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Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS AND ADULT SOLID TUMORS Orlando, Florida Wednesday, February 22, 2017, 12:15 – 2:15 pm

Co-Chair: Amrita Krishnan, MD, FACP, City of Hope National Medical Center, Duarte, CA; Telephone: 626-359-8111; E-mail: [email protected]

Co-Chair: Cristina Gasparetto, MD, Duke University Medical Center, Durham, NC; Telephone: 919-668-1017; E-mail: [email protected]

Co-Chair: Yago Nieto, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-792-2466; E-mail: [email protected]

Co-Chair: Tomer Mark, MD, University of Colorado Hospital, Aurora, CO; Telephone: 212-746-3964; E-mail: [email protected]

Scientific Director: Parameswaran Hari, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-4600; E-mail: [email protected]

Assistant Scientific Director: Anita D’Souza, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; E-mail: [email protected]

Statistical Directors: Raphael Fraser, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4849; E-mail: [email protected]

Statistician: Omar Dávila Alvelo, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0686; E-mail: [email protected]

1. Introduction

a. Minutes and Overview Plan from February 2016 meeting (Attachment 1)

b. Introduction of incoming co-Chair: Shaji Kumar, MD; Mayo Clinic Rochester

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. MM08-02 Beksac M, Gragert L, Fingerson S, Maiers M, Zhang M, Albrecht M, Zhong X, Cozen W, Dispenzieri A, Lonial S, Hari P. HLA-C*07:02 is Associated with Increased Risk of Multiple Myeloma. Leukemia. 2016 Nov 1; 30(11):2260-2264.

b. MM11-02 Cornell F, Bachanova V, D'Souza A, Ahn KW, Huang J, Gasparetto C, Nieto Y, Tomer M, Hari P. Outcomes after Allogeneic Transplant for Lymphoplasmacytic Lymphoma/ Waldenstrom Macroglobulinemia (LPL/WM): A Center for International Blood and Marrow Transplant Research Analysis. Biology of Blood and Marrow Transplantation. doi:10.1016/j.bbmt.2016.11.011. Epub 2016 Nov 15. Poster presentation at BMT Tandem in Hawaii, Feb 2016.

c. MM11-04 Rodriguez T, Parameswaran H, Stiff P, Zhong X, Sterrenberg D, Vesole D. Busulfan/Melphalan/Bortezomib (BUMELVEL) vs. High Dose Melphalan (MEL200) As Conditioning

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Regimen For Autologous Hematopoietic Stem Cell Transplantation In Multiple Myeloma (MM). Biology of Blood and Marrow Transplantation. 2016 Aug 1; 22(8):1391-1396.

d. MM13-02 Scott EC, Hari P, Sharma M, Le-Rademacher J, Huang J, Vogl D, Abidi M, Beitinjaneh A, Fung H,Ganguly S, Hildebrandt G, Holmberg L, Kalaycio M, Kumar S, Kyle R, Lazarus H, Lee C, Maziarz RT,Meehan K, Mikhael J, Nishihori T, Ramanathan M, Usmani S, Tay J, Vesole D, Wirk B, Yared J, Savani BN,Gasparetto C, Krishnan A, Mark T, Nieto Y, D'Souza A. Post-transplant outcomes in high-risk compared tonon-high risk multiple myeloma, a CIBMTR analysis. Biology of Blood and Marrow Transplantation.2016 Oct 1; 22(10):1893-1899.

e. MM15-01 Cornell F, Costa L, Adetola K, Innis-Shelton R, Zhang MJ, Huang J, Krishnan A, Mark T, Nieto Y,Gasparetto C, D'Souza A, Hari P. Maintenance versus induction therapy choice on outcomes afterautologous transplantation for multiple myeloma. Biology of Blood and Marrow Transplantation.doi:10.1016/j.bbmt.2016.11.011. Epub 2016 Nov 15.

f. ST10-01 Cheng YC, Shi Y, Zhang MJ, Brazauskas R, Hemmer MT, Bishop MR, Nieto Y, Stadtmauer E,Ayash L, Gale RP, Lazarus HM, Holmberg L, Lill M, Olsson R, Wirk MB, Arora M, Hari P, Ueno N. Long-Term Outcome of Inflammatory Breast Cancer Compared to Non-Inflammatory Breast Cancer in theSetting of High-Dose Chemotherapy with Autologous Hematopoietic Cell Transplantation. Journal ofCancer 2016.

g. MM14-02 A Mahindra, C Gasparetto, M Fei, A Krishnan, J Huang, M Tomer, P Hari, Y Nieto, A D’Souza.Autologous hematopoietic cell transplantation in patients with renal insufficiency. Submitted. Oralpresentation at the American Society of Hematology, Dec 2016.

h. MM15-03 J Schriber, P Hari, KW Ahn, M Fei, L Costa, M Kharfan-Dabaja, M Angel-Diaz, RP Gale, SGanguly, S Girnius, S Hashmi, A Pawarode, D Vesole, P Wiernik, BM Wirk, D Marks, T Nishihori, R Olsson,S Usmani, T Mark, Y Nieto, A D’Souza. Significant Differences in Stem Cell Transplant Utilization Rates(STUR) of Autologous Hematopoietic Cell Transplant (AHCT) in Multiple Myeloma (MM) Based onEthnicity without Differences in Efficacy: a CIBMTR Report. Submitted. Oral presentation at theAmerican Society of Hematology, Dec 2016

i. SC16-03 A D’Souza, J Huang, M Fei, P Hari. Trends in Pre- and Post-Transplant Therapies Prior to FirstAutologous Hematopoietic Cell Transplantation Among Patients with Multiple Myeloma in the UnitedStates, 2004-2014. Submitted. Oral presentation at the American Society of Hematology, Dec 2016.

j. MM15-02 M Sharma, A Krishnan, B Bruno, N Tank et. al. Post-relapse Survival Rates after Tandem Auto-HSCT vs. Auto/Allo-HSCT in Multiple Myeloma. Oral presentation at the American Society ofHematology, Dec 2016.

k. MM14-03 S Kumar, A Dispenzieri, R Fraser, J Huang, C Gasparetto, A Krishnan, T Mark, Y Nieto, AD’Souza, P Hari. Trends in survival outcomes among patients relapsing early after autologous stem celltransplantation for multiple myeloma. Oral presentation at BMT Tandem in Orlando, Feb 2017.

