a g e n d a cibmtr working committee for plasma cell … · 2013. 12. 23. · mm02-03/mm03-01 graft...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS Tampa, Florida Thursday, February 12, 2009, 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: Donna Reece, MD, Princess Margaret Hospital, Ontario, Canada Telephone: 416-946-2253; Fax: 416-946-6546; 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: Smriti Shrestha, MS, CIBMTR Statistical Center Telephone: 414-805-0647; Fax: 414-805-0714; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center 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, 2008 meeting (Attachment 1)

b. Newly appointed chair: Sagar Lonial, MD; Emory University Hospital, Atlanta, GA; Phone: 404-778-1900; Fax: 404- 727-3520; E-mail: [email protected]

2. Accural summary (Attachment 2) 3. Presentations, published or submitted papers

a. MM00-02 Bashey A, Pérez WS, Zhang MJ, Anderson KC, Ballen K, Berenson JR, Fonseca R, Freytes CO, Gale RP, Gibson J, Giralt SA, Kyle RA, Lazarus HM, Maharaj D, McCarthy PL, Milone GA, Nimer S, Pavlovsky S, Reece DE, Schiller G, Vesole DH, Hari P. Comparison of twin and autologous transplants for Multiple Myeloma. Biol Blood Marrow Transplant 14:1118-1124, 2008.

b. MM02-02 Kumar S, Pérez WS, Zhang M-J, Ballen K, Bashey A, Bik To L, Bredeson CN,

Cairo MS, Elfenbein GJ, Freytes CO, Gale RP, Gibson J, Kyle RA, Lacy MQ, Lazarus HM, McCarthy PL, Milone GA, Moreb JA, Pavlovsky S, Reece DE, Vesole DH, Wiernik PH, Hari P. Comparable outcomes in non-secretory and secretory Multiple Myeloma after autologous stem cell transplantation. Biol Blood Marrow Transplant 14:1134-1140, 2008.

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c. MM04-01 Hari P, Zhang M-J, Roy V, Pérez WS, Bashey A, To LB, 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 DH. Is The International Staging System superior to the Durie Salmon staging system? A comparison in Multiple Myeloma patients undergoing autologous transplant. Submitted.

d. Reece D, Vesole DH, Shrestha S, Dispenzieri A, Milone G, Pérez WS, Zhang M-J and Hari

P on behalf of the Plasma Cell Disorders Writing Committee, CIBMTR, Milwaukee, WI, USA. Outcome of patients with IgD and IgM Multiple Myeloma undergoing autologous Hematopoietic stem cell transplants: A retrospective CIBMTR study. Presented at the American Society of Hematology in San Francisco, California, December 2008.

e. Vogl DT, Pérez WS, Wang T, Stadtmauer EA, Dispenzieri A, Milone G, Reece D and Hari P

on behalf of the Plasma Cell Disorders Working Committee, CIBMTR, Milwaukee, WI, USA. Effect of obesity on outcomes after autologous hematopoietic stem cell transplantation for Multiple Myeloma: An analysis from the CIBMTR. Presented at the American Society of Hematology in San Francisco, California, December 2008.

f. Hari P, Majhail N, Hassebroek A, Zhang M-J, Siddiqui F, Mehta P for the Health Policy and

Plasma Cell Disorders Working Committees, CIBMTR, Minneapolis, MN, USA. Similar outcomes among African-Americans and Whites after autologous hematopoietic-cell transplantation for Multiple Myeloma. Presented at the American Society of Hematology in San Francisco, California, December 2008.

g. Beksac M, Maiers M, Gragert L, Spellman S, Shrestha S, Zhang M-J, Dispenzieri A, Reece

D, Vesole DH and Hari P on behalf of the Plasma Cell Disorders Writing Committee, CIBMTR, Milwaukee, WI, USA. HLA specificities and predisposition to the development of Multiple Myeloma. Presented at the American Society of Hematology in San Francisco, California, December 2008.

4. Studies in progress

a. MM02-01/D01-117 Second autologous HCT vs. NST after relapsed autologous HCT for MM (C Freytes/D Vesole) (Attachment 3)

Data Collection

b. MM02-03/MM03-01 Graft versus myeloma effect (O Ringdén) (Attachment 4)

Analysis

c. MM05-01 Autotx for IgD/IgM MM (D Reece) (Attachment 5) Manuscript Preparation d. MM05-02 Effect of obesity on SCT outcome in MM (D Vogl)

(Attachment 6) Analysis

e. MM06-03/HS06-01 African American vs Caucasian after autologous HCT for MM (P Mehta/ P Hari) (Attachment 7)

Manuscript Preparation

f. MM06-04 Post PR with induction vs salvage therapy in autologous HCT for MM (R Vij/D Reece/S Kumar) (Attachment 8)

Protocol Development

g. MM08-01 Time trends in allo HCT for MM (S Kumar) (Attachment 9)


h. MM08-02 HLA specificities and predisposition to the development of MM (M Beksac) (Attachment 10)

Manuscript Preparation

i. MM08-03 Effect of renal failure after auto HCT for MM (B Wirk) (Attachment 11)


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j. MM08-04 Auto HCT for MM: Compare North and South America (G Milone) (Attachment 12) (will also be presented at the International Working Committee meeting, 2009 Tandem meetings)


4. Future/ Proposed studies

a. PROP 0308-01 Comparison of outcome after initial upfront autologous peripheral blood stem cell transplant with delayed initial autologous PBSC transplant in Multiple Myeloma patients (L Holmberg) (Attachment 13)

b. PROP 1108-06 Comparison of early transplantation (< 12 months from diagnosis) to delayed transplantation after relapse (> 12 months) in Multiple Myeloma patients treated with novel induction therapy (D Vesole) (Attachment 14)

c. PROP 1208-17 Outcome of salvage second autologous stem cell transplantation in relapse Multiple Myeloma (A Saad/P Hari) (Attachment 15)

d. PROP 1208-20 An analysis of unplanned, second autologous stem cell transplant in patients with relapsed Multiple Myeloma using CIBMTR data (L Michaelis/D Vesole) (Attachment 16)

e. PROP 1208-15 Clinical outcomes and prognostic factors for donor lymphocyte infusions for relapsed or persistent Multiple Myeloma after allogeneic hematopoietic stem cell transplantation. (B Wirk/J Wingard) (Attachment 17)

f. PROP 1208-46 Plasma Cell Leukemia: Outcomes with autologous or allogeneic stem cell transplantation (A Mahindra/ M Kalaycio) (Attachment 18)

g. PROP 1208-47 Autologous and allogeneic stem cell transplantation in Plasma Cell Leukemia (J Vela/D Vesole) (Attachment 19)

5. Other business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS San Diego, California Thursday, February 14, 2008, 12:15 pm - 2:15 pm Co-Chair: Donna Reece, MD, Princess Margaret Hospital, Ontario, Canada Telephone: 416-946-2253; Fax: 416-946-6546; E-mail: [email protected] Co-Chair: David H. Vesole, MD, PhD, St. Vincent's Comprehensive Cancer Center, NY Telephone: 212-367-1879; Fax: 212-604-6029; 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: Waleska S. Pérez, MPH, CIBMTR Statistical Center Telephone: 414-456-4980; Fax: 414-456-6530; E-mail: [email protected] Smriti Shrestha, MS, CIBMTR Statistical Center Telephone: 414-456-5776; Fax: 414-456-6530; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Scientific Director: Parameswaran Hari, MD, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-4604; Fax: 414-805-4606; E-mail: [email protected] 1. Introduction

The working committee meeting for the Plasma Cell Disorder Working Committee started at 12:25 pm. Drs. Vesole, Reece and Milone chaired the meeting. Dr. Vesole mentioned that this meeting time overlapped with the GVHD working committee meeting and recommended to avoid this overlap in the future. He requested the members to sign up the attendance sheet and to vote for the studies in progress and the new proposals submitted to the committee. The members were encouraged to take into consideration the year the study started for prioritization of the studies in progress. Minutes from the 2007 meeting were approved by the committee without any modification.

Dr. Reece introduced Dr. Angela Dispenzieri as the newly appointed co-chair for the Plasma Cell Disorders Working Committee. She acknowledged the former chair Dr. Vesole for his outstanding contribution to the committee for the past 11 years. Dr. Reece mentioned that Waleska Pérez will no longer be the statistician of the committee and acknowledged her wonderful work. The new working committee statistician, Smriti Shrestha was introduced. Dr. Hari and Waleska were acknowledged for correcting the discrepancies found in approximately 2500 Multiple Myeloma Report Forms regarding best response post transplant and current disease status which affected the outcomes of treatment-related mortality, relapse/progression and progression-free survival.

