, PhD, Guenther Koehne, MD, PhD from Memorial Sloan Kettering Cancer Center, New York, NY Specific Aims: To develop a prognostic scoring system in patients with multiple myeloma (MM) that is predictive of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT). Scientific Justification: Treatment of MM with high-dose melphalan and autologous HSCT (autoHSCT) results in extended event-free and overall survival compared with conventionally dosed chemotherapy; however, this approach is not curative, even among patients who achieve CR. Treatment with myeloablative conditioning (MAC) and alloHSCT results in longer disease-free survival and a late plateau in relapse rates, suggesting that a graft-versus-myeloma effect may be curative for a minority of patients. With a median time to relapse of 56 months, curative potential is difficult to ascertain.[1] Significant transplant-related mortality (TRM) after MAC alloHSCT yields reduced overall survival compared with autoHSCT, and a survival advantage is not apparent until after three years. While nonmyeloablative/reduced-intensity conditioning (RIC) reduces TRM, it appears to be at the expense of higher rates of relapse,[2] and comparisons of tandem autoHSCT with auto/RIC-alloHSCT do not demonstrate a consistent advantage.[3-5] The International Staging System (ISS) and molecular scoring strategies are able to identify patients at high risk of treatment failure after autoHSCT.[6-8] Clinical and molecular risk factors for relapse after alloHSCT have been identified in single-institution studies,[9, 10] including chemoresistance, high �2-microglobulin and duration and extent of disease; genetic mutations (chromosome 13 deletion, DNA ploidy and IgH translocations) are also associated with relapse, although perhaps less after alloHSCT than autoHSCT.[11] The proposed study will use patient, disease, and transplant-specific factors acquired in the CIBMTR dataset to develop a prognostic scoring system to quantify risk of MM relapse or death after alloHSCT. The need for better information on risk of relapse emerged as a priority in the NCI International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation (Bethesda 2009).[12] Definition of relapse risk might improve patient selection for alloHSCT and identify strategies to individualize conditioning regimens and/or preemptive approaches to improve survival. No single center can assess the multiple factors that likely contribute, nor evaluate adequate patient numbers to achieve sufficient statistical power. Analysis of CIBMTR data from multiple sites will address these issues. Patient Eligibility Population: All patients with MM reported to the CIBMTR who received a MAC, non-MAC or RIC peripheral blood stem cell, bone marrow, or cord blood alloHSCT for MM between 1995 and 2008. Data Requirements: The proposed study does not require supplemental data outside of the current CIBMTR data collection forms. Many data requirements may be included in the MM09-04 Dataset. Additional, disease-specific data are included on 2016 an 2116; the majority of transplant and outcome data are included in TED Forms 2400 and 2455. Sample Requirements: None

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Study Design: Initial analysis - Variables related to patient, disease, and transplant characteristics (Table 1) will be summarized using descriptive statistics. The primary analysis will be actuarial (Kaplan-Meier) curve of time to progression or relapse (in which non-relapse deaths will be censored). Cumulative incidence curves will also be calculated for (1) relapse competing with non-relapse mortality (NRM) and (2) NRM. Variables found to be significant in univariate (log-rank) analyses will subsequently be evaluated in a Cox proportional hazards model. Secondary analyses will explore associations between the variables identified within this scoring system and transplantation outcomes, including late relapse (>12 months after transplant), survival after relapse, and NRM. Three patient cohorts will be evaluated for the primary outcome (relapse): a) Patients at transplant baseline prior to starting conditioning; b) Patient survivors at day 100 post transplant in which case the impact of early post-transplant variables and acute GVHD will be included; c) Patient survivors at 12 months post transplant in which case the impact of post-transplant variables and acute and chronic GVHD will be included. Relapse risk score development - Our primary objective is to develop a risk score for relapse in patients at transplant baseline using the predictive variables identified above. Each individual factor that is significantly associated with a given outcome in a univariate analysis and is then found to be jointly prognostic in a Cox model will be included in the final final risk score, which, for simplicity of implementation, will consist of the number of such factors that a patient possesses. Variables From CIBMTR Data To Be Analyzed Patient Age at Dx (Date of Dx, DOB); Gender; CMV

Comorbidities at alloHSCT Karnofsky/Lansky Performance Score at alloHSCT

Disease MM/PCD Subtype Disease Response Status at alloHSCT �2-M & Platelet Count or ISS @ Diagnosis; @ alloHSCT Cytogenetics at Dx; at alloHSCT Sites at Dx; at alloHSCT; @ relapse % Plasma Cells/ BM at Dx; at alloHSCT SPEP/Monoclonal Ig at Dx; at alloHSCT

MM Therapy Prior MM Rx (# Rx Regimens) Pre-HSCT IMID Rx: Y/N Pre-HSCT Proteasome Inhibitor Rx: Y/N Prior AutoHSCT(s)/Date(s), +/-TBI

AlloHSCT Date (Time from Dx; Time from autoHSCT) HSCT Type/donor relationship Donor HLA disparity; gender; parity; CMV Stem Cell Collection/Rx Conditioning: Radiation; Drugs Allograft manipulation; Infused CD34+ cell dose; Infused CD3+ cell dose GVHD prophylaxis ATG given, indication Alemtuzumab given, indication ANC Recovery PLT Recovery Best Donor Chimerism %: BM/CD3/Myeloid/Dates HSCT Best Response/Date Additional donor cell infusion (Date, Dose, Indication) Grade maximum acute GVHD, Date of Onset Severity maximum chronic GVHD, Date of Onset

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Outcome Post-transplant PD: Y/N, date, detection Post-relapse CR: Date/Rx/TTP IMID; Proteasome Inhibitor Rx Post-alloHSCT: Y/N; Indication Date, Survival at Last F/U Disease Status @ Last F/U Cause of Death: Relapse vs. NRM vs. Other

References: 1. Bjorkstrand, B.B., et al., Allogeneic bone marrow transplantation versus autologous stem cell

transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood, 1996. 88(12): p. 4711-8.