4. Studies in progress (Attachment 3)

a. MM14-03 Trends in survival outcomes among patients relapsing early after autologous stem cell transplantation for multiple myeloma (S Kumar/ A Dispenzieri) Manuscript Preparation

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b. MM15-02 Post-relapse survival rates after tandem AutoHCT vs. Auto/AlloHCT in Multiple Myeloma (MSharma/A Krishnan/B Bruno/N Tank) Manuscript Preparation

c. MM14-01 Characteristics and outcomes of patients with refractory germ cell tumor undergoingautologous hematopoietic stem cell transplantation (M Qayed/D Kilari/ T Olson/ KY Chiang/P Hari)Protocol Development

d. MM16-01 Validation of R-ISS in real world population of MM undergoing High dose Melphalan (HDM)and evaluate outcomes of autologous hematopoietic cell transplantation in patients with high riskmultiple myeloma using the international myeloma working group 2014 and 2015 criteria (S Kumar/EScott) Protocol Development

e. MM16-02 Alternative donor allogeneic hematopoietic transplantation strategies for multiple myelomain adult patients: comparing umbilical cord blood versus haploidentical related donor transplantation (AKanate/N Shah/Q Bashir/S Ciurea) Protocol Development

f. MM16-03 Third stem cell transplant for multiple myeloma: An analysis from the CIBMTR database (RNath) Protocol Development

5. Future/proposed studies

Multiple Myeloma: a. PROP 1611-50 Outcomes of patients with t(11;14) genetic abnormalities in multiple myeloma (Liana

Nikolaenko/Amrita Krishnan) (Attachment 4)

b. PROP 1611-106 Prevalence of cytogenetic abnormalities by patient race in multiple myeloma and outcomes after stem cell transplant (Sikander Ailwadhi/Shaji Kumar/Parmeswaran Hari) (Attachment 5)

c. PROP 1611-34 Exploring the transplant center volume outcomes relationship in MM (Saurabh Chhabra/Binod Dhakal) (Attachment 6)

Plasma Cell Leukemia: d. Proposal 1609-02/1611-40/1611-53/1611-133 Hematopoietic Cell Transplantation for Primary Plasma

Cell Leukemia in the Era of Novel Agents (Saulius Girnius/Sagar Patel/Lohith Bachegowda/Binod Dhakal)(Attachment 7)

Amyloidosis: e. PROP 1611-153 The impact of bortezomib-based induction therapy vs no induction therapy on

outcomes for light chain amyloidosis (Robert Cornell/ Luciano Costa/ Stacey Goodman)(Attachment 8)

Dropped proposed studies a. PROP 1610-01 Outcomes after autologous stem cell transplant outcomes for patients with POEMS

syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) Droppeddue to feasibility – POEMS not collected in CIBMTR data collection forms before 2013

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b. PROP 1611-21 Frequency of salvage autologous stem cell transplantation for patients with plasma celldyscrasia Dropped due to feasibility- objectives too broad by spanning across several different plasmacell dyscrasia

c. PROP 1611-115 Outcomes for patients with polyneuropathy, organomegaly, endocrinopathy,monoclonal protein, and skin changes (POEMS) treated with autologous or allogeneic transplantationDropped due to feasibility – POEMS not collected in CIBMTR data collection forms before 2013

d. PROP 1611-130 A retrospective study to evaluate the safety and efficacy of bortezomib-containingpreparative regimens in multiple myeloma patients underwent the first autologous stem cell transplantfrom 2008 to 2014 Dropped due to feasibility-Bortezomib not collected on CIBMTR data collection formsas part of preparative regimen

e. PROP 1611-137 Outcome analysis of donor lymphocyte infusion for multiple myeloma patients whounderwent allogeneic hematopoietic stem cells Dropped due to feasibility - low number of patients

f. PROP 1611-149 Outcomes of second autologous HCT for patients with relapsed AL-amyloidosis Droppeddue to feasibility - low number of patients

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR PLASMA CELL DISORDERS AND ADULT SOLID TUMORS Honolulu, Hawaii Sunday, February 21, 2016, 12:15 – 2:15 pm

Co-Chair: Amrita Krishnan, MD, FACP, City of Hope National Medical Center, Duarte, CA; Telephone: 626-359-8111; E-mail: [email protected]

Co-Chair: Cristina Gasparetto, MD, Duke University Medical Center, Durham, NC; Telephone: 919-668-1017; E-mail: [email protected]

Co-Chair: Yago Nieto, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-792-2466; E-mail: [email protected]

Co-Chair: Tomer Mark, MD, University of Colorado Hospital, Aurora, CO; Telephone: 212-746-3964; E-mail: [email protected]

Scientific Director: Parameswaran Hari, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-4600; E-mail: [email protected]

Assistant Scientific Director: Anita D’Souza, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; E-mail: [email protected]

Statistical Directors: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8375; E-mail: [email protected] Raphael Fraser, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4849; E-mail: [email protected]

Statistician: Jiaxing Huang, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0686; E-mail: [email protected]

1. Introduction

The meeting starts at 12:15PM. Dr. Hari introduced the committee leadership and welcomed the committee participants. Dr. Hari introduced the committee goal and expectations to the audience and reviewed previous meeting presentations, published/submitted papers in 2015. The CIBMTR statistical resource was clarified to the audience. The average time to complete a study is 2-3 years upon statistical hour allocation and other competing projects.

2. Accrual summary The accrual summary provides information about the number of patients available in the registration level and research level for potential studies. As of December 2015, 58,943 plasma cell disorder cases were reported at the registration level and 11,103 cases at the research level to the CIBMTR for (first) autologous transplant. For first allogeneic transplants, these numbers are 4,435 cases and 1,885 cases respectively.