2. Presentations, published or submitted papers Dr. Vesole presented the submitted papers and presentations of the Working Committee. One paper has been submitted to Blood and two ASH presentations were made during the past year. These include:

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a. MM00-02 Bashey A, Pérez WS, Zhang M-J, Anderson KC, Ballen K, Berenson JR, Fonseca

R, Freytes CO, Gale RP, Gibson J, Giralt SA, Kyle RA, Lazarus HM, Maharaj D, McCarthy PL, Milone GA, Nimer S, Pavlovsky S, Reece DE, Schiller G, Vesole DH, Hari P. Comparison of twin and autologous transplants for Multiple Myeloma: estimating the impact of graft contamination on posttransplant relapse. Submitted.

b. Kumar S, Pérez WS, Zhang M-J, Bredeson CN, Lacy MQ, Milone G, Reece D, Vesole DH

and Hari P on behalf of the Writing Committee, CIBMTR, Milwaukee, WI, USA. Comparable outcomes in secretory versus non-secretory Multiple Myeloma with autologous hematopoietic stem cell transplantation. Presented at the American Society of Hematology in Atlanta, Georgia, December 2007.

c. Hari P, Pérez WS, Zhang M-J, Bredeson CN, Milone G, Reece D, Roy V and Vesole DH on

behalf of the Writing Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Current staging systems are inadequate predictors of treatment failure after autologous hematopoietic stem cell transplants in Multiple Myeloma. Presented at the American Society of Hematology in Atlanta, Georgia, December 2007.

3. Studies in progress a. 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 objectives of this study are to (a) 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; and (b) identify a graft-versus-myeloma effect after allogeneic stem cell transplantation for Multiple Myeloma by comparing myeloma recurrence rates in patients who underwent allogeneic transplantation after an autologous transplant failure with patients who underwent second autologous transplant after a previous autologous transplant failure. This will include patients who underwent a second autologous transplant (n=112), HLA-identical sibling non myeloablative transplant (n=62) and unrelated non myeloablative transplants (n=122). Planned second transplant cases were excluded from the study and comorbidity information will not be included in the study since it was not collected during the study period. Since the previous NMDP disease-specific form did not capture all the detailed data needed for the study, the new Multiple Myeloma H-form will be sent to the centers in the next two months.

b. MM02-03/MM03-01 Graft versus myeloma effect (O Ringdén)

Dr. Vesole presented this study. The objectives of this study 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 nonmyeloablative transplants; and (b) determine the competing effects of GVHD and relapse on disease-free survival in these patient groups. The study has been under data collection for three years. To date, there are 146/201 patients with complete research information. The committee suggested to prepare the data file with the available cases (146) and not to spend more time on data collection. It was also mentioned that the inclusion of unrelated donor will contribute to heterogeneity in the study and will complicate the study. EBMT has collected the largest dataset set (n=320) for a similar study.

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c. MM05-01 Autotx for IgD/IgM MM (D Reece) Dr. Reece presented this study. The primary objective of this study is to describe the clinical outcomes of IgD and IgM Multiple Myeloma patients undergoing stem cell transplantation. This will be a descriptive study of IgD and IgM on Multiple Myeloma patients. Data is available for 31 patients with IgD myeloma and 10 patients with IgM myeloma. Dr. Reece will contact the centers of nine additional cases whose Report Form has not been received. It was suggested to provide three months for the submission of these forms otherwise, to proceed with the data file preparation and univariate analysis of the 46 available cases.

d. M05-02 Effect of obesity on SCT outcome in MM (D Vogl)

Dr. Hari presented this study. The specific aims of the study are to (a) compare the outcomes in patients who are normal weight, overweight, obese, severely obese, and morbidly obese; (b) assess the frequency at which obese patients receive a reduced dose of melphalan; and (c) compare outcomes in obese patients who receive full doses of melphalan or reduced doses of melphalan. The study is under data file preparation and a submission of an abstract of this study is planned for the ASH 2008 meeting.

e. MM06-01 Outcomes of autologous stem cell transplantation after initial treatment with IMID (Thalidomide or Lenalidomide) containing or non-IMID containing induction regiment for Multiple Myeloma (V Roy) Dr. Vesole presented this study in Dr. Roy’s absence. The objective of this study was changed from a thalidomide-based study to a thalidomide-lenalidomide based study. The new objective of the study is to compare the outcomes of patients receiving autologous stem cell transplant as initial planned treatment of Multiple Myeloma after induction therapy with an IMID (thalidomide or Lenalidomide) containing versus non-IMID containing regimen. Currently, there are only 13 cases who reported lenalidomide (revlimid) as part of their first and second line of treatment between 2005 and 2007. It was suggested to put this study on hold for few years until we have enough information about the new drug.

f. MM06-03/HS06-01 African American vs. Caucasian after autologous HCT for MM

(P Mehta/ P Hari) Dr. Hari presented this study. This is a joint study with HPWC measuring the outcomes of African American vs. Caucasian. The specific objectives of this study are to: (a) compare the outcome of autologous transplants for Multiple Myeloma in the African American versus the Caucasian population; and (b) describe any differences in previous therapy, comorbidity, and status of Multiple Myeloma at the time of HCT between the African American and Caucasian populations. The study is under data file preparation. The cytogenetics information was not included since the data is missing for most of the cases. It was suggested to use education and income as a cut off point for the comparison. Submission of an abstract of this study is planned for the ASH 2008 meeting.

g. MM06-04 Post PR with induction vs. salvage therapy in autologous HCT for MM (R Vij)

Dr. Vij presented this study. This study measures 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. The specific objectives of the study are to: (a) compare the response rates, disease free survival and overall survival of patients of these two cohorts of patients; and (b) attempt to define a target pre-transplant “threshold” paraprotein to determine appropriate timing for stem cell transplantation based on a large cohort of patients reported to the CIBMTR. The draft protocol is available for review.

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3. Future/ Proposed studies

a. PROP 0907-03 Outcome of patients relapsing within 12 months of autologous stem cell transplantation for Multiple Myeloma (S Kumar) Dr. Dispenzieri presented this proposal in Dr. Kumar’s absence. The objectives of the proposal are to (a) compare the overall survival among patients relapsing with 12 months of their first auto transplant to those relapsing beyond 12 months; (b) compare the overall survival from the time of relapse among patients with early (


failure on the outcomes of autologous stem cell transplant (first and tandem). The outcomes are complete remission rates, transplant related mortality, event free survival, and overall survival. The secondary endpoints analyzed will be the quality of the stem cell collections, kinetics of engraftment, reversibility of renal failure and dialysis dependence and optimal conditioning regimen. It was suggested to see how many cases were on dialysis.

f. PROP 1207-22 A retrospective analysis of the effect of bisphosphonates on hematopoietic progenitor cell mobilization efficiency (G Chen) Dr. Chen presented this study. The specific aims of the study are to: (a) determine if pre-transplant zoledronic acid or pamidronate treatment affects hematopoietic progenitor cell (HPC) mobilization efficiency defined as CD34 cells/unit of blood volume of apheresis collected; (b) determine if pre-transplant bisphosphonates treatment affects mobilized HPC subsets; (c) determine if pre-transplant bisphosphonates treatment affects treatment outcomes in terms of day of neutrophil/platelet engraftment and infectious complications; and (d) approximate the washout period of zoledronic acid and pamidronate in patients who have received multiple doses. To date, there are only 22/3208 cases who reported receiving the drug bisphosphonates. If approved, a supplemental form will be needed to capture information on bisphosphonates since this is under reported as is only reported on the “other, specify” field of the forms.

g. PROP 1207-33 Impact of Pre-Transplant Therapy and Depth of Disease Response Prior To Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma (S Kumar/ D Reece) Dr. Reece presented this study. The specific aims of the study are to: (a) examine the relationship between disease status at transplant and outcomes after stem cell transplantation; (b) 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; and (c) examine the relationship between the degree of reduction in the M-protein (urine and serum) prior to transplant and the outcomes after stem cell transplantation. The committee suggested to combine this proposal with study# MM06-04 “Comparison of outcomes of patients undergoing autologous transplantation after achieving less than a partial response to initial chemotherapy compared with those receiving additional salvage chemotherapy prior to undergoing autologous stem cell transplantation”.

h. PROP 1207-44 Outcome of hematopoietic progenitor cells transplantation in patients with Multiple Myeloma, comparison of patients from North vs. South America (G Milone) Dr. Milone presented this study. The specific objective of this proposal is to analyze the outcome of autologous transplants in patients with Multiple Myeloma in North vs. South America. According to the ISS staging system there should not be any difference on access to transplantation between the two continents. It was noted that the transplant cases from South America are under reported and therefore, it was suggested to see how many cases are registered but not reported for South America. It was recommended to share primary responsibility of this proposal with the International Working Committee.