2. Crawley, C., et al., Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood, 2007. 109(8): p. 3588-94.

3. Bruno, B., et al., A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med, 2007. 356(11): p. 1110-20.

4. Moreau, P., et al., Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood, 2008. 112(9): p. 3914-5.

5. Rosinol, L., et al., A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood, 2008. 112(9): p. 3591-3593.

6. Greipp, P.R., et al., International staging system for multiple myeloma. J Clin Oncol, 2005. 23(15): p. 3412-20.

7. Inamoto, Y., et al., Combinations of cytogenetics and international scoring system can predict poor prognosis in multiple myeloma after high-dose chemotherapy and autologous stem cell transplantation. Am J Hematol, 2009. 84(5): p. 283-6.

8. Schilling, G., et al., Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia, 2008. 22(6): p. 1250-5.

9. Gahrton, G., et al., An update of prognostic factors for allogeneic bone marrow transplantation in multiple myeloma using matched sibling donors. European Group for Blood and Marrow Transplantation. Stem Cells, 1995. 13 Suppl 2: p. 122-5.

10. Lee, C.K., et al., Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp Hematol, 2003. 31(1): p. 73-80.

11. Pavletic, S.Z., et al., NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biology of Blood and Marrow Transplantation, 2010. 16(7): p. 871-890.

12. Bishop, M.R., et al., Introduction to the reports from the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 16(5): p. 563-4.

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Characteristics of patients who underwent a first allogeneic transplant for multiple myeloma, reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%) Number of patients 583Number of centers 146Sex Male 352 (60) Female 231 (40)Age at transplant, years ≤ 29 12 ( 2) 30-39 85 (15) 40-49 247 (42) 50-59 196 (34) 60-69 40 ( 7) ≥ 70 3 (<1)Karnofsky score prior to transplant, % ≥ 90 485 (83) < 90 91 (16) Unknown 7 ( 1)Durie-Salmon stage at diagnosis Stage I 57 (10) Stage II 159 (27) Stage III 332 (57) Unknown 35 ( 6)Immunochemical subtype of myeloma IgG 239 (41) IgA 67 (11) IgD 4 (<1) Light chain 97 (17) Non-secretory 38 ( 7) Secretory, not specified 113 (19) Missing 25 ( 4)Time from diagnosis to transplant, median (range), months 9 (1 - 216) < 6 months 124 (21) 6-12 months 233 (40) 12-18 months 81 (14) >18 months 145 (25)Graft type Bone marrow 210 (36) Peripheral blood 274 (64)Sensitivity to chemotherapy prior to transplant Sensitive 306 (52) Resistant 115 (20) Not applicable/unknown 162 (28)

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Continued. Characteristics of patients N (%) Conditioning regimen Melphalan alone 127 (22) Melphalan + total body irradiation(TBI) ± others 105 (18) Melphalan ± others, not TBI 46 ( 8) Total body irradiation ± others, not Melphalan 154 (26) Busulfan + cyclophosphamide ± others 98 (17) Others 53 ( 9)Prior chemotherapy regimens MP ± others 122 (21) VAD ± others 177 (30) Cy ± others 67 (11) Corticosteroids ± others 44 ( 8) Thal ± others 22 ( 4) Other/unknown 51 (26)Disease status prior to transplant Complete response 77 (13) Partial response 199 (34) Minimal response 49 ( 8) No response/Stable disease 86 (15) Relapse from complete response 6 ( 1) Progressive disease 166 ( 4) Missing 145 (25)Year of transplant 1995 47 ( 8) 1996 77 (13) 1997 61 (10) 1998 43 ( 7) 1999 42 ( 7) 2000 61 (10) 2001 82 (14) 2002 48 ( 8) 2003 33 ( 6) 2004 23 ( 4) 2005 20 ( 3) 2006 11 ( 2) 2007 9 ( 2) 2008 26 ( 5)Median follow-up of survivors, median (range), months 15 (<1 - 171)Progressive free at various time period <5 years 195 5-10 years 62 >10 years 34

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Study Proposal 0910-02

Study Title: High-dose therapy for patients with primary systemic Amyloidosis Leena Varkey Maramattom, MD, Medical College of WI, Milwaukee, WI Objectives:

– To evaluate the results of autologous transplantation in primary systemic amyloidosis patients. Outcomes to be assessed from the date of transplant include the following:

Remission/response rates; Relapse;

– Treatment-related mortality; – Progression-free survival; – Overall survival.

– To identify patient-, disease-, and transplant-related prognostic factors for outcome after autologous transplantation for primary systemic amyloidosis. Scientific Justification: Primary systemic amyloidosis is a clonal B cell disease manifested as beta-pleated sheets of immunoglobulin light chain deposition in various organs including the heart, tongue, liver, spleen, kidneys, and bone marrow. The incidence is 5- 12 patients per million per year. Although the burden of clonal plasma cells in AL amyloidosis is low, the accumulation of amyloid deposits in the heart, kidney, liver, GI tract and autonomic nervous system leads to progressive disability, organ failure and death. It is an incurable disease with a median survival of 12-18 months; fewer than 1% survive 10 years (1). Standard treatment is alkylating agent-based chemotherapy which produce demonstrable responses in 20-30%. Most patients never demonstrate objective evidence of disease regression. They usually progress rapidly to irreversible end organ failure and, ultimately, succumb to their disease. Even in responding patients, the median survival is short, considerably shorter than that observed in multiple myeloma, another clonal B cell disease. High-dose therapy (HDT) supported by hematopoietic stem cell transplantation is increasingly utilized in primary systemic amyloidosis. Initial pilot studies, often involving patients with advanced or refractory disease, reported encouraging remission rates after this procedure, including occasional complete remissions (CR), an uncommon outcome with conventional therapy (2,3,4). Remissions achieved by autotransplantation were relatively prolonged in some patients, although eventual recurrence or progression of amyloidosis occurred in most patients. After the observation that HDT and autologous hematopoietic stem cell transplantation could produce high-grade remissions, with a relatively low treatment-related mortality and morbidity, this therapy was evaluated earlier in the disease course, usually in the first year of diagnosis (2,3,4). Boston University has reported their experience with high dose therapy with autologous transplantation in systemic amyloidosis using melphalan doses ranging from 100-200 mg/m2. Their largest series of patients was treated with melphalan 200 mg/m2 followed by peripheral blood stem cell transplant. With a median follow-up of 24 months, 17 of 25 patients (68%) are alive and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated at 3 months posttransplant had a complete response of their clonal plasma cell disorder. Two-thirds of the surviving patients (11/17) have experienced improvement of amyloid-related organ involvement in all systems, while 4 of 17 have stable disease. Three patients relapsed at 12, 12, and 24 months (5).