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mailto:[email protected]


3. Presentations, published or submitted papers The following publications and presentations came from the committee’s work during this year.

a. MM08-02 Beksac M, Gragert L, Fingerson S, Maiers M, Zhang M, Albrecht M, Zhong X, Cozen W, Dispenzieri A, Lonial S, Hari P. HLA-C*07:02 is Associated with Increased Risk of Multiple Myeloma. Submitted not accepted yet.

b. MM11-02 Cornell F, Bachanova V, D'Souza A, Ahn KW, Huang J, Gasparetto C, Nieto Y, Tomer M, Hari P. Outcomes after Allogeneic Transplant for Lymphoplasmacytic Lymphoma/ Waldenstrom Macroglobulinemia (LPL/WM): A Center for International Blood and Marrow Transplant Research Analysis. Poster at Tandem 2016.

c. MM11-03(a) D'Souza A, Dispenzieri A, Wirk B, Zhang MJ, Huang J, Gertz M, Kyle R, Kumar S, Comenzo R, Gale R, Lazarus H, Savani B, Cornell R, Weiss B, Vogl D, Freytes C, Scott E, Landau H, Moreb J, Costa L, Ramanathan M, Callander N, Kamble R, Olsson R, Ganguly S, Nishihori T, Kindwall-Keller T, Wood W, Mark T, Hari P. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study. JCO 2015.

d. MM11-03(b) D’Souza A, Huang J, Hari P. Validation of the 2012 hematologic response criteria in light chain (AL) amyloidosis using the Center for International Blood and Marrow Transplant (CIBMTR) database. Poster at IMW 2015, BBMT 2015.

e. MM11-04 Rodriguez T, Parameswaran H, Stiff P, Zhong X, Sterrenberg D, Vesole D. Busulfan/Melphalan/Bortezomib (BUMELVEL) vs. High Dose Melphalan (MEL200) As Conditioning Regimen For Autologous Hematopoietic Stem Cell Transplantation In Multiple Myeloma (MM) BBMT 2016.

f. MM13-01 Uy G, Costa L, Hari P, Zhang MJ, Huang JX, Anderson K, Bredeson C, Callander N, Cornell R, Perez M, Dispenzieri A, Freytes C, Gale R, Garfall A, Gertz M, Gibson J, Hamadani M, Lazarus H, Kalaycio M, Kamble R, Kharfan-Dabaja M, Krishnan A, Kumar S, Kyle R, Landau H, Lee C, Maiolino A, Marks D, Mark T, Munker R, Nishihori T, Olsson R, Ramanathan M, Rodriguez T, Saad A, Savani A, Schiller G, Schouten H, Schriber J, Scott E, Seo S, Sharma M, Ganguly S, Stadtmauer E, Tay J, To L, Vesole D, Vogl D, Wagner J, Wirk B, Wood W, D'Souza A. Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation. BMT 2015.

g. MM13-02 Sharma M, Scott E, Hari P, Le-Rademacher J, Krishnan A, Mark, T, Nieto Y, Gasparetto C, Huang J, D'Souza A. Autologous hematopoietic cell transplantation in patients with high risk multiple myeloma: post- transplant responses do not translate to longer survival. Poster at ASH 2015.

h. MM15-01 Cornell F, Costa L, Adetola K, Innis-Shelton R, Zhang MJ, Huang J, Krishnan A, Mark T, Nieto Y, Gasparetto C, D'Souza A, Hari P. Post-transplant therapy is more important than induction regimen choice in autologous hematopoietic cell transplantation (AHCT) recipients for multiple myeloma (MM). Poster with discussion at IMW 2015, Oral presentation at ASH 2015.

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4. Studies in progress Dr. D’Souza introduced the following studies in progress and goal by July 2016.

a. ST10-01 The value of high-dose chemotherapy and autologous HCT as adjuvant treatment in patients with high risk inflammatory Breast Cancer after neoadjuvant chemotherapy (N Ueno/Y Cheng) This study will compare the long-term outcomes including secondary malignancy, of patients treated with high-dose chemotherapy and autologous transplantation for inflammatory breast cancer compared to those patients transplanted for non-inflammatory breast cancer. The draft manuscript is under revision with committee leaders and PIs. The goal of the study is to submit this year.

b. MM11-02 Waldenstrom Macroglobulinemia: Retrospective analysis with HCT (R Cornell/V Bachanova) This study proposes to analyze the outcomes of patients undergoing autologous and allogeneic stem cell transplantation for Waldenstrom Macroglobulinemia or Lymphoplamacytic Lymphoma and to determine potential prognostic factors associated with outcomes. A poster is been presented at Tandem 2016. Manuscript preparation is underway.

c. MM15-01 Post-transplant therapy is more important than induction regimen choice in autologous hematopoietic cell transplantation (AHCT) recipients for multiple myeloma (RF Cornell/A Kassim/L Costa/R Innis-Shelton) The primary aim of the study is to compare 2-drug induction regimens (bortezomib/dexamethasone and lenalidomide/dexamethasone) with 3-drug induction regimens VD + either cyclophosphamide or lenalidomide and determine pre-transplant disease status, day-100 post-transplant disease status, TRM, relapse/progression progression-free survival and overall survival in patients with newly diagnosed MM. The study was presented at the IMW 2015 (poster) and ASH 2015 (oral). A draft manuscript is under revision with PIs. The goal of the study is to submit by July 2016.

d. MM14-02 Autologous hematopoietic cell transplantation in patients with renal insufficiency (A Mahindra) The primary purpose of this study is to identify the safety and efficacy of autologous hematopoietic stem cell transplant for Multiple Myeloma patients with renal insufficiency. The study protocol with a demographic table was presented at the statistical meeting in December. The goal of the study is to complete analysis by July 2016.

e. MM14-03 Trends in survival outcomes among patients relapsing early after autologous stem cell transplantation for multiple myeloma (S Kumar/ A Dispenzieri) The study proposed to determine if overall survival from the time of relapse has improved over time among patients relapsing early after autologous stem cell transplantation for multiple myeloma. (Relapse within 12 months). We are planning to present the study to the statistical meeting after Tandem and complete analysis by July 2016.