6. Other business

BMT CTN (Multiple Myeloma): Dr. Vesole will be new recommended ad-hoc representative for the BMT CTN Multiple Myeloma committee. Dr. Sergio Giralt stated that the BMT CTN will share the data with the registry.

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Based on the voting results, the goals for next fiscal year is as follows: Study # and PI

Status at tandem 02/08

Anticipated status by 06//08

Anticipated status by 06//09

Studies in progress: MM02-01/D01-117 (Freytes) Protocol/Form dev Data collection Submit MM02-02 (Kumar) Ms preparation Submit ----- MM02-03/ MM03-01 (Ringdén)

Data collection Analysis Submit

MM04-01 (Hari) Ms preparation Submit ----- MM05-01 (Reece) Data collection Data collection Submit MM05-02 (Vogl) Data file prep Ms preparation Submit MM06-01 (Roy) Deferred Deferred Deferred MM06-03/HS06-01 (Mehta/Hari)

Data file prep Ms preparation Submit

MM06-04 (Vij/Reece/Kumar) Protocol devel Protocol devel Analysis MM07-01 (Bashey) Dropped Dropped ----- Proposals: PROP 0907-03 (Kumar) ----- Dropped ----- PROP 1007-02 (Kumar) ----- Protocol devel Data file prep PROP 1107-02 (Kamble) ----- Dropped ----- PROP 1207-02 (Beksac) ----- Ms preparation Submit PROP 1207-29 (Wirk) ----- Protocol devel Analysis PROP 1207-22 (Chen) ----- Dropped ----- PROP 1207-33 (Reece) ----- Merged with MM06-04 PROP 1207-44 (Milone) ----- Protocol devel Data file prep Without additional comments, the meeting was adjourned at 2:10 pm.

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Accrual Summary for Plasma Cell Disorders Working Committee

Characteristics of recipients of autologous transplants for Plasma Cell Disorders reported to the CIBMTR between 1990 and 2008

Variables

Registration N(%)a

Median (range)b

Research N(%)a

Median (range)b

Multiple Myeloma 26895 5582 Number of centers 405 236 Age at transplant, years 57 (22 - 83) 57 (22 - 83) Gender

Male 15809 (59) 3309 (59) Female 10997 (41) 2270 (41) Missing 89 (


Continued.

Variables

Registration N(%)a

Median (range)b

Research N(%)a

Median (range)b

Other Plasma Cell Disorders 1956 461 Plasma cell leukemia 219 (11) 45 (10) Waldenstrom macroglobulinemia 98 ( 5) 24 ( 5) Amyloidosis 1173 (60) 339 (74) Solitary plasmacytoma 143 ( 7) 20 ( 4) Other/unclassified 323 (17) 33 ( 7)

Abbreviations: PBSC=peripheral blood stem cells a For Categorical variables b For continuous variables c Cases continue to be reported in this interval

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Accrual Summary for Plasma Cell Disorders Working Committee

Characteristics of recipients of allogeneic transplants for Plasma Cell Disorders reported to the CIBMTR between 1990 and 2008

Variables

Registration N(%)a

Median (range) b

Research N(%)a

Median (range) b

Multiple Myeloma 2581 986 Number of centers 296 194 Age at transplant, years 47 (15 - 78) 46 (22 - 74) Gender

Male 1568 (61) 606 (61) Female 1009 (39) 380 (39) Missing 4 (


Continued.

Variables

Registration N(%)a

Median (range) b

Research N(%)a

Median (range) b

Year of transplant 1990-1991 157 ( 6) 111 (11)1992-1993 301 (12) 160 (16)1994-1995 390 (15) 163 (17)1996-1997 437 (17) 168 (17)1998-1999 344 (13) 83 ( 8)2000-2001 423 (16) 150 (15)2002-2003 280 (11) 87 ( 9)2004-2005 134 ( 5) 45 ( 5)2006-2007 115 ( 4) 19 ( 2)2008 c 0 0

Median follow-up of survivors, (range), months 56 (


CIBMTR 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

REVISED PROTOCOL

Study Chair: César O. Freytes, MD, FACP

Director, Adult Bone Marrow Transplant Program University of Texas Health Science Center at San Antonio & South Texas Veterans Health Care System 7703 Floyd Curl Drive San Antonio, TX 78284-7880

Telephone: 210-617-5268 Fax: 210-617-5271 E-mail: [email protected] Study Co-Chair: David H. Vesole, MD, PhD Professor of Medicine

St. Vincent's Comprehensive Cancer Center 325 West 15th Street New York, NY 10011 Telephone: 212-367-1879 Fax: 212- 604-6029 E-mail: [email protected]

Study Statistician: Smriti Shrestha, MS CIBMTR 9200 West Wisconsin Ave.

Milwaukee, WI 53226 USA Telephone: 414-805-0647 Fax: 414-805-0714

E-mail:[email protected]

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Scientific Director: Parameswaran Hari, MD Assistant Professor Division of Neoplastic Diseases and Related Disorders Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53266 Telephone: 414-805-4604 Fax: 414-805-4606 E-mail: [email protected]

Working Committee Chairs: Angela Dispenzieri, MD

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

Email: [email protected] Donna E. Reece, MD Associate Professor of Medicine Department of Medical Oncology/Haematology Princess Margaret Hospital 610 University Avenue, Suite 5-207 Toronto, Ontario M5G2M9 Canada Telephone: 416-946-2253 Fax: 416-946-6546 E-mail: [email protected] Gustavo Milone, MD Angelica Ocampo-Hospital and Research Center-Fundaleu Uirburu 1450 Buenos Aires C1114AAN, Argentina Phone: 54-11-4807-1313 Fax: 54-11-4805-1703 E-mail: [email protected]

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1.0 OBJECTIVES

1.1 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.

1.2 To identify a graft-versus-myeloma effect after allogeneic stem cell transplantation for multiple myeloma by comparing myeloma recurrence rates in patients who underwent allogeneic transplantation after an autologous transplant failure with patients who underwent second autologous transplant after a previous autologous transplant failure.

2.0 SCIENTIFIC JUSTIFICATION:

Randomized studies have clearly established that autologous stem cell transplantation (ASCT) prolongs the survival of patients with multiple myeloma.1, 2 Based on these studies, most experts consider ASCT as part of the initial therapy of multiple myeloma. As a result of this approach, multiple myeloma has emerged as the most frequent indication for ASCT in North America.3 Unfortunately, most patients relapse after ASCT and succumb to the disease. For this reason, clinicians are faced increasingly with the decision as to the best therapeutic alternative for patients who experienced a relapse of the multiple myeloma after ASCT. Despite the availability of new therapeutic agents and the optimal use of combination chemotherapy, no therapy is considered curative and clinicians often consider several therapeutic alternatives after autologous transplant failure. Since many patients with multiple myeloma experience their longest remissions after ASCT, second autologous stem cell transplantation has been utilized after progression of the initial autologous transplant.4-5 Nevertheless, there is limited information regarding the outcome of second autologous transplants in this setting. One of the initial reports of this approach described a 72% 3-year survival after second autologous stem cell transplantation in patients with myeloma who relapsed or did not respond to a previous autologous stem cell transplant. The 1-year treatment-related mortality after a second autologous transplant was approximately 10%. A more recent report described 26 patients who underwent second autologous stem cell transplantation after progression of the previous autotransplant. Forty-two percent of the patients achieved a response (only one complete), and the event-free survival and overall survival were 9 months and 36 months, respectively. The transplant-related mortality in this study was 4%. Factors that predicted a superior survival included response to therapy to the first transplant and the length of time between autologous transplants. The authors concluded that second autologous transplantation was feasible for patients who relapse after a previous autologous transplant, particularly those with a prolonged remission after the first autotransplant. Another approach to treat patients who relapse after an autotransplant is to perform an allogeneic stem cell transplant. Advantages of allogeneic stem cell transplantation over autologous stem cell transplantation include a tumor-free allograft and a graft-versus-myeloma effect.6 Since myeloablative allogeneic stem cell transplantation is associated with a high transplant-related mortality, most reports of allogeneic transplants after autologous transplant failures consist of nonmyeloablative or reduced intensity conditioning regimens.7 The Seattle Group reported on 14 patients who underwent nonmyeloablative allogeneic stem cell transplantation after failing an autologous transplant. Although the follow-up was short, they predicted a 4-year 40% overall survival in these patients. The treatment-related mortality was 2% at day 100 and 17% overall. Einselle and colleagues reported on 22 patients who underwent nonmyeloablative allogeneic stem cell transplantation after failing an autotransplant.8 They estimated a 2-year overall and event-free survival of 25% and 22%, respectively, for the whole patient group, and 62.5% and 57.1% for