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The Intergroupe Français du Myélome (IFM) reported better outcomes after autotransplants in a subset of patients with single organ dysfunction. In contrast, when two or more organ dysfunctions were documented, autotransplant was associated with an intolerable risk of toxic death of >75% (6). Identification of prognostic factors for attainment of remission/response, as well as for other outcome parameters, would be helpful to direct future transplant efforts.

Study Population: Patient eligibility/selection criteria include:

– Patients undergoing autologous transplantation for biopsy-proven primary systemic amyloidosis from 1999 through 2008, reported to the CIBMTR.

– Patient must not have evidence of overt multiple myeloma. Patients must not have secondary, familial, or localized amyloidosis.

Potential numbers of subjects are given in Table 1.

Outcomes: – Remission/response rate: to be assessed at 100 days, 6 months, 1 year and 2 years. – Relapse: reappearance of clinical symptoms or laboratory evidence of progressive disease, as

described in Table 2. – Transplant-related mortality: time to death without progression or relapse. Patients with disease

progression or relapse from remission/response are censored. – Progression-free survival: survival without progressive disease or relapse from

remission/response. Progressive disease, relapse from remission/response and death in remission are considered events.

– Overall survival: events are death by any cause. Surviving patients are censored at time of last contact regardless of ongoing treatment.

Variables to be Described: Patient-related:

– Age: continuous – Gender: (male vs female) – Karnofsky performance status: ( �0% vs > 90%)

Disease-related: – Organ involvement at diagnosis (GI vs cardiac vs renal) – Paraprotein subtype if present: (None vs Kappa vs Lambda light chain) – Left ventricular ejection fraction at diagnosis – Interventricular septal thickness at diagnosis (<15 mm vs >15 mm) – 24 hour Urine Protein g/24 H at diagnosis(< 3g/24h vs > 3g/24h) – Serum creatinine level, mg/dl at diagnosis – Serum Albumin level, g/dl at diagnosis – Serum alkaline phosphatase level, U/L at diagnosis – Plasma cells in bone marrow at diagnosis: % – Left ventricular ejection fraction prior to transplant – Interventricular septal thickness prior to transplant (<15 mm vs >15 mm) – 24 hour Urine Protein g/24 H prior to transplant(< 3g/24h vs > 3g/24h) – Serum creatinine level, mg/dl prior to transplant – Serum Albumin level, g/dl prior to transplant – Serum alkaline phosphatase level, U/L prior to transplant – Plasma cells in bone marrow prior to transplant: %s) – Prior chemotherapy: (steroids vs melphalan and prednisone vs others)

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Transplant-related: – Year of transplant: continuous – Interval from diagnosis to transplant: continuous – Interval from date of first treatment to transplant: (continuous and – categorical: <6 months vs 6-12 months vs >12 months) – Conditioning regimen:(melphalan alone vs TBI-containing vs other) – Dose of melphalan, mg/m2

Study Design: Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probability of progression-free survival and overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints will be generated using cumulative incidence estimates (7). Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models. These analyses will fit models to determine which risk factors (Sec 5.0) may be related to a given outcome. All variables will first be examined to assure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for relapse, treatment-related mortality, progression-free survival and overall survival.

References:

1. Kyle RA, Greipp PR, O'Fallon WM. Primary systemic amyloidosis: Multivariate analysis of prognostic factors in 168 cases. Blood 1986; 68: 220-225.

2. Comenzo RL, Vosburgh E, Simms RW et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996; 88: 2801-2806.

3. Van Buren M, Hene RJ, Verdonck L et al. Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Ann Int Med 1995; 122: 508-510.

4. Moreau P, Milpied N, de Faucal P et al. High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement. Blood. 1996; 87: 3063-3064.

5. Comenzo R, Vosburgh E, Falk R et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood 1998; 91: 3662-3670.

6. Moreau P, Leblond V, Bourquelot P et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. British Journal of Haematology 1998; 101: 766-769.

7. Gooley TA, Leisenring W, Crowley J et al. Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Statistics in Medicine. 1999; 18: 695-706.

8. Giralt S, Weber D, Colome M et al. Phase I trial of cyclosporine induced autologuous graft-versus-host disease in patients with multiple myeloma undergoing high-dose chemotherapy with autologuous stem cell rescue. J Clin Oncol 1997; 15: 667-673.

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9. Girnius S, Seldin DC, Skinner M, Finn KT, Quillen K, Doros G, Sanchorawala V. Short and long-term outcome of treatment with high-dose melphalan and stem cell transplantation for multiple myeloma-associated AL amyloidosis. Ann Hematol. 2010 Jun;89(6):579-84. Epub 2009 Dec 10.