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f. MM15-02 Post-relapse Survival Rates after Tandem Auto-HSCT vs. Auto/Allo-HSCT in Multiple Myeloma (M Sharma/A Krishnan/B Bruno/N Tank) The primary purpose of this study is to ompare Tandem Auto-HSCT and AUTO/ALLO HSCT for post-relapse patients and determine TRM, relapse/progression progression-free survival and overall survival in patients with MM who underwent PB autologous stem cell transplant. Protocol development and data file preparation is underway. The goal of the study is to finalize protocol and present the study by July 2016.

g. MM15-03 Race and outcomes of autologous stem cell transplantation for multiple myeloma in Hispanic patients (Jeffrey R. Schriber) The study proposed to compare Hispanic patients with non-Hispanic patients and determine TRM, relapse/progression progression-free survival and overall survival in patients with MM who underwent PB autologous stem cell transplant. Protocol development and data file preparation is underway. The goal of the study is to finalize protocol and present the study by July 2016.

h. MM14-01 Characteristics and Outcomes of patients with refractory germ cell tumor undergoing autologous hematopoietic stem cell transplantation (M Qayed/D Kilari/ T Olson/ KY Chiang/P Hari) The primary aim of the study is to determine the overall outcomes of patients with testicular and extragonadal GCT (excluding intracranial tumors) who underwent high-dose chemotherapy and autologous SCT. We looked into our database in Aug 2014 and realized that the newer version of research level disease from (version 2008) needs to be updated among 200 records. This study was deferred owing to data merge needed from FormsNet to database. Until merge complete (estimated April 2016) the study cannot be done.

5. Future/proposed studies This year, we received 22 proposals, 9 of which were invited to present at the meeting (including 3 merged proposals with similar interest). Dr. D’Souza introduced future topics of interests proposed by the committee leadership and suggested the participants to avoid the recurring topics that has been published or overlapped ongoing studies. After the introduction of the voting process, the following new proposals were presented and voted on. Dr. Mark introduced the first two studies.

a. PROP 1509-09&1511-08 Validation of R-ISS in real world population of MM undergoing HDM and evaluate outcomes of autologous hematopoietic cell transplantation in patients with high risk multiple myeloma using the international myeloma working group 2014 and 2015 criteria (S Kumar/E Scott) Dr. Sathish Kumar introduced the rationale and specific aims of the proposal. The primary aim is to assess the newly recommended R-ISS definition and to validate the prognostic significance of the 2014 and 2015 IMW group high risk models. Early relapse (<12 months after transplant), long term responses and post-transplant therapy impact will also be assessed. The estimated eligible number of patients for 2014 IMW criteria and 2015 R-ISS criteria are 1829 and 839 respectively. The major concern from the participants is the accuracy of reported cytogenetic abnormality. There is 20% missing cytogenetic reports which might lead to the bias of the distribution. FISH vs.

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convention test methods should also be separated for the cytogenetic results. There is suggestion to request and confirm the cytogenetic results from centers. Dr. Kumar and Dr. Hari agreed with the comments and Dr. Hari mentioned that since 2013 we have established auditing process to the cytogenetic results. This proposal was accepted by the committee members and leadership.

b. PROP 1511-01 Incidence of cytogenetic abnormalities by patient race in multiple myeloma and outcomes after stem cell transplant (S Ailawadhi/S Kumar/A Krishnan/S Usmani/V Roy) Dr. Shaji Kumar presented the proposal on behalf of the proposal team. The proposal objective is to assess the incidence of cytogenetic abnormalities by race and disease subtypes. Overall and disease free survival after HSCT will also be estimated in different cytogenetic types by race. The defined high risk cytogenetic abnormalities include del17p, t(14;16), t(14;20), 1q+; intermediate risk include t(4;14), del13/hypodiploidy; all others are standard risk. There are 265, 181 and 1528 eligible patients for high, intermediate and standard risks respectively. About 1/5 of each group are African American patients. In addition, there seems to be a relatively low incidence of translocation abnormality in African American. Compared to MM15-03 Hispanic MM study that collected subjects from 1990-2010, this proposal is limited to year of transplant in 2008-2014, which allows us to have cytogenetic reports collected during this period of time. Major concern is the small group of population breakdown by each cytogenetic abnormalities and races, which might restrict us from further analysis. It was also recommended to look at the breakdown of trisomy by each category. Furthermore, the population needs to be restricted to US and Canada for completeness and homogeneous distribution. Owing to the small numbers and inability to answer the proposed research question using this dataset, this study did not receive a high enough priority score for acceptance and was therefore dropped.

Dr. Gasparetto introduced the next two studies.

c. PROP 1511-10&1511-70 Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Multiple Myeloma in Adult Patients: Comparing Umbilical Cord Blood versus Haploidentical Related Donor Transplantation (A Kanate/N Shah/Q Bashir/S Ciurea) Dr. Kanate presented the proposal to the audience, which aimed at the comparison of the post-transplantation outcomes in patients with MM undergoing UCB versus haplo-identical allo-HCT. There are estimated of 64 CB and 132 HLA-mismatched other relatives in registration level data. One suggestion was to exclude the plasma cell leukemia cases and only keep myeloma cohort, which was agreed by Dr. Kanate. Another suggestion was to invite and include EBMT data to increase the statistical power. Dr. Hari commented that there is a good potential of the collaboration. In addition, the participants recommended looking at a uniform cohort of haplo-transplants, ie using post-transplant CY and to exclude <2005 transplant cases and to analyze the effect of prior autoHCT. This proposal was accepted by the committee members and leadership.

d. PROP 1511-72&1511-123 A Retrospective Study to Evaluate the Safety and Efficacy of Bortezomib-Containing Preparative Regimens in Multiple Myeloma Patients Underwent the First Autologous Stem Cell Transplant from 2008 to 2014 (S Girnius /E Malek/ M Lima/ S Giralt) Dr. Malek presented the project on behalf of the proposal

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team. The primary aim of the proposal is to compare Bortezomib (BTZ) -containing preparative regimens to non-BTZ regimens. A second aim to compare outcomes of AHCT with HDM vs. Alternate conditioning regimens will also be compared. One major concern of the proposal was whether the dosage of the conditioning regimens is collected and the time of dose given. Dr. Hari confirmed that we collected the dose in registration level data. BTZ and Melphalan dose are reported separately. However, if the BTZ dose is given as part of the treatment and not as conditioning – we could have a center variability. The other concern from the audience was whether BTZ is involved in induction and this could be very crucial to the result; unfortunately this may not be captured on all registration level data. This study did not receive a high enough priority score for acceptance and was therefore dropped.