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patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation and absence of chronic graft-versus-host disease (cGVHD) were associated with shorter event-free survival. They concluded that long-term disease control can be achieved in this group of patients but that it was restricted to patients responding to prior salvage chemotherapy. A study by Gerull and coworkers published this year reported on 52 patients with relapsed multiple myeloma who underwent nonmyeloablative allogeneic transplantation.9 Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. With a median follow-up of 1.5 years, the transplant related mortality was 17%. The estimated progression-free and overall survival was 29.4% and 41.1%, respectively. Patients with cGVHD had a significantly higher progression-free survival as did patients with up to 8 cycles of chemotherapy. A recent study from the European Group for Blood and Marrow Transplantation described the outcome of patients with multiple myeloma who received reduced intensity conditioning regimens.10 Approximately 75% of these patients had a previous autologous transplant. Transplant-related mortality at 1 year was 22%. The 3-year overall survival and progression-free survival were 41% and 21%, respectively. Adverse overall survival was associated with chemoresistant disease, more than one prior transplantation, and male patients with female donors. The authors concluded that reduced intensity was feasible in this population of patients but that heavily pretreated patients and patients with progressive disease do not benefit from this approach. As illustrated by the above mentioned studies, there is limited and conflicting information regarding the outcome of patients who undergo second transplant procedures as salvage of autologous stem cell transplantation failures. Most studies report a small number of patients, and the results and transplant-related mortality vary widely from study to study. Clinicians are faced increasingly with the dilemma of the best transplant alternative for patients who relapse after autotransplantation as the number of patients transplanted for myeloma increase in number. The database of the Center for International Blood and Marrow Transplant Research (CIBMTR) is uniquely suited to allow a comparison between the different transplant modalities after autologous transplant failure. To date, the database has more than 200 patients who have undergone autologous, related or unrelated nonmyeloablative stem cell transplants as therapy for persistent or recurrent disease after an initial autologous transplant. We propose to compare the outcome of these approaches (autologous, related or unrelated nonmyeloablative stem cell transplantation) after autologous stem cell failure since this is a clinically important and frequently asked question. The paucity of studies of myeloablative allogeneic stem cell transplantation after autologous stem cell transplantation failure and the fact that less than 20 myeloablative transplants after autologous transplant failure have been reported to the CIBMTR precludes a reliable analysis of patients with multiple myeloma who underwent allogeneic stem cell transplantation after autotransplant failure. We also propose to exclude patients who undergo a planned nonmyeloablative transplant after autologous transplantation since this represents a different therapeutic strategy and a different clinical situation than performing transplants for salvage of autologous transplant failure.11-13

3.0 STUDY POPULATION: Patient eligibility/selection criteria include:

Patients who undergo a second autologous stem cell transplant related or unrelated nonmyeloablative transplantation as therapy for persistent or recurrent disease after autologous transplantation. Patients who undergo planned second autologous or allogeneic transplants will be excluded from the study. Potential numbers of subjects are given in Table 1.

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4.0 OUTCOMES:

4.1 Response rate after second transplant: to be assessed at 1 year. 4.2 Acute graft-versus-host disease: maximum overall grade, and occurrence of grade II, III

and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Glucksberg criteria of acute GVHD.

4.3 Chronic graft-versus-host disease: occurrence of symptoms in any organ system fulfilling

the criteria of chronic GVHD.

4.4 Treatment-related mortality: time to death occurring in continuous complete remission, partial response, minimal response or stable disease. This event is summarized by the cumulative incidence estimate with relapse as the competing risk.

4.5 Relapse/progression: time to first evidence of laboratory recurrence or progression of

myeloma according to the standard EBMT/IBMTR/ABMTR/ criteria. This event is summarized by the cumulative incidence estimate with treatment-related mortality as the competing risk.

4.6 Progression-free survival: survival without progressive disease or relapse from CR. Progressive disease, relapse from CR and death in remission are considered events.

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

4.7 Current-myeloma free survival: progression of multiple myeloma after second transplant. 4.8 Overall survival: Events are death by any cause. Surviving patients are censored at the

time of last contact.

5.0 VARIABLES TO BE ANALYZED:

Patient-related: - Age - Gender - Karnofsky performance score before the second transplant

Disease-related:

- Immunochemical subtype of myeloma: to be determined - Salmon-Durie stage at diagnosis: I vs. II vs. III - Albumin prior to transplant:


- Interval from diagnosis to first, autologous transplantation - Interval from first transplant to progression - Interval from first to second transplant - Source of stem cell: BM vs. PBSC - Year of transplant - GVHD prohylaxis - Maintenance therapy: yes/no - DLI given: yes/no, number of DLI, dose of T-cells, cyclosporine/cyclosporine +

MTX/cyclosporine + MMF 6.0 STUDY DESIGN:

Patient-, disease- and treatment-related factors will be compared between the two transplants groups, using Chi-square test for categorical and Mann-Whitney test for continuous variables. Probabilities of survival and progression-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints included in Sec. 4.0 will be generated using cumulative incidence estimates.14 Comparison of survival curves will be done using the log-rank test. The transplant groups will be compared using proportional hazards regression models. Individual models will be build for each cohort separately using the outcomes of interest (Section 4.0) as dependent variables and all the relevant exposure variables (Section 6) as explanatory variables. This initial modeling will identify variables requiring adjustment for each transplant group to assure that the comparisons made in the later stages are not confounded by other factors. The proportional hazards assumptions for all the variables will be examined using time-varying covariate and graphical approaches. Construction of stratified proportional hazards model or time-dependent covariates shall be the alternative procedure whenever non-proportional variables are identified. After the exploratory phase described above and using the explanatory variables identified to be related to outcome, models that directly compare the two types of transplant groups will be built. One step in this process is to determine if the effect of a given factor is the same for both types of transplants. This will be examined by fitting a proportional hazards model, stratified on transplant type, and examining the interaction between the factor of interest and the type of transplant. If the interaction term is significant, then the final model will have an interaction term between the factor and type of transplant and separate inferences about the effect of transplant type will be made for each level of the confounding factor. The final model constructed by this technique will include all the factors found plus a term for transplant type. The proportional hazards assumption will again be examined, and should it be found that the hazards are non-proportional for the effect of interest, the best fitting model with time-varying risk coefficients will be found. Here the best cut-off point between early and late effects is found by finding the model that yields the largest partial likelihood. SAS programs will be used in all the analyses.

19


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(19):1875-83.

3. Hari P, Pasquini MC, Vesole DH: Cure of multiple myeloma - more hype, less reality. Bone Marrow Transplant 2006; 37: 1-18.

4. Mehta J, Tricot G, Jagannath S et al: Salvage autologous or allogeneic transplantation for multiple myeloma refractory or relapsing after a first line autograft? Bone Marrow Transplant. 1998; 21:887-892.

5. Olin RE, Porter DL, Luger SM et al: Second autologous stem cell transplant (ASCT) as salvage therapy for relapsed multiple myeloma. Blood 2005; 106:342a.

6. Tricot G, Vesole DH, Jagannath S et al: Graft-versus-myeloma effect: proof of principle. Blood. 1996; 87:1196-1198.

7. Storb R: From myeloablative to nonmyeloablative conditioning regimens in multiple myeloma. In Boccadero M, Pileri A (eds.) Multiple Myeloma 2004. Turin, Italy, 2004, p. 148.

8. Einsele H, Schafer HJ, Hebart H et al: Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121:411-418.

9. Gerull S, Goerner M, Benner A et al: Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36: 963-969.

10. Crawley C, Lalancette M, Szydlo R: Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 2005; 105:4532-4539.

11. Giralt S, Estey E, Albitar M et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89:4531-4536.

12. Nicolaus Kröger, Rainer Schwerdtfeger, Michael Kiehl et al: Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100: 755-760.