10. Frossard V, Ketterer N, Rosselet A, Meier P, Cairoli A, Duchosal MA, Kovacsovics T. Early intensification and autologous stem cell transplantation in patients with systemic AL amyloidosis: a single-centre experience. Ann Hematol. 2009 Jul;88(7):681-5. Epub 2008 Dec 6.

11. A Jaccard, P Moreau, V Leblond, X Leleu. High dose Melphalan versus Melphalan plus Dexamethasone for AL Amyloidosis. New England Journal of Medicine Sept 13,2007; 357;11.

12. M Skinner, V Sanchorawala, D Seldin, L Dember. High dose Melphalan and Autologous Stem – Cell Transplantation in Patients with AL Amyloidosis – An 8 Year Study. Ann Intern Med 2004; 140; 85 -93

13. M Gertz, M Lacy, A Dispenzieri, S Hayman. Transplantation for Amyloidosis. Curr Opin Oncol 19; 136-141; 2007.

14. V Sanchorawala, D Wright, D Seldin, L Dember. An Overview of the use of high dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis.

15. A Dispenzieri, R Kyle, M Lacy, T Therneau. Superior survival in primary systemic amyloidosis in patients undergoing peripheral blood stem cell transplantation: a case control study.

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Characteristics of patients who underwent a first autologous transplant for amyloidosis, reported to the CIBMTR between 1999 and 2008

Characteristics of patients N (%)Number of patients 277Number of centers 68Sex Male 172 (62) Female 105 (38)Age at transplant, years 30-39 9 ( 3) 40-49 49 (18) 50-59 121 (44) 60-69 73 (26) ≥70 17 ( 6) Missing 8 ( 3)Karnofsky score prior to transplant, % ≥ 90 136 (43) < 90 175 (55) Unknown 6 ( 2)Time from diagnosis to transplant, median (range), months 5 (1 - 178) < 6 months 170 (61) 6-12 months 62 (22) 12-18 months 19 ( 7) >18 months 26 ( 9)Conditioning regimen None 1 (<1) Melphalan alone 268 (97) Melphalan + total body irradiation(TBI) ± others 1 (<1) Melphalan ± others, not TBI 4 ( 1) Total body irradiation ± others, not Melphalan 3 ( 1)Year of transplant 1995-1996 56 (20) 1997-1998 43 (16) 1999-2000 52 (18) 2001-2002 107 (38) 2003-2004 19 ( 6) 2005-2006 56 (20) 2007-2008 43 (16)Median follow-up of survivors, median (range), months 53 (<1 - 133)Bone marrow only were excluded

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Characteristics of patients who underwent a first allogeneic transplant for amyloidosis, registered to the CIBMTR between 1995 and 2009

Characteristics of patients N (%)Number of patients 21Number of centers 16Sex Male 15 (71) Female 6 (29)Age at transplant, years 30-39 2 (10) 40-49 5 (24) 50-59 9 (43) 60-69 3 (14) ≥70 1 ( 5) Missing 1 ( 5)Time from diagnosis to transplant, median (range), months 7 (<1 - 103) < 6 months 10 (48) 6-12 months 3 (14) 12-18 months 4 (19) >18 months 4 (19)Graft type Bone marrow 2 (10) Peripheral blood 19 (90)Conditioning regimen Melphalan alone 10 (48) Total body irradiation(TBI) ± others 5 (24) Others 6 (29)Year of transplant 1995-1999 5 (24) 2000-2005 15 (72) 2006-2008 6 (28)Median follow-up of survivors, median (range), months 31 (<1 - 89)

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Study Proposal 1210-12 Study Title: Outcomes of allogeneic hematopoietic cell transplantation for AL amyloidosis. Baldeep Wirk, MD, University of Florida College of Medicine, Gainesville, FL Objectives: To study the outcomes of allogeneic hematopoietic cell transplantation(HCT) for AL amyloidosis. The primary endpoints will be to analyze the overall survival, progression free survival, treatment related mortality, and response rate (hematologic and organ response rate). The secondary endpoints will be to assess the incidence of acute graft versus host disease (GVHD) and chronic GVHD and to analyze the factors impacting overall survival. Scientific Justification: From retrospective studies, autologous HCT has been reported to have higher response rates and better overall survival than standard chemotherapy in immunoglobulin light chain AL amyloidosis.1 However, a randomized prospective trial comparing high dose melphalan conditioned autologous HCT with standard dose melphalan plus high dose dexamethasone in patients with AL amyloidosis showed the survival was better with chemotherapy (58.9 months) than with autologous HCT (median overall survival 22.2 months p=0.004). 2 High dose chemotherapy with autologous stem cell rescue is also associated with high treatment related mortality of between 13% to 43%.3,4 There are few options available for long term survival for AL amyloidosis patients who relapse after autologous HCT or have unresponsive disease even with the advent of bortezomib and the immunomodulatory drugs (IMiDs). AL amyloidosis patients with organ involvement have multiple comorbidities. Nonmyeloablative HCT has broadened the inclusion criteria to allow patients with comorbidities to undergo HCT. There are case reports and small series of allogeneic HCT as being potentially curative for AL amyloidosis.5,6 Even in patients who are not sensitive to chemotherapy, case reports have shown allogeneic HCT can provide a complete response after allogeneic HCT suggestive of a graft versus plasma cell dyscrasia effect.5,6 The CIBMTR data base will provide a unique opportunity to study in a larger cohort of patients the outcomes of allogeneic HCT for AL amyloidosis and to assess the feasibility and applicability of this approach in a disease where there are few other treatment options. Study Population: All AL-amyloidosis patients undergoing allogeneic HCT with myeloablative or nonmyeloablative/reduced intensity conditioning from 1990 to 2009 compared to those undergoing autologous HCT. Outcomes:

– Response rate: to be assessed at 100 days and at 1 year. – Best response post transplant: CR, PR, NR/SD,PD , hematologic and organ response as defined in

CIBMTR form 2117 – Transplant related mortality: time from the transplant to death occurring in continuous complete

remission, partial response, minimal response or stable disease. This event is summarized by the cumulative incidence estimated with disease progression as the competing risk.