Dr. Nieto introduced the last two studies.

e. PROP 1511-107 Third Stem Cell Transplant (SCT) for Multiple Myeloma: An analysis from the CIBMTR database (R Nath) Dr.Nath presented the proposal and introduced the background of the study idea. There is limited data on the outcomes of 3rd HCT (autologous or allogeneic) performed for progression after tandem or a salvage 2nd HCT. There are 1031 3rd Allo HCTs and 500 3rd Auto HCTs in CIBMTR registry database from 2001 to 2014. The study aim is to evaluate the frequency and outcomes (TRM, PFS and OS) of these patients. These results will help define the role of 3rd SCT and guide development of new treatment strategies for multiple myeloma patients relapsing after their 2nd HCT. The suggestions from the participants include to evaluate the prior transplant type (tandem vs. not) and whether the cells were collected again at the 3rd HCT. It was also recommended to look at the rate of secondary malignancy after 3rd transplant. Dr. Hari commented that the disease related characteristics will be captured for planned tandem transplants that are on comprehensive research form track. This proposal was accepted by the committee members and leadership.

f. PROP 1511-116 Second Autologous Hematopoietic Cell Transplantation for Myeloma: Is it needed today? (S Chhabra/S Jain) Dr. Jain presented the proposal aimed at the comparison of outcomes between single AHCT vs. tandem AHCT. The impact of post-transplant treatment will also be evaluated as the secondary objective. There are total of 376 Tandem AHCTs (planned/done) vs. 1167 Single AHCT with post-transplant therapy vs. 732 single AHCT without post-transplant therapy. One of the questions was about the definition of tandem transplant planned vs done. Dr. Hari explained that among the 376 tandem AHCTs, 248 have completed the subsequent tandem transplants with complete data file in CTN trial, the other 128 cases reported a planned subsequent transplant, which is not intended for relapsed disease, and therefore assumed tandem. Many members were also concerned regarding the novelty of this study, as the results of the randomized BMT CTN 0702 which are expected to be released by end of this year will answer the questions proposed by this study. Thus the results of this study which may take 2 years to complete would not be of great interest. This study did not receive a high enough priority score for acceptance and was therefore dropped.

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The working committee meeting ended at 1:30PM. The committee leadership waited until 2 pm to meet with members of the committee and answer questions. A total of 900 hours of MS biostatistician time was allocated to our WC for the 2016-2017 academic year. Thus, we will be able to accept 3 new studies.

Working Committee Overview Plan for 2016 - 2017

MM14-01: Characteristics and Outcomes of patients with refractory germ cell tumor undergoing autologous hematopoietic stem cell transplantation (M Qayed/D Kilari/ T Olson/ KY Chiang/P Hari) We will resume working on the study when the data is ready by the database team.

MM14-02: Autologous hematopoietic cell transplantation in patients with renal insufficiency (A Mahindra) The goal of the study is to complete analysis by July 2016 and submit the manuscript by July 2017.

MM14-03: Trends in survival outcomes among patients relapsing early after autologous stem cell transplantation for multiple myeloma (S Kumar/ A Dispenzieri) We are planning to complete analysis by July 2016 and submit the manuscript by July 2017.

MM15-01: The Impact of Novel Agent Induction Regimen Choice on Autologous Stem Cell Transplant Outcomes for Newly Diagnosed Multiple Myeloma (R Cornell/A Kassim/L Costa/R Innis-Shelton) First draft of manuscript was sent to the writing committee for comments in March. The goal of the study is to submit manuscript by July 2016.

MM15-02: Post-relapse Survival Rate after Tandem Auto-HSCT vs. Auto/Allo-HSCT in Multiple Myeloma (M Sharma/A Krishnan/B Bruno/N Tank) We are planning to present the study to the statistical meeting and finalize protocol by July 2016. The goal is to submit manuscript by July 2017.

MM15-03: Race and outcomes of autologous stem cell transplantation for multiple myeloma in Hispanic patients (J Schriber) We are planning to finalize protocol by July 2016 and submit the manuscript by July 2017.

MM16-01: Validation of R-ISS in real world population of MM undergoing HDM and evaluate outcomes of autologous hematopoietic cell transplantation in patients with high risk multiple myeloma using the international myeloma working group 2014 and 2015 criteria (S Kumar/E Scott) We will start working on the proposal around August 2017. The goal of the study is to complete the analysis by July 2017.

MM16-02: Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Multiple Myeloma in Adult Patients: Comparing Umbilical Cord Blood versus Haploidentical Related Donor Transplantation (A Kanate/N Shah/Q Bashir/S Ciurea). The goal of the study is to complete data file for analysis by July 2017.

MM16-03: Third Stem Cell Transplant (SCT) for Multiple Myeloma: An analysis from the CIBMTR database (R Nath) The goal of the study is to finalize the proposal and present at the statistical meeting by July 2017.