13. Maloney DG, Molina AJ, Sahebi F et al: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447-3454.

14. Cox RD. Regression analysis and life tables. J of Royal Statist Soc 1972; B 34:187-220.

20


Table 1. Characteristics of patients, who underwent second autologous, related or unrelated nonmyeloablative transplantation as therapy for persistent or recurrent disease after autologous transplantation up to 2005

Variables

Autologous N (%)

HLA-identical N (%)

URD N (%)

Number of patients 112 62 122†Number of centers 50 37 52Age at 2nd transplant, median (range),years 56 (28-74) 51 (33-66) 53 (32-69)Age at 2nd transplant, years 20-29 y 2 ( 2) 0 0 30-39 y 3 ( 3) 6 (10) 9 ( 7) 40-49 y 27 (24) 23 (37) 38 (31) 50-59 y 41 (37) 25 (40) 56 (46) 60-69 y 35 (30) 8 (13) 19 (16) ≥70 y 4 ( 4) 0 0Male sex 68 (61) 37 (60) 75 (61) Missing 1 0 0Karnofsky score pre-transplant


Table 1. Continued. Variables

Autologous N (%)

HLA-identical N (%)

URD N (%)

Percent of plasma cell prior to transplant 7 (


Table 1. Continued. Variable

Autologous N (%)

HLA-identical N (%)

URD N (%)

Graft type Bone marrow 2 ( 2) 1 ( 2) 35 (29) Peripheral blood ± bone marrow 110 (98) 61 (98) 87 (71)Year of transplant ≤ 1996 6 ( 6) 0 0 1997-1998 5 ( 4) 2 ( 3) 3 ( 2) 1999-2000 12 (11) 8 (13) 21 (17) 2001-2002 24 (21) 22 (36) 31 (26) 2003-2004 38 (34) 25 (40) 39 (32) 2005 27 (24) 5 (8) 28 (23)GVHD prophylaxis NA FK506+MTX ± other 16 (26) 24 (20) FK506 ± other 3 ( 5) 27 (22) MTX+CSA ± other 11 (17) 10 ( 8) CSA ± other 28 (45) 54 (44) T-cell depletion 1 ( 2) 4 ( 3) Other 1 ( 2) 1 ( 1) None/missing 2 ( 3) 2 ( 2)Maintenance therapy No 45 (40) 36 (58) 8 ( 7) Yes 67 (60) 25 (40) 1 ( 1) Missing 0 1 ( 2) 113 (92) Median (range) follow-up of survivors, months

42 (4-88)

45 (3-73)

56 (


MEMORANDUM TO: Writing Committee for Study MM02-03/MM03-01 FROM: Olle Ringdén, MD, PhD, Smriti Shrestha, MS, and Parameswaran N. Hari, MD, MS DATE: XXXX, 2009 RE: Study #MM02-03/MM03-01: The Graft-versus-Myeloma Effect in Patients Receiving

Non-Myeloablative Conditioning

Enclosed is a description of the patient population and results of univariate analysis describing the outcomes of patients who undergoing HLA identical sibling bone marrow and/or peripheral blood transplants for Multiple Myeloma (MM) receiving a nonmyeloablative conditioning transplant within 18 months of diagnosis, between 1997 and 2005. Eligible cases came from 69 centers. Nonmyeloablative and reduced intensity conditioning allogeneic HCT have been introduced for patients with MM because of a presumed graft versus myeloma effect potentially resulting in improved disease free and overall survival. It is important to determine whether the graft versus myeloma effect is clinically significant leading to improved disease free and overall survival for patients with MM. The main objective of the study is to identify a graft versus myeloma effect after allogeneic transplant for MM by comparing myeloma recurrence in patients with and without acute and/or chronic graft versus host disease (GVHD) after nonmyeloablative/reduced intensity conditioning transplants and to determine the competing effects of GVHD and relapse on disease free survival in these patient groups. Probabilities of progression-free survival and overall survival were calculated using the Kaplan-Meier estimator; GVHD, transplant-related mortality and relapse/progression were calculated using cumulative incidence estimates. Table 1 shows the patient, disease and transplant characteristics by transplant type. Table 2 shows univariate analyses of the outcomes of interests by transplant type. Multivariate analyses will be performed using Cox proportional hazards models. These analyses treat GVHD as a time dependent covariate (patient having GVHD will be considered only if current study time is greater than his/her on set time of GVHD). Patients belonging to the GVHD group depend on the current study time. It will be considered as the main effect. A stepwise model building approach will be used to identify the significant risk factors associated with the outcomes of relapse, treatment-related mortality, progression-free survival and overall survival. Table 3 shows all the variables that will be considered in the multivariate analysis.

24


Please review this summary critically and send your comments to: Olle Ringdén, MD, PhD, Department of Clinical Immunology, F79, Huddinge University Hospital B56, Karolinska Institute, Huddinge, Sweden 14186, Telephone: 46-8-558-2672, Fax 46-8-746-6699, Email: [email protected] with a copy to via Fax or E-mail to Smriti Shrestha, MS at the CIBMTR via E-mail: [email protected] or Fax: (414-805-0714) by XXXX, 2009 and copies will be forwarded to the study chairs. You should note that any member of a Writing Committee who does not make a substantive contribution to the design, analysis, interpretation or manuscript would be expected to withdraw as a co-author or, alternatively, the lead author could remove names of non-contributors. If we do not hear from you by XXXX, 2009 we may assume you no longer wish to participate in the study. Enclosures

25


Table 1. Characteristics of patients transplanted within 18 months of diagnosis from HLA-identical sibling donor receiving non-myeloablative transplant between 1997 and 2005 by transplant type, reported to the CIBMTR

First allo Auto + AlloVariables N (%) N (%)Patient- related Number of patients 72 105 Number of centres 43 35 Age, median (range), years 49 (24 - 66) 50 (24 - 69) Age at transplant, years 20 – 29 years 2 ( 3) 1 ( 1) 30 – 39 years 8 (11) 11 (10) 40 – 49 years 32 (44) 33 (31) 50 – 60 years 22 (31) 46 (44) >60 years 8 (11) 14 (13) Male sex 44 (61) 58 (55) Karnofsky score at transplant


Table 1. Continued. First allo Auto + AlloVariables N (%) N (%)β2-microglobulin level at diagnosis


Table 1. Continued. First allo Auto + AlloVariables N (%) N (%)Transplant-related Conditioning regimen TBI


Table 1. Continued. First allo Auto + AlloVariables N (%) N (%)Year of transplant 1997 3 ( 4) 0 1998 1 ( 1) 0 1999 1 ( 1) 1 ( 1) 2000 13 (18) 4 ( 4) 2001 21 (29) 7 ( 6) 2002 15 (21) 9 ( 9) 2003 10 (14) 8 ( 8) 2004 4 ( 6) 40 (38) 2005 4 ( 6) 36 (34) Median (range) follow-up of survivors, months 55 (3 - 98) 25 (3 - 76)Abbreviations: CR = complete remission; PR = partial response; MR = minimal response; SD = stable disease; NST = non-myeloablative transplant; TBI = total body irradiation; CsA = cyclosporine; MTX = methotrexate; FK506 = tacrolimus; MMF = mycophenolate.

Note: Patients with auto + not planned allo transplants were excluded from the study (N=16).

29


Table 2. Univariate analyses among patients transplanted within 18 months of diagnosis from HLA-identical sibling donor receiving non-myeloablative transplant between 1997 and 2005 by transplant type, reported to the CIBMTR.

First allo Auto + Allo Outcomes

N Eval Probability (95% CI)

N Eval Probability (95% CI)

Maximum overall Acute GVHD grade, N (%)

0 34 (47) 58 (55) I 16 (22) 16 (15) II 11 (15) 16 (15) III 10 (14) 13 (13) IV 1 ( 2) 2 ( 2) Acute GVHD (grade I –IV) @ 100 days 72 47 (37 - 60) 105 37 (28 - 46) Chronic GVHD 72 104 @ 1 yr 45 (34 - 57) 44 (35 - 54) @ 3 yrs 55 (43 - 67) 58 (43 - 72) @ 5 yrs 59 (46 - 71) 58 (43 - 72) Any GVHD 72 105 @ 100 days 49 (37 - 60) 40 (31 - 49) @ 1 yr 67 (56 - 77) 67 (57 - 76) @ 3 yrs 69 (58 - 79) 73 (64 - 81) @ 5 yrs 72 (60 - 82) 73 (64 - 81) 100-Day mortality 72 14 (7 - 23) 105 5 (2 - 10) Treatment related mortality 72 105 @ 1 yr 20 (12 - 30) 11 (5 - 17) @ 3 yrs 27 (17 - 38) 16 (10 - 25) @ 5 yrs 29 (19 - 41) 23 (11 - 37) Relapse/Progression 72 105 @ 1 yr 32 (21 - 43) 15 (8 - 22) @ 3 yrs 48 (36 - 60) 41 (29 - 54) @ 5 yrs 54 (41 - 67) 53 (32 - 74) Progression free survival 72 105 @ 1 yr 48 (36 - 60) 74 (66 - 83) @ 3 yrs 25 (15 - 37) 42 (20 - 43) @ 5 yrs 17 (7 - 29) 24 (7 - 48) Overall survival 72 105 @ 1 yr 62 (50 - 73) 84 (77 - 91) @ 3 yrs 45 (33 - 58) 64 (53 - 75) @ 5 yrs 27 (15 - 41) 58 (42 - 73)

30


Table 3. Variables for the multivariate analysis: Main Effect: Acute GVHD as the time dependent covariate and Chronic GVHD as the time dependent covariate Patient Related: Age at transplant: continuous Gender: male* vs. female Karnofsky performance prior to transplant: 2 lines vs. missing Type of transplant: First allo* vs. Auto+Allo Transplant Related: Donor-recipient sex match: M-M* vs. M-F vs. F-M vs. F-F Year of transplant: ≤2001* vs. >2001

31


ASH 2008 Outcome of Patients with IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplants: A Retrospective CIBMTR Study: Donna Reece, David H. Vesole, Smriti Shrestha, Angela Dispenzieri, Gustavo Milone, Waleska S. Pérez, Mei-Jie Zhang and Parameswaran Hari on behalf of the Plasma Cell Disorders Writing Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995-2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2-130) months for pts with IgD and 58 (range 5-101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was single-agent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period.