– Relapse/progression: reappearance of disease for patients with complete remission; evidence of progressive disease after stable disease, minimal response or partial response. This event is summarized by the cumulative incidence estimate with treatment-related mortality as the competing risk.

– Progression free survival: time from transplant to death, disease progression, or relapse after complete response. Patients who are alive and in continuous complete remission, partial response, minimal response or stable disease are censored at the time of last contact.

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– Overall survival: events are death by any cause. Surviving patients are censored at the time of last contact regardless of ongoing treatment.

– Acute GVHD: grade I-IV according to Seattle criteria.7

Chronic GVHD: according to criteria by Shulman et al.8

Variables to be Analyzed:

Patient related: – Age: years – Gender: male vs. female – KPS: <70,70, >70

Disease related: – Serum monoclonal immunoglobulin: – Serum free light chain: – Organs involved: 1,2,3,4 or more – Cardiac left ventricular ejection fraction <40%: yes vs. no – Cardiac interventricular septal thickness >15 mm: yes vs. no – Liver involvement :alkaline phosphatase >2xULN – Serum creatine >2 mg/dl: yes vs. no – Urinary protein excretion >200 mg/24 hours: yes vs. no – Nephrotic syndrome: yes vs. no – Bone marrow plasma cells % – Chemotherapy: # lines, bortezomib, IMiDs, melphalan prednisone, VAD – Cardiac involvement: yes vs. no – Liver involvement:yes vs. no – Renal involvement:yes vs. no – Autonomic nervous system involvement: yes vs. no

Transplant related: – Previous autologous HCT: yes vs. no – Time from diagnosis to allogeneic HCT: – Graft: BM vs. PBSC – Donor: Matched related donor, matched unrelated donor – Year of HCT: – Disease status at HCT: CR, PR, NR/SD, PD – Conditioning:myeloablative vs. nonmyeloablative/reduced intensity – TBI in conditioning: yes vs. no – Antithymocyte globulin :yes vs. no – Acute GVHD: yes vs. no – Chronic GVHD: yes vs. no – Best response to transplant: Hematologic response, organ response (CIBMTR form 2117)

Causes of Death: Infection, pulmonary organ dysfunction (interstitial pneumonitis, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, bronchiolitis obliterans), liver dysfunction (VOD), congestive heart failure, neurologic dysfunction (seizure, stroke) second malignancy, graft failure, relapsed disease Data Collection: All data requested will be provided by existing data collection forms and no supplemental data will be required. Follow up will be complete by the end of 2011.

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Study Design: Overall survival and progression free survival will be calculated using the Kaplan-Meier method. The log rank test will be used for univariate comparisons to examine the association between overall survival and patient, disease and transplant related characterisitics such as acute and chronic GVHD. Multivariate analysis with Cox proportional hazards regression model for progression free survival and overall survival will be used. References:

1. Dispenzieri A, Kyle RA, Lacy MQ et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case control study. Blood 2004;103:3960-3

2. Jaccard A, Moreau P, Leblond V et al. High dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007;357:1083-93

3. Skinnner M, Sachorawalla V, Seldin DC et al. High-dose melphalan and autologous stem cell transplantation in patients with AL amyloidosis: a 8 year study. Ann Intern Med 2004;140:85-93

4. Moreau P, Leblond V, Bourquelot P et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report in 21 patients. Br J Haematol 1998;101:766-9

5. Gillmore JC, Davies J, Iqbal A et al. Allogeneic bone marrow transplantation for systemic AL amyloidosis. Br J Haematol 1998;100:226-8

6. Kawal Y, Kinoshita K, Arai H et al. Reduced intensity allogeneic stem cell transplantation for systemic primary amyloidosis refractory to high dose melphalan. Eur J Haematol 2004;72:448-50

7. Thomas ED, Storb R, Clift RA et al. Bone Marrow Transplantation. N Engl J Med 1975;292:895-902

8. Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft-versus-host disease syndrome in man: A long-term clinicopathologic study in 20 Seattle patients. Am J Med 1980;69:204-217

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Characteristics of patients who underwent a first autologous transplant for amyloidosis, reported to the CIBMTR between 1999 and 2008

Characteristics of patients N (%)Number of patients 277Number of centers 68Sex Male 172 (62) Female 105 (38)Age at transplant, years 30-39 9 ( 3) 40-49 49 (18) 50-59 121 (44) 60-69 73 (26) ≥70 17 ( 6) Missing 8 ( 3)Karnofsky score prior to transplant, % ≥ 90 136 (43) < 90 175 (55) Unknown 6 ( 2)Time from diagnosis to transplant, median (range), months 5 (1 - 178) < 6 months 170 (61) 6-12 months 62 (22) 12-18 months 19 ( 7) >18 months 26 ( 9)Conditioning regimen None 1 (<1) Melphalan alone 268 (97) Melphalan + total body irradiation(TBI) ± others 1 (<1) Melphalan ± others, not TBI 4 ( 1) Total body irradiation ± others, not Melphalan 3 ( 1)Year of transplant 1995-1996 56 (20) 1997-1998 43 (16) 1999-2000 52 (18) 2001-2002 107 (38) 2003-2004 19 ( 6) 2005-2006 56 (20) 2007-2008 43 (16)Median follow-up of survivors, median (range), months 53 (<1 - 133)Bone marrow only were excluded

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Characteristics of patients who underwent a first allogeneic transplant for amyloidosis, registered to the CIBMTR between 1995 and 2009