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Amrita Krishnan: MM14-03: Outcomes after early relapse autoHCT for MM MM11-02: Transplant outcomes for waldenstrom’s macroglobulinemia

Tomer Mark: MM15-03: Race and outcomes of auto MM in Hispanic patients MM15-01: Novel Agent Induction on auto MM MM16-01: Validation of R-ISS in real world population of MM

Cristina Gasperetto:

MM14-02: Serum creatinine <2g/dl vs. >2g/dl for autoHCT MM MM15-02: Post-relapse Survival on Tandem Auto vs. Auto/Allo tx in MM MM16-03: Third HCT for MM

Yago Nieto: ST10-01: High-dose chemo and autoHCT as adjuvant Rx in BC MM14-01: High dose chemotherapy and autoHCT for germ cell tumors MM16-02: CB vs haplo HCT for MM

Work Assignments for Working Committee Leadership (March 2016)

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Accrual Summary for the Plasma Cell Disorders and Adult Solid Tumor Working Committee

Recipients of first autologous transplant for Plasma Cell Disorders registered to the CIBMTR, 1990-2016

Characteristics TED CRF Number of patients 65695 12131 Number of centers 449 297 Age at transplant, median (range), years 59 (18-84) 58 (20-83) Disease

Multiple Myeloma 61789 (94) 10884 (90) Amyloidosis 2160 (3) 979 (8) Plasma cell leukemia 564 (<1) 106 (<1) Solitary plasmacytoma 294 (<1) 44 (<1) Waldenstrom macroglobulinemiaa 261 (<1) 37 (<1) Osteosclerotic myeloma/POEMS Syndrome 330 (<1) 41 (<1)

LCDD 180 (<1) 29 (<1) Multiple Plasmacytomas 43 (<1) 3 (<1) Othersb 74 (<1) 8 (<1)

Graft type BM 365 (<1) 81 (<1) PB 64064 (98) 11907 (98) CB 7 (<1) 0

Missing 1259 (2) 143 (1) Year of transplant

1990-1991 207 (<1) 44 (<1) 1992-1993 322 (<1) 70 (<1) 1994-1995 630 (<1) 243 (2) 1996-1997 1328 (2) 474 (4) 1998-1999 2336 (4) 696 (6) 2000-2001 3503 (5) 931 (8) 2002-2003 4626 (7) 850 (7) 2004-2005 4923 (7) 1489 (12) 2006-2007 5190 (8) 1383 (11) 2008-2009 6253 (10) 1527 (13) 2010-2011 9836 (15) 673 (6) 2012-2013 10675 (16) 1176 (10)

2014-2015 11309 (17) 1859 (15) 2016 c 4557 (7) 716 (6)

Median follow-up of survivors (range), months 47 (<1-292) 71 (<1-264) a Small lymphoplasmacytic lymphoma cases were not included. b Other include: other plasmacytoma (n=31), plasmablastic (n=13), plasma cell dyscrasia (n=8), plasmacytosis (n=5), c Cases continue to be reported.

Abbreviations: TED=Transplant essential data, CRF=Comprehensive report form.

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Recipients of first allogeneic transplant for Plasma Cell Disorders registered to the CIBMTR, 1990-2016

Characteristics TED CRF Number of patients 4674 1921 Number of centers 328 251 Age at transplant, median (range), years 50 (1-78) 50 (10-77) Disease Multiple Myeloma 4242 (91) 1729 (90) Plasma cell leukemia 200 (4) 98 (5) Waldenstrom macroglobulinemia 106 (2) 65 (3) Amyloidosis 32 (<1) 9 (<1) Solitary plasmacytoma 39 (<1) 5 (<1) Multiple Plasmacytomas 0 1 (<1) Othersb 55 (1) 14 (<1) Graft type BM 1139 (24) 615 (32) PB 3416 (73) 1265 (66) CB 25 (<1) 37 (2) Missing 94 (2) 4 (<1) Donor HLA-identical sibling 3097 (66) 1243 (65) Monozygotic twin 131 (3) 122 (6) Other relative 262 (6) 73 (4) Unrelated donor 1056 (23) 456 (24) Missing 128 (3) 27 (1) Prior Auto transplant No 2225 (48) 1152 (60) Yes 2449 (52) 769 (40) Year of transplant 1990-1991 70 (1) 96 (5) 1992-1993 171 (4) 141 (7) 1994-1995 282 (6) 146 (8) 1996-1997 339 (7) 144 (7) 1998-1999 311 (7) 128 (7) 2000-2001 460 (10) 248 (13) 2002-2003 567 (12) 208 (11) 2004-2005 459 (10) 255 (13) 2006-2007 377 (8) 203 (11) 2008-2009 399 (9) 134 (7) 2010-2011 426 (9) 59 (3) 2012-2013 378 (8) 51 (3) 2014-2015 336 (7) 83 (4) 2016 c 99 (2) 25 (1) Median follow-up of survivors (range), monthsc 59 (<1-291) 96 (<1-264)

a Small lymphoplasmacytic lymphoma cases were not included. b Other include: LCDD (1), anaplastic plasmacytoma (2), Plasma cell dyscrasia (1), plasmablastic (1), plasmacytoma (2), primary nodal plasmacytoma (1), recurrent plasmacytomas (1), unspecified (n=60). c Cases continue to be reported.

Abbreviations: TED=Transplant essential data, CRF=Comprehensive report form.

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First adult autologous transplant for Sarcoma registered to the CIBMTR, 1990-2016

Characteristics

Bone Sarcoma Other Sarcoma TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) Number of patients 480 150 213 81 Number of centers 156 75 97 47 Age at transplant, years, median (range) 23 (18-61) 23 (18-59) 29 (18-64) 28 (18-61) Disease

Bone sarcoma (exc. Ewing) 124 (26) 35 (23) 0 0 Ewing sarcoma 356 (74) 115 (77) 0 0 Soft tissue sarcoma 0 0 162 (76) 67 (83) Sarcoma unspecified 0 0 51 (24) 14 (17)

Gender Male 330 (69) 98 (65) 133 (62) 38 (47) Female 150 (31) 52 (35) 80 (38) 43 (53)

Graft type BM 37 (8) 17 (11) 30 (14) 10 (12) PB 429 (89) 133 (89) 171 (80) 71 (88) Missing 14 (3) 0 12 (6) 0