Outcomes, probability (95% CI) IgD (36) IgM (11) IgG/IgA (1475)100-day mortality, % 0 9 ( 0 - 32) 7 (5 - 8)Non MM deaths, % @ 1 yr 0 9 (0 - 32) 5 (4 - 7) @ 3 yrs 3 (0 - 13) 21 (2 - 51) 16 (14 - 18)Relapse/ Progression, % @ 1 yr 21 (9 - 37) 20 (2 - 49) 18 (16 - 20) @ 3 yrs 59 (41 - 76) 32 (8 - 64) 36 (34 - 39)Progression-free survival, % @ 1 yr 79 (63 - 91) 71 (41 - 93) 77 (74 - 79) @ 3 yrs 38 (21 - 56) 47 (17 - 78) 47 (44 - 50)Overall survival, % @ 1 yr 87 (74 - 97) 91 (68 - 100) 79 (77 - 85) @ 3 yrs 69 (51 - 84) 68 (36 - 93) 53 (50 - 57) No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD / IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115-7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51-4).

32


ASH 2008 Effect of Obesity on Outcomes after Autologous Hematopoietic Stem Cell Transplantation (Auto HCT) for Multiple Myeloma (MM): An Analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR): Dan T. Vogl, Waleska S. Pérez, Tao Wang, Edward A. Stadtmauer, Angela Dispenzieri, Gustavo Milone, Donna Reece and Parameswaran Hari on behalf of the Plasma Cell Disorders Working Committee, CIBMTR, Milwaukee, WI, USA. Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5-24.9), overweight (25-29.9), obese (30-34.9), or severely obese (≥35). Underweight patients (BMI


doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation.

Probability of PFSProbability of PFS

Years0 1 2 543

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Figure 2. Melphalan alone

Years0 1 2 543

Figure 1. Melphalan/TBI

Overweight

Normal

Obese

Severely obese

Overweight

Normal

Obese

Severely obese

34


ASH 2008 Similar Outcomes among African-Americans (AA) and Whites after Autologous Hematopoietic-cell transplantation (Auto HCT) for Multiple Myeloma (MM): Parameswaran Hari, Navneet Majhail, Anna Hassebroek, Mei-Jie Zhang, Fareeha Siddiqui, Paulette Mehta for the Health Policy and Plasma Cell Disorders Working Committees of the Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, MN, USA. MM is the most common hematological malignancy among AA adults and AA have twice the incidence and mortality from MM compared to Whites (SEER data, 2007). Based on CIBMTR registration rates of Auto HCT and incidence rates for MM, AA patients have been shown to have significantly lower likelihood of receiving Auto HCT (age adjusted odds ratio 0.58) compared to White patients with MM. The characteristics of AA patients who undergo Auto HCT for MM and their post transplant outcomes have not been compared to that of White MM patients. We compared characteristics and post-transplant outcomes of AA (N=303) and White (N=1892) patients receiving a first Auto HCT for MM and reporting to the CIBMTR between 1995 and 2005. Recipients of tandem Auto HCT were excluded. Compared to Whites, AA were significantly younger (29% aged


CIBMTR MM06-04

IMPACT OF PRE-TRANSPLANT THERAPY AND DEPTH OF DISEASE RESPONSE PRIOR TO AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION IN

MULTIPLE MYELOMA

DRAFT REVISED PROTOCOL

Study Co-chair: Ravi Vij, MD Assistant Professor

Section of BMT and Leukemia, Campus Box 8007 Washington University School of Medicine 660 S Euclid Ave, St Louis, MO 63110 Telephone: 314-454-8323 Fax: 314-454-7551 E-mail: [email protected]

Shaji Kumar, MD Division of Hematology Mayo Clinic 200 First St SW Rochester, MN

Telephone: 507-284-2176 Fax: 507-266-4972

E-mail: [email protected] Donna E. Reece, MD Associate Professor of Medicine

Princess Margaret Hospital 910 University Avenue Toronto, ON M5G 2M9 Telephone: 416-946-2824 Fax: 416-946-6546 E-mail: [email protected]

36


Study Statistician: Min Chen, MS CIBMTR

9200 West Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-0710 Fax: 414-805-0647 E-mail: [email protected]

Scientific Director: Parameswaran Hari, MD Assistant Professor Division of Neoplastic Diseases and Related Disorders Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53266 Telephone: 414-805-4604 Fax: 414-805-4606 E-mail: [email protected]

Working Committee Chairs: Angela Dispenzieri, MD Associate Professor of Medicine Mayo Clinic Transplant Center Rochester, Minnesota Telephone: 507-284-2479 Fax: 507-266-4972 E-mail: [email protected] Donna E. Reece, MD Associate Professor of Medicine Department of Medical Oncology/Haematology Princess Margaret Hospital 610 University Avenue, Suite 5-207 Toronto, Ontario M5G2M9 Canada Telephone: 416-946-2253 Fax: 416-946-6546 E-mail: [email protected] Gustavo Milone, MD Angelica Ocampo-Hospital and Research Center-Fundaleu Uirburu 1450 Buenos Aires C1114AAN, Argentina Phone: 54-11-4807-1313 Fax: 54-11-4805-1703 E-mail: [email protected]

37


1.0 OBJECTIVES:

1.1 Examine the relationship between disease status at transplant (responsive, progression after initial response, primary refractory) and outcomes after stem cell transplantation (response, progression free survival and overall survival).

1.2 To compare the response rates, disease free survival and overall survival of patients achieving less than a Partial Response to initial chemotherapy compared with those receiving additional salvage chemotherapy prior to undergoing autologous stem cell transplantation.

1.3 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.

1.4 Finally, 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.


High dose chemotherapy with autologous stem cell transplantation has been shown to improve both overall and disease free survival in large randomized clinical trials. In these trials patients were randomized to HDCT or conventional therapy as long as they did not have evidence of disease progression after a few cycles of induction chemotherapy.[1,2] Unfortunately, the optimal time to transplant patients with responsive disease based on the level of disease response is still not known. On one hand there is data to suggest that patients with a lower paraprotein nadir pre-transplant after a finite period of therapy have better outcomes. On the other hand, small single center experiences suggest that even patients with disease progression after initial chemotherapy benefit by high dose chemotherapy.[3,4,5] Therefore, it is unclear whether patients with less than an optimalresponse after a finite period of initial therapy should be taken to transplant immediately or be switched to a salvage regimen to improve the level of response. The achievement of a complete remission (CR) after ASCT has been the best surrogate for long-term disease control and improved survival in these patients. However, it is not clear if patients who are in a CR at the time of transplant have better survival compared to those who obtain a CR after ASCT. Moreover, little is known about the effect of the new response category “very good partial remission” (VGPR = 90% reduction in serum monoclonal protein) or other degrees of protein response before ASCT on the post-transplant outcome. The CIBMTR database offers the possibility of examining these questions. Also, in this study we seek to compare the response rates, disease free survival and overall survival of patients undergoing autologous transplantation after achieving less than a partial response to initial chemotherapy with those receiving additional salvage chemotherapy prior to undergoing autologous stem cell transplantation. We will also attempt to define a target pre-transplant “threshold” paraprotein to determine appropriate timing for stem cell transplantation based on a large cohort of patients reported to the IBMTR.

3.0 STUDY POPULATION:

Patient eligibility/selection criteria include:

All patients ≥18 years of age undergoing autologous stem cell transplantation for MM and reported to the IBMTR/ABMTR between 1995 and 2001 will be eligible. Patients with plasma cell leukemia will be excluded.