Characteristics of patients N (%)Number of patients 21Number of centers 16Sex Male 15 (71) Female 6 (29)Age at transplant, years 30-39 2 (10) 40-49 5 (24) 50-59 9 (43) 60-69 3 (14) ≥70 1 ( 5) Missing 1 ( 5)Time from diagnosis to transplant, median (range), months 7 (<1 - 103) < 6 months 10 (48) 6-12 months 3 (14) 12-18 months 4 (19) >18 months 4 (19)Graft type Bone marrow 2 (10) Peripheral blood 19 (90)Conditioning regimen Melphalan alone 10 (48) Total body irradiation(TBI) ± others 5 (24) Others 6 (29)Year of transplant 1995-1999 5 (24) 2000-2005 15 (72) 2006-2008 6 (28)Median follow-up of survivors, median (range), months 31 (<1 - 89)

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Study Proposal 1210-48 Study Title: Comparison of the efficacy of conditioning regimens in autologous hematopoietic cell transplantation for plasma cell myeloma. Baldeep Wirk, MD, University of Florida College of Medicine, Gainesville, FL Objectives: To compare the conditioning regimens used for autologous hematopoietic cell transplantation (HCT) in plasma cell myeloma (PCM) and their impact on engraftment, treatment related mortality, response rate, progression free survival and overall survival. Scientific Justification: The optimal conditioning regimen for autologous HCT in PCM is unknown. Although autologous HCT prolongs event free survival and overall survival compared to chemotherapy alone, ultimately most if not all PCM will relapse. One approach to reduce the rate of relapse is to optimize the conditioning regimens for autologous HCT. There is only one randomized trial comparing melphalan 200 mg/m2 [MEL 200] to melphalan 140 mg/m2 [MEL140] and TBI 8 Gy and found MEL200 to have less treatment related mortality and better overall survival at 45 months (66% vs. 46% p=0.05) although the event free survival was the same (21 months). 1 A Spanish retrospective study showed the median event free survival with busulfan 12mg/kg and melphalan 140 mg/m2 conditioned autologous HCT for PCM was 32 months versus 22 months for MEL200 reaching statistical significance and there was also a trend to better median overall survival of 64 months with busulfan melphalan versus 37 months for MEL200.2 There is a clear dose response relationship with melphalan. In 27 PCM patients treated with melphalan 220 mg/m2 autologous HCT the 3 year OS was 66.7% and event free survival 64.3% without any toxic deaths. This is in comparison to a median overall survival and event free survival of 43 months and 21 months for MEL200 in 67 patients with a treatment related mortality of 1.5%.4 Other more intense regimens such as thiotepa busulfan cyclophosphamide and carmustine cyclophosphamide vepeside have been used as well and shown to be feasible.5,6 Recently, ascorbic acid, arsenic trioxide preceding MEL200 was shown to enhance the antimyeloma activity of melphalan alone as was bortezomib and melphalan.7 ,8 It is important to compare the numerous conditioning regimens that have been used before autologous HCT for PCM to determine which if any has been associated with a better progression free survival and overall survival and also guide the future development of better conditioning regimens. The CIBMTR data base will provide a unique opportunity to address this important issue. Study Population: All patients with PCM over the age of 18 undergoing autologous HCT between 1990 and 2009 (first autologous HCT and tandem) and divided into groups according to the conditioning regimen and the following outcomes and variables analyzed. Outcomes:

– Response rate: to be assessed at 100 days and at 1 year. – Best response post transplant: defined by EBMT-IBMTR criteria. – Transplant related mortality: time from the transplant to death occurring in continuous complete

remission, partial response, minimal response or stable disease. This event is summarized by the cumulative incidence estimated with disease progression as the competing risk.

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– Relapse/progression: reappearance of disease for patients with complete remission; evidence of progressive disease after stable disease, minimal response or partial response. This event is summarized by the cumulative incidence estimate with treatment-related mortality as the competing risk.

– Progression free survival: time from transplant to death, disease progression, or relapse after complete response. Patients who are alive and in continuous complete remission, partial response, minimal response or stable disease are censored at the time of last contact.

– Overall survival: events are death by any cause. Surviving patients are censored at the time of last – contact regardless of ongoing treatment.

Variables to be Analyzed: Patient related:

– Gender: male or female – Age: years – Karnofsky performance status: > or = to 70, or <70

Disease related prior to transplant: – Time from diagnosis to transplantation: mean (range) – Multiple myeloma monoclonal protein: IgG, IgA, IgD, IgM (not Waldenstrom’s), only

– light chain, or nonsecretory. – Kappa light chain – Lambda light chain – Lytic bone lesions: yes or no – Previous radiation: yes or no – Clinical stage at presentation: Durie-Salmon I, II, III or international staging system – Disease status at transplantation: complete remission, partial response, minimal response,

stable disease, progression – Sensitivity of multiple myeloma prior to conditioning: sensitive or resistant – Lactate dehydrogenase IU/L >ULN vs. < ULN – Serum M component g/dl – Creatinine at diagnosis: 2 mg/dl or more or <2 mg/dl – Bone marrow plasma cells % – Bone marrow cytogenetics abnormal: yes, no – Type of abnormal cytogenetics: 13 q14, 14 q32, 17 p- – Pretransplant chemotherapy: one line, two lines, 3 or more lines – Type of pretransplant chemotherapy: VAD vs. melphalan prednisone vs. thalidomide based

vs. bortezomib based vs. lenalidomide based. – Duration of prior therapy: <12 months vs. >12 months – Dialysis: yes, no – Tandem autologous stem cell transplant: yes, no – Time from first transplant to second transplant

Transplant related: – Stem cell source for autologous stem cell transplant: peripheral blood, bone marrow, or both – Conditioning regimen: melphalan220 mg/m2, 200 mg/m2, 140 mg/m2, 100 mg/m2 ; melphalan