Year of transplant 1990-1991 18 (4) 8 (5) 23 (11) 6 (7) 1992-1993 28 (6) 14 (9) 27 (13) 4 (5) 1994-1995 22 (5) 12 (8) 23 (11) 8 (10) 1996-1997 28 (6) 33 (22) 20 (9) 20 (25) 1998-1999 50 (10) 37 (25) 28 (13) 21 (26) 2000-2001 57 (12) 15 (10) 17 (8) 9 (11) 2002-2003 52 (11) 2 (1) 28 (13) 3 (4) 2004-2005 44 (9) 3 (2) 9 (4) 3 (4) 2006-2007 34 (7) 12 (8) 13 (6) 2 (2) 2008-2009 47 (10) 10 (7) 6 (3) 3 (4) 2010-2011 39 (8) 1 (<1) 11 (5) 0 2012-2013 30 (6) 3 (2) 4 (2) 0 2014-2015 24 (5) 0 1 (<1) 2 (2) 2016 c 7 (1) 0 3 (1) 0

Follow-up of survivors, months, median (range) 49 (<1-284) 107 (3-193) 65 (<1-181) 97 (15-131) a Cases continue to be reported in this interval. Abbreviations: TED=Transplant essential data, CRF=Comprehensive report form.

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First adult autologous transplant for Neuroblastoma, Medulloblastoma & Wilm’s Tumor registered to the CIBMTR, 1990-2016

Neuroblastoma Medulloblastoma Wilm’s Tumor

Characteristics TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) TED

N (%) Number of patients 113 25 155 29 33 Number of centers 69 22 82 24 29 Age at transplant, years, median (range) 24 (18-62) 22 (18-39) 27 (18-66) 28 (19-49) 24 (18-53) Disease

Neuroblastoma 113 25 0 0 0 Medulloblastoma 0 0 155 29 0 Wilm’s Tumor 0 0 0 0 33

Gender Male 64 (57) 13 (52) 97 (63) 17 (59) 18 (55) Female 49 (43) 12 (48) 58 (37) 12 (41) 15 (45)

Graft type BM 7 (6) 3 (12) 11 (7) 3 (10) 4 (12) PB 103 (91) 21 (84) 142 (92) 26 (90) 28 (85) Missing 3 (3) 1 (4) 2 (1) 0 1 (3)

Year of transplant 1990-1991 7 (6) 2 (8) 0 1 (3) 1 (3) 1992-1993 9 (8) 2 (8) 1 (<1) 1 (3) 1 (3) 1994-1995 5 (4) 4 (16) 2 (1) 1 (3) 2 (6) 1996-1997 3 (3) 5 (20) 6 (4) 1 (3) 2 (6) 1998-1999 7 (6) 4 (16) 13 (8) 8 (28) 1 (3) 2000-2001 4 (4) 2 (8) 16 (10) 1 (3) 4 (12) 2002-2003 6 (5) 1 (4) 13 (8) 1 (3) 3 (9) 2004-2005 10 (9) 2 (8) 22 (14) 3 (10) 5 (15) 2006-2007 6 (5) 1 (4) 9 (6) 5 (17) 3 (9) 2008-2009 12 (11) 0 19 (12) 5 (17) 1 (3) 2010-2011 15 (13) 0 20 (13) 0 4 (12) 2012-2013 12 (11) 0 11 (7) 2 (7) 2 (6) 2014-2015 14 (12) 1 (4) 19 (12) 0 4 (12) 2016 a 3 (3) 1 (4) 4 (3) 0 0

Follow-up of survivors, months, median (range)

50 (1-148) 86 (6-86) 50 (<1-170)

82 (2-82) 62 (2-202)

a Cases continue to be reported in this interval. Abbreviations: TED=Transplant essential data, CRF=Comprehensive report form.

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First adult autologous transplant for Ovarian Cancer & Germ Cell Tumor registered to the CIBMTR, 1990-2016

Ovarian cancer Germ Cell Tumor

Characteristics TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) Number of patients 2678 1125 894 110 Number of centers 249 165 190 65 Age at transplant, years, median (range) 38 (18-73) 43 (18-76) 31 (18-69) 32 (19-58)

Disease Ovarian (epithelial) 1073 (40) 603 (54) 0 0 Testicular 1605 (60) 522 (46) 0 0 Germ cell tumor, extragonadal 0 0 894 110

Gender Male 1609 (60) 520 (46) 773 (86) 88 (80) Female 1069 (40) 605 (54) 121 (14) 22 (20)

Graft type BM 187 (7) 195 (17) 27 (3) 8 (7) PB 2352 (88) 921 (82) 855 (96) 101 (92) Missing 139 (5) 9 (<1) 12 (1) 1 (<1)

Year of transplant 1990-1991 146 (5) 98 (9) 4 (<1) 5 (5) 1992-1993 138 (5) 126 (11) 20 (2) 7 (6) 1994-1995 194 (7) 197 (18) 36 (4) 6 (5) 1996-1997 360 (13) 230 (20) 14 (2) 6 (5) 1998-1999 374 (14) 171 (15) 90 (10) 11 (10) 2000-2001 149 (6) 74 (7) 94 (11) 8 (7) 2002-2003 159 (6) 43 (4) 71 (8) 7 (6) 2004-2005 180 (7) 36 (3) 69 (8) 12 (11) 2006-2007 127 (5) 26 (2) 94 (11) 8 (7) 2008-2009 92 (3) 78 (7) 53 (6) 21 (19) 2010-2011 226 (8) 7 (<1) 78 (9) 3 (3) 2012-2013 223 (8) 17 (2) 98 (11) 3 (3) 2014-2015 251 (9) 15 (1) 129 (14) 10 (9) 2016 a 59 (2) 7 (<1) 44 (5) 3 (3)

Follow-up of survivors, months, median (range) 54 (<1-292) 81 (1-217) 36 (<1-217) 61 (1-172) a Cases continue to be reported in this interval. Abbreviations: TED=Transplant essential data, CRF=Comprehensive report form.