38


The analysis will be restricted to patients undergoing auto SCT within 12 months of their diagnosis. Additional analysis will be performed within this group among patients who have had


− Ist line − Salvage chemotherapy

Transplant characteristics

− BM vs. SCT − Conditioning regimens

6.0 STUDY DESIGN:

This will be a retrospective analysis of prospectively collected data. All the above information is prospectively collected on Reporting Forms and available in the database. Data will be analyzed to evaluate for correlations outlined in the Specific aims.

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. Probabilities of survival and progression-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Multivariate analyses will be performed using Cox proportional hazards models.

7.0 REFERENCES:

1. Attal, M., J. L. Harousseau, et al. (1996). "A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome." N Engl J Med 335(2): 91-7.

2. Child, J. A., G. J. Morgan, et al. (2003). "High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma." N Engl J Med 348(19): 1875-83.

3. Alexanian, R., D. Weber, et al. (2004). "Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma." Bone Marrow Transplant 34(3): 229-34.

4. Kumar, S., M. Q. Lacy, et al. (2004). "High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy." Bone Marrow Transplant 34(2): 161-7.

5. Singhal, S., R. Powles, et al. (2002). "Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma." Bone Marrow Transplant 30(10): 673-9.

40


Table 1. Characteristics of patients ≥18 years of age who underwent autologous transplants for Multiple Myeloma within 12 months of diagnosis, reported to CIBMTR 1995-2004

Variables One line > one lines UnknownNumber of patients 1584 716 31Number of centers 165 132 22Gender

Male 952 (60) 428 (60) 19 (61)Female 632 (40) 288 (40) 12 (39)

Age, median(range), years 56 (23 - 80) 56 (22 - 75) 51 (35 - 69)Age at transplant, years

18-30 9 ( 1) 4 ( 1) 30-39 75 ( 5) 35 ( 5) 2 ( 6)40-49 323 (20) 143 (20) 11 (35)50-59 651 (41) 275 (38) 11 (35)60-69 475 (30) 224 (31) 7 (23)≥70 51 ( 3) 35 ( 5) 0

Karnofsky score pre- transplant


Variables One line > one lines UnknownHemoglobin at diagnosis, g/dL

2 226 (14) 103 (14) 2 ( 6)Missing 292 (18) 157 (22) 6 (19)

Beta-2-microglobulin level at diagnosis, mg/L 10.5 mg/dL 247 (16) 113 (16) 1 (3)≤10.5 mg/dL 1014 (64) 439 (61) 24 (77)Missing 323 (20) 164 (23) 6 (19)

Plasma cells in bone marrow at diagnosis, median(range) 46 (0 - 100) 50 (0 - 100) 48 (0 - 100)Missing 862 (54) 411 (57) 17 (55)

Serum monoclonal Ig at diagnosis, , median(range), g/dL 3 (0 - 14) 3 (0 - 13) 1 (0 - 13)Serum monoclonal Ig at diagnosis, g/dL


Variables One line > one lines UnknownDisease status prior to transplant

Complete remission 319 (20) 107 (15) 0Partial remission 877 (55) 390 (54) 0Minimal response 106 ( 7) 52 ( 7) 9 (29)No response/Stable disease 168 (11) 89 (12) 19 (61)Relapse 4 (


Variables One line > one lines UnknownTotal number of transplants

1 1229 (78) 534 (75) 25 (81)2 328 (21) 169 (24) 6 (19)> 2 27 ( 2) 13 ( 2) 0

Year of transplant 1995-1996 128 ( 8) 58 ( 8) 5 (16)1997-1998 298 (19) 90 (13) 8 (26)1999-2000 305 (19) 133 (19) 10 (32)2001-2002 444 (28) 209 (29) 6 (19)2003-2004 409 (26) 226 (32) 2 ( 6)

Median follow-up of survivors, (range) months 57 (


CIBMTR MM08-01

EXAMINATION OF TIME TRENDS IN ALLOGENEIC STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA: PATIENT DEMOGRAPHICS, DISEASE CHARACTERISTICS

AND SURVIVAL

DRAFT PROTOCOL Study Chair: Shaji Kumar, MD Division of Hematology Mayo Clinic 200 First St SW Rochester, MN Telephone: 507- 284-2176 Fax: 507-266-4972 E-mail: [email protected] Study Statistician: Smriti Shrestha, MS

CIBMTR 9200 West Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-0647 Fax: 414-805-0714 E-mail: [email protected] Scientific Director: Parameswaran Hari, MD, MS

Assistant Professor Division of Neoplastic Diseases and Related Disorders Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53266 Telephone: 414-805-4604 Fax: 414-805-4606 E-mail: [email protected]

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Working Committee Chairs: Angela Dispenzieri, MD Associate Professor of Medicine Mayo Clinic Transplant Center Rochester, Minnesota Telephone: 507-284-2479 Fax: 507-266-4972

E-mail: [email protected] Donna E. Reece, MD Associate Professor of Medicine Department of Medical Oncology/Haematology Princess Margaret Hospital 610 University Avenue, Suite 5-207 Toronto, Ontario M5G2M9 Canada Telephone: 416-946-2253 Fax: 416-946-6546 E-mail: [email protected] Gustavo Milone, MD Angelica Ocampo-Hospital and Research Center-Fundaleu Uirburu 1450 Buenos Aires C1114AAN, Argentina Phone: 54-11-4807-1313 Fax: 54-11-4805-1703 E-mail: [email protected]

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1.0 OBJECTIVES:

1.1 Examine the demographics of patients undergoing allogeneic stem cell transplantation for myeloma and the trends over time.

1.2 Examine the changes over time in the disease characteristics among patients undergoing allogeneic stem cell transplantation for myeloma. 1.2.1 Time to allogeneic HCT from diagnosis 1.2.2 Number of therapies prior to allogeneic HCT 1.2.3 ISS stage, cytogenetic abnormalities 1.2.4 Planned auto HCT followed by allogeneic HCT 1.2.5 Myeloablative vs. non-myeloablative, condition regimens employed 1.2.6 GVHD prophylaxis regimens 1.2.7 Use of DLI 1.2.8 Planned maintenance therapies

1.3 Examine the rates of GVHD, TRM, disease free and overall survival among patients undergoing allogeneic HCT for myeloma.


There has been limited success with allogeneic stem cell transplant (AlloHCT) for treatment of myeloma, largely a result of high treatment related toxicity in this patient population. This along with the paucity of well designed randomized trials precludes development of firm recommendation regarding the optimal use of this modality and should primarily be considered in the context of clinical trials. There is little doubt that a graft versus myeloma effect exists and is obvious from the higher rate of molecular responses following alloHCT compared to autoHCT which in turn translates into longer remissions.1 In a study using PCR based assessment of clonal markers half of those undergoing alloHCT achieved a molecular CR compared to 16% of autoHCT and had a significantly lower relapse rate and longer PFS (35 vs. 110 months).2 Most of the initial reports on the utility of allogeneic approaches have come from small studies or from transplant registries (Table 3).3-6 The recent trials have attempted to compare the allogeneic approach with AHCT, with enrichment for patients with high risk disease. Data from the EBMTR suggests that the TRM with allogeneic transplant fell from 46% at 2 years for transplants done 1983-1993 to 30% for that done 1994-19987. Non-myeloablative or reduced intensity conditioning alloHCT relies primarily on the immunological effects of the graft with the conditioning chemotherapy primarily facilitating engraftment. 8-10 The prospective trials of reduced intensity conditioning regimen trials show a trend towards reduced mortality. 11,12 AutoHCT remains the standard of care for patients with multiple myeloma who are eligible for the procedure. Initial studies of autoHCT were confined to younger patients, based on the results of randomized trials. Meanwhile alloHCT has been used very sparingly in the setting of myeloma, partly due to high treatment related mortality seen historically. More recently, there has been an increased interest in the role of allogeneic stem cell transplantation partly due to incurable nature of the other available therapies, ability to determine patients with high risk myeloma who would do poorly with autologous HCT, improved supportive care related to allogeneic stem cell transplant and finally the increasing experience with non-myeloablative transplantation. This is highlighted by the recently completed CTN trial as well as the recent results form the Italian trial that demonstrated a survival advantage for alloHCT. Clearly these could have led to significant trends in the demographics of patients going to alloHCT as well as the disease characteristics of those who proceed to an alloHCT. The CIBMTR data set offers a unique resource to examine these trends.

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3.0 STUDY POPULATION:

Patient eligibility/selection criteria include: Patients undergoing allogeneic transplantation for Multiple Myeloma between 1989 and 2005 reported to the CIBMTR. Potential numbers of subjects are given in Table 1.