140 and TBI, melphalan and busulfan, busulfan and cyclophosphamide, idarubicin cyclophosphamide melphalan, arsenic ascorbic acid melphalan, bortezomib melphalan, thiotepa busulfancyclophosphamide, other

– Leukocyte engraftment: first of 3 consecutive days to 0.5 x 109 granulocytes/L – Platelet engraftment: days to 20 x 109 platelets/ L and days to 50 x 109/L – Year of transplant – Creatinine at HCT: 2 or more vs <2 mg/dl – Autotransplant: first or second (tandem)

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– Causes of death: infection, hemorrhage, organ failure (veno-occlusive disease, renal failure), secondary malignancy, vascular, other

– Response to first transplant: complete remission, partial response, minor response, stable disease, progressive disease

– Response to tandem transplant: complete remission, partial response, minor response, stable disease, progressive disease

Data Collection: All data requested will be provided by existing data collection forms and no supplemental data will be required. Follow up will be complete by the end of 2011. Study Design: Overall survival and progression free survival will be calculated using the Kaplan-Meier method. The log rank test will be used for univariate comparisons to examine the association between overall survival and patient, disease and transplant related characterisitics such conditioning regimen. Multivariate analysis with Cox proportional hazards regression model for progression free survival and overall survival will be used. References:

1. Moreau P, Facon T, Attal M et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus melphalan 140 mg/m2 as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 2002; 99:731-5

2. Lahuerta JJ, Martinez-Lopez J, Grande C et al. Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma. Br J Haematol 2000;109:138-47

3. Moreau P, Milpied N, Mahe B et al. Melphalan 220 mg/m2 followed by peripheral blood stem cell transplantation in 27 patients with advanced multiple myeloma. Bone Marrow Transplant 1999;23: 1003-6

4. Vesole DH, Barlogie B, Jagannath S et al. High dose therapy for refractrory multiple myeloma: improved prognosis with better supportive care and double transplants. Blood 1994;84:950-6

5. Shimoni A, Smith TL, Aleman A et al. Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma. Bone Marrow Transplant 2001;27:821-8

6. Ventura GJ, Barlogie B, Hester JP et al. High dose cyclophosphamide, BCNU, VP16 with autologous blood stem cell support for refractory multiple myeloma. Bone Marrow Transplant 1990;5:265-8

7. Qazilbash MH, Saliba RM, Nieto Y et al. Arsenic trioxide with ascorbic acid and high dose melphalan: results of a phase II randomized trial. Biol Blood Marrow Transplant 2008;14(12):1401-7

8. Roussel M, Moreau P, Huynh A et al. Bortezomib and high dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase II study of the Intergroupe Francophone du Myelome (IFM). Blood 2010115:32-7

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Characteristics of patients ≥18 years old who underwent a first autologous transplant within 18 months after the diagnosis for Multiple Myeloma, reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%) Number of patients 4831Number of centers 202Sex Male 2849 (59) Female 1982 (41)Age at transplant, years ≤ 29 21 (<1) 30-39 199 ( 4) 40-49 895 (19) 50-59 1912 (40) 60-69 1487 (31) ≥ 70 238 ( 5) Missing 79 ( 2)Karnofsky score prior to transplant, % ≥ 90 4254 (88) < 90 395 ( 8) Unknown 182 ( 4)Time from diagnosis to transplant, median (range), months 8 (2 -18) < 6 months 1281 (26) 6-12 months 2897 (60) 12-18 months 643 (14)Durie-Salmon stage at diagnosis Stage I 337 ( 7) Stage II 1189 (25) Stage III 2724 (56) Unknown 581 (12)Conditioning regimen Melphalan alone 4017 (83) Melphalan + total body irradiation(TBI) ± others 249 ( 5) Melphalan ± others, not TBI 223 ( 5) Total body irradiation ± others, not Melphalan 48 (<1) Busulfan + cyclophosphamide ± others 248 ( 5) Others 46 (<1)Prior chemotherapy regimens MP ± others 312 ( 6) VAD ± others 1787 (37) Cy ± others 841 (17) Corticosteroids ± others 265 ( 5) Thal ± other 974 (20) Other/unknown 652 (13)

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Continuted. Characteristics of patients N (%) Immunochemical subtype of myeloma IgG 2145 (44) IgA 753 (16) IgD 39 (<1) Light chain 718 (15) Non-secretory 266 ( 6) Secretory, not specified 711 (15) Missing 199 ( 4)Disease status prior to transplant Complete response 756 (16) Partial response 2603 (54) Minimal response 650 (13) No response/Stable disease 475 (10) Relapse from complete response 9 (<1) Progressive disease 49 ( 1) Missing 289 ( 6)Sensitivity to chemotherapy prior to transplant Sensitive 3323 (69) Resistant 535 (11) Not applicable/unknown 973 (20)Year of transplant 1995 102 ( 2) 1996 150 ( 3) 1997 249 ( 5) 1998 231 ( 5) 1999 252 ( 5) 2000 273 ( 6) 2001 396 ( 8) 2002 362 ( 7) 2003 272 ( 6) 2004 483 (10) 2005 575 (12) 2006 540 (11) 2007 296 ( 6) 2008 650 (13)Median follow-up of survivors, median (range), months 50 (<1 - 181)Bone marrow only were excluded Patients who had two autologous transplants within 6 months were excluded