4.0 OUTCOMES:

The aim is to assess the time trends of the following baseline features and transplant outcomes. 4.1 Demographic characteristics: time trends 4.2 Baseline clinical features: time trends 4.3 Treatment-related mortality: time to death occurring in continuous complete remission,

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

4.4 Progression-free survival: survival without progressive disease or relapse from CR.

Progressive disease, relapse from CR and death in remission are considered events. Patients who are alive and in complete remission, partial response, minimal response or stable disease are censored at time of last follow-up

4.5 Overall survival: events are death by any cause. Surviving patients are censored at the time

of last contact 5.0 VARIABLES TO BE DESCRIBED:

Patient-related: - Age: continuous - Gender: male vs female - Karnofsky performance status prior to transplant: upper limit of normal - B2-microglobulin level at diagnosis: ≤3 mg/L vs >3 mg/L - Lytic bone lesions: yes/no - Bone marrow plasma cell percentage at diagnosis: continuous - Interval from diagnosis to first chemotherapy: continuous - Number of prior chemotherapy regimens: ≤1 vs 2 vs >2 - Best response to last prior treatment: CR vs PR vs MR/SD vs progressive - Radiation prior to transplant: yes/no - Chemosensitive disease prior to transplant: yes/no - Disease status prior to conditioning: CR vs PR vs MR/SD vs progressive - Albumin prior to transplant: continuous - LDH prior to transplant: ≤ vs > upper limit of normal - B2-microglobulin level prior to transplant: continuous - Cytogenetics at anytime prior to transplant: normal vs abnormal - Bone marrow plasma cell percentage prior to transplant: continuous

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Transplant-related:

- Interval from diagnosis to transplant: continuous - Interval from last chemo to transplant: continuous - Previous autologous HCT: yes/No - Date of previous autologous HCT: continuous - Source of stem cells: BM vs PBSC - Donor: Related/ unrelated - Donor Age: continuous - Number of cells infused: continuous - Ex vivo manipulation of graft: yes/no - Conditioning regimen: melphalan alone vs melphalan+TBI± other vs melphalan± other (not

TBI) vs TBI ± other (not melphalan) vs others - Year of transplant - Post transplant maintenance: yes/no

6.0 VARIABLES TO BE ANALYZED:

- Age at transplant - Karnofsky performance status prior to transplant: 2 - Time from diagnosis to transplant: continuous - Disease status prior to conditioning: CR vs PR vs MR/SD vs progressive vs other - Conditioning regimen: melphalan alone vs melphalan+TBI± other vs melphalan± other (not

TBI) vs TBI ± other (not melphalan) vs others - Related vs. unrelated donor - Prior autologous HCT - Time between autologous HCT and allo HCT - Post transplant maintenance: yes/no - Year of transplant - Donor lymphocyte infusion used

7.0 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 (9). 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 6.0) 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.

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8.0 REFERENCES:

1. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood. 1996;87:1196-1198.

2. Martinelli G, Terragna C, Zamagni E, et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma. J Clin Oncol. 2000;18:2273-2281.

3. Arora M, McGlave PB, Burns LJ, et al. Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant. 2005;35:1133-1140.

4. Bjorkstrand BB, Ljungman P, Svensson H, 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;88:4711-4718.

5. Alyea E, Weller E, Schlossman R, et al. Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: impact of graft-versus-myeloma effect. Bone Marrow Transplant. 2003;32:1145-1151.

6. Kuruvilla J, Shepherd JD, Sutherland HJ, et al. Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biology of blood and marrow transplantation. 2007;13:925-931.

7. 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.

8. Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood. 2005;105:4532-4539.

9. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003;102:3447-3454.

10. Kroger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood. 2002;100:755-760.

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. 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.

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Table1. Characteristics of patients who underwent allogeneic transplants for Multiple Myeloma between 1989 and 2005 by year of transplant, reported to the CIBMTR

1989-1994 1995-1999 2000-2005 Variables N (%) N (%) N (%) Patient-Characteristics Number of patients 355 315 640 Number of centers 86 90 132 Age at transplant, years Median (range) 44 (24 - 59) 46 (22 - 62) 51 (24 - 70) 20-29 9 ( 3) 8 ( 3) 5 ( 1) 30-39 93 (26) 52 (16) 68 (11) 40-49 211 (59) 159 (50) 231 (36) 50-59 42 (12) 93 (30) 256 (40) 60-69 -- 3 ( 1) 80 (12) Male sex 203 (57) 202 (64) 388 (60) Karnofsky score pre-transplant


Table 1. Continued. 1990-1994 1995-1999 2000-2005 Variables N (%) N (%) N (%) LDH prior transplant Below normal 19 ( 5) 141 (45) 256 (40) Above normal 3 ( 1) 39 (12) 62 (10) Missing 333 (94) 135 (43) 322 (50) β2-microglobulin level prior transplant ≤3.5 mg/L 171 (48) 111 (35) 237 (37) >3.5 mg/L 44 (12) 53 (17) 175 (27) Missing 140 (40) 151 (48) 228 (36) Plasma cell count in bone marrow prior tx 10 (


Table 1. Continued. 1990-1994 1995-1999 2000-2005 Variables N (%) N (%) N (%) Number of treatments prior transplant ≤1 10 ( 3) 64 (20) 88 (14) 2 10 ( 3) 93 (30) 102 (16) >2 13 ( 4) 89 (28) 212 (33) Missing 322 (90) 69 (22) 238 (37) Time from last chemotherapy to transplant 163 (1 - 793) 173 (11 - 2051) 184 (3 - 1807) Missing 327 94 300 Prior auto transplant Yes 6 ( 2) 28 ( 9) 222 (35) No 337 (95) 211 (67) 212 (33) Unknown 12 ( 3) 76 (24) 206 (32) Graft type Bone marrow (BM) 352 (99) 189 (60) 78 (12) Peripheral blood stem cell ± BM 3 ( 1) 126 (42) 562 (88) Type of donor HLA identical 324 (91) 229 (73) 414 (65) Other related 12 ( 3) 18 ( 6) 13 ( 2) Unrelated donor 16 ( 4) 68 (21) 211 (33) Missing 3 ( 1) 0 2 (


Table 1. Continued. 1990-1994 1995-1999 2000-2005 Variables N (%) N (%) N (%) GVHD prophylaxis CsA ± other (not MTX) 47 (13) 58 (19) 59 ( 9) MTX± other (not CsA) 4 ( 1) 4 ( 1) 3 (


ASH 2008 HLA Specificities and Predisposition to the Development of Multiple Myeloma (MM): Meral Beksac, Martin Maiers, Loren Gragert, Stephen Spellman, Smriti Shrestha, Mei-Jie Zhang, Angela Dispenzieri, Donna Reece, David H. Vesole and Parameswaran Hari on behalf of the Plasma Cell Disorders Writing Committee, Center for Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Background: HLA associations for the risk of developing MM have been described in various non-Caucasian ethnic groups but have not revealed consistent results. Racial and genetic differences in cytokine polymorphisms linked to extended haplotypes; association of autoimmune disorders with HLA types; the proximity of the HLA Class I and II genes to TNF and other Class III genes responsible for complement and cytokines suggest that HLA polymorphisms may be associated with the risk of developing MM. Aim: We compared 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. Methods: A cohort of 1803 US Caucasian patients with MM were identified based on availability of HLA-A, B, DRB1 DNA-based typing or serologic typing converted to 2-digit alleles. These patients had either received a matched sibling allogeneic transplant for MM reported to the CIBMTR (N=174) or had HLA typing performed for an unrelated donor search conducted through the US National Marrow Donor Program (NMDP) (N=1629). HLA-A, B and DRB1 allele frequencies among patients were compared to A-B-DRB1 frequencies in HLA typed healthy US Caucasian controls (N= 433838) from the NMDP database. The most frequent alleles among patients and controls as well as HLA haplotype frequencies generated using the EM (expectation-maximization) algorithm were compared using Chi-Square analysis with Bonferroni correction for the number of comparisons. Results: Patients with MM had a median age of 49 (range 3-78) years and M/F ratio of 1.86 (1172/631). The controls had a median age of 44 (range 18-60) years and M/F ratio of 0.735 (183785 / 250053). Comparison of HLA-A, -B and –DRB1 single-locus allele frequencies between the myeloma patients and controls (those in the top 10 in either group) revealed similarity except for HLA-B*07 and

a g e n d a cibmtr working committee for plasma cell … · 2013. 12. 23. · mm02-03/mm03-01 graft...

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