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Study Proposal 1210-61

Study Title: High dose intravenous busulfan and melphalan followed by bortezomib (bumelvel) vs high dose melphalan (mel) as conditioning regimen for autologous peripheral blood stem cell transplantation for patients with multiple myeloma. Tulio E. Rodriguez, MD, Loyola University Chicago Medical Center, Maywood, IL Patrick J. Stiff, MD, Loyola University Chicago Medical Center, Maywood, IL Jonathan L. Kaufman, MD, Emory University, Winship Cancer Institute, Atlanta, GA Scott E. Smith, MD, PhD, Loyola University Chicago Medical Center, Maywood, IL Sagar Lonial, MD, Emory University, Winship Cancer Institute, Atlanta, GA David H.Vesole, MD, PhD. Hackensack University Medical Center, Hackensack, NJ. Introduction: Overall survival for patients with Multiple Myeloma (MM) has improved significantly over the past 10 years primarily as a result of novel therapeutics. High dose therapy with autologous stem cell transplantation (ASCT) continues to be an effective modality but the progression-free survival following ASCT has improved minimally over the same period of time due to a continued reliance on single agent melphalan. Many chemotherapy and chemoradiotherapy regimens have been used in preparation for stem cell transplantation. However, no regimen has proven superior to high dose melphalan 200 mg/ m2 (MEL) which is considered the standard conditioning for patients with MM with relatively predictable results. In order to improve progression free survival (PFS) and overall survival (OS), continued efforts in developing effective preparative regimens are needed. Busulfan is an alkylating agent that affects cells in an AUC-dependent manner. Recent data suggests that the combination of busulfan and MEL delivers better PFS compared to MEL 200 alone (Grande and Lahuerta; PETHEMA, 36th EBMT meeting. Vienna 2010). Moreover, the addition of bortezomib (BTZ) following MEL 200 appears to increase the VGPR rate when compared to historical cohort receiving MEL 200 alone (Lonial, et al; Blood. ASH Annual Meeting Abstracts, Nov 2008; 112: 3332). Furthermore, the recently published IFM trial of MEL 200 plus BTZ also demonstrated superior response rates and PFS compared to historical controls (Roussel et al Blood. 2010;115:32-7). In a preliminary analysis, 20 patients with multiple myeloma transplanted with BuMelVel at our institution achieved a VGPR or higher response, and CR/sCR of 85% and 55% respectively, as compared to responses reported with MEL/BTZ (70% and 32%, respectively); and to MEL 200 alone (43% and 11%, respectively) by Roussel et al. No cases of VOD have been observed and the incidence and severity of mucositis are comparable to our institutional experience with MEL 200 and BuCy. Therefore, we concluded that the regimen of BuMelVel may lead to improvements in PFS and OS, critical criteria to improve the outcomes of patients with MM. Study Aims: The aim of the proposed study is to compare the outcome and toxicity observed in MM patients transplanted at our institution using a BuMelVel preparative regimen with MM recipients of ASCT using MEL reported to the CIBMTR. Survival analysis may be done using a Cox proportional hazards regression to adjust for differences between the groups.

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We propose comparing patients for the following variables:

- Age - Performance Status - Cytogenetics/FISH - International Staging System at Diagnosis - Number of therapies pre transplantation - Disease status prior to preparative regimen (PR, VGPR, CR) - Transplant as initial therapy vs later in the disease course - Neutrophil and platelet engraftment - Regimen related toxicity: Diarrhea, VOD, IP, mucositis, etc. - Best Response (PR, VGPR, CR, and sCR) at day 100 post transplantation. - Overall Survival - Progression Free Survival

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Characteristics of patients ≥18 years old who underwent a first autologous transplant within 18 months after the diagnosis for Multiple Myeloma, reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%) Number of patients 4831Number of centers 202Sex Male 2849 (59) Female 1982 (41)Age at transplant, years ≤ 29 21 (<1) 30-39 199 ( 4) 40-49 895 (19) 50-59 1912 (40) 60-69 1487 (31) ≥ 70 238 ( 5) Missing 79 ( 2)Karnofsky score prior to transplant, % ≥ 90 4254 (88) < 90 395 ( 8) Unknown 182 ( 4)Time from diagnosis to transplant, median (range), months 8 (2 -18) < 6 months 1281 (26) 6-12 months 2897 (60) 12-18 months 643 (14)Durie-Salmon stage at diagnosis Stage I 337 ( 7) Stage II 1189 (25) Stage III 2724 (56) Unknown 581 (12)Conditioning regimen Melphalan alone 4017 (83) Melphalan + total body irradiation(TBI) ± others 249 ( 5) Melphalan ± others, not TBI 223 ( 5) Total body irradiation ± others, not Melphalan 48 (<1) Busulfan + cyclophosphamide ± others 248 ( 5) Others 46 (<1)Prior chemotherapy regimens MP ± others 312 ( 6) VAD ± others 1787 (37) Cy ± others 841 (17) Corticosteroids ± others 265 ( 5) Thal ± other 974 (20) Other/unknown 652 (13)

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Continued. Characteristics of patients N (%) Immunochemical subtype of myeloma IgG 2145 (44) IgA 753 (16) IgD 39 (<1) Light chain 718 (15) Non-secretory 266 ( 6) Secretory, not specified 711 (15) Missing 199 ( 4)Disease status prior to transplant Complete response 756 (16) Partial response 2603 (54) Minimal response 650 (13) No response/Stable disease 475 (10) Relapse from complete response 9 (<1) Progressive disease 49 ( 1) Missing 289 ( 6)Sensitivity to chemotherapy prior to transplant Sensitive 3323 (69) Resistant 535 (11) Not applicable/unknown 973 (20)Year of transplant 1995 102 ( 2) 1996 150 ( 3) 1997 249 ( 5) 1998 231 ( 5) 1999 252 ( 5) 2000 273 ( 6) 2001 396 ( 8) 2002 362 ( 7) 2003 272 ( 6) 2004 483 (10) 2005 575 (12) 2006 540 (11) 2007 296 ( 6) 2008 650 (13)Median follow-up of survivors, median (range), months 50 (<1 - 181)Bone marrow only were excluded Patients who had two autologous transplants within 6 months were excluded

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a g e n d a cibmtr working committee for plasma cell …€¦ · jl, gibson j, hale ga, kumar s,...

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