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First adult autologous transplant for Breast Cancer, Lung Cancer & CNS Tumora registered to the CIBMTR, 1990-2016

Breast Cancer Lung Cancer CNS Tumor

Characteristics TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) Number of patients 16957 5646 87 119 545 105 Number of centers 275 199 42 26 121 45 Age at transplant, years, median (range)

46 (19-73) 46 (19-72) 50 (21-74) 50 (30-66) 34 (18-69) 34 (18-62)

Disease Breast cancer, NOS 14650 (86) 4982 (88) 0 0 0 0 BC, inflammatory 431 (3) 87 (2) 0 0 0 0 BC, non-inflammatory 1876 (11) 577 (10) 0 0 0 0 Lung, small cell 0 0 58 (67) 114 (96) 0 0 Lung, non-small cell 0 0 22 (25) 5 (4) 0 0 Lung, not specified 0 0 7 (8) 0 0 0 CNS tumor, including CNS PNET 0 0 0 0 545 105

Gender Male 134 (<1) 27 (<1) 47 (54) 64 (54) 350 (64) 64 (61) Female 16823 (99) 5619 40 (46) 55 (46) 195 (36) 41 (39)

Graft type BM 1802 (11) 820 (15) 7 (8) 15 (13) 42 (8) 21 (20) PB 13750 (81) 4821 (85) 73 (84) 104 (87) 462 (85) 84 (80) Missing 1405 (8) 5 (<1) 7 (8) 0 41 (8) 0

Year of transplant 1990-1991 619 (4) 495 (9) 13 (15) 16 (13) 40 (7) 6 (6) 1992-1993 1852 (11) 930 (16) 8 (9) 30 (25) 37 (7) 7 (7) 1994-1995 3477 (21) 1269 (22) 19 (22) 28 (24) 38 (7) 12 (11) 1996-1997 5374 (32) 1472 (26) 13 (15) 34 (29) 71 (13) 13 (12) 1998-1999 4597 (27) 1273 (23) 16 (18) 11 (9) 81 (15) 17 (16) 2000-2001 755 (4) 181 (3) 11 (13) 0 45 (8) 12 (11) 2002-2003 150 (<1) 19 (<1) 1 (1) 0 33 (6) 4 (4) 2004-2005 78 (<1) 5 (<1) 2 (2) 0 49 (9) 4 (4) 2006-2007 17 (<1) 0 0 0 22 (4) 6 (6) 2008-2009 29 (<1) 2 (<1) 3 (3) 0 26 (5) 17 (16) 2010-2011 9 (<1) 0 0 0 36 (7) 0 2012-2013 0 0 0 0 31 (6) 4 (4) 2014-2015b 0 0 0 0 30 (6) 2 (2) 2016 1 (1) 0 6 (1) 1 (<1)

Follow-up of survivors, months, median (range)

127 (<1-298)

113 (<1-221)

46 (<1-216)

58 (4-193)

56 (<1-263)

84 (2-184)

a Includes CNS PNET. b Cases continue to be reported in this interval. Abbreviations: BC=Breast cancer, CNS=Central nervous system, PNET=Primitive neuroectodermal tumor, TED=Transplant essential data, CRF=Comprehensive report form.

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Recipients of first adult allogeneic transplant for Adult Solid Tumor registered to the CIBMTR, 1990-2016

Hepatobiliary Renal

carcinoma/kidney Ovarian cancer Breast cancer

Characteristics TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) TED

N (%) CRF

N (%) Number of patients 13 12 267 210 15 9 93 89 Year of transplant 1990-1991 0 0 0 0 1 (7) 0 2 (2) 2 (2) 1992-1993 0 0 0 0 0 0 2 (2) 3 (3) 1994-1995 0 0 0 0 1 (7) 0 3 (3) 12 (13) 1996-1997 0 2 (17) 1 (<1) 0 0 0 11 (12) 24 (27) 1998-1999 0 2 (17) 19 (7) 2 (<1) 2 (13) 2 (22) 14 (15) 23 (26) 2000-2001 1 (8) 3 (25) 102 (38) 121 (58) 2 (13) 0 22 (24) 12 (13) 2002-2003 6 (46) 3 (25) 114 (43) 55 (26) 4 (27) 2 (22) 17 (18) 5 (6) 2004-2005 3 (23) 2 (17) 19 (7) 21 (10) 2 (13) 5 (56) 13 (14) 7 (8) 2006-2007 3 (23) 0 2 (<1) 5 (2) 0 0 6 (6) 1 (1) 2008-2009 0 0 4 (1) 6 (3) 1 (7) 0 2 (2) 0 2010-2011 0 0 6 (2) 0 1 (7) 0 1 (1) 0 2014-2015 0 0 0 0 1 (7) 0 0 0

Characteristics TED

N (%) CRF

N (%)

TED N (%)

CRF N (%)

Other disease 170 76 (continued) Other malignant, unknown 77 (45) 25 (33) Wilm tumor 1 (<1) 1 (1) Head and neck 1 (<1) 1 (1) Ewing sarcoma 18

(11) 14

(18) Lung cancer, small cell 3 (2) 1 (1) Germ cell tumor 8 (5) 3 (4) Lung cancer, non-small cell 6 (4) 0 Medulloblastoma 1 (<1) 1 (1) Pancreas 7 (4) 6 (8) PNET 0 1 (1) Prostate 6 (4) 2 (3) Gastric malignancy 1 (<1) 0 Testis 7 (4) 5 (7) Thymoma 1 (<1) 1 (1) Cervical 0 1 (1) Rhabdomyasarcoma 9 (5) 1 (1) Sarcoma unspecified 10 (6) 3 (4) Leiomyosarcoma 1 (<1) 0 Bone sarcoma (exc. Ewing) 9 (5) 6 (8) Fibrosarcoma 2 (1) 0 CNS tumors 1 (<1) 4 (5) Synovial sarcoma 1 (<1) 0

(continued on next column) Abbreviations: CNS=Central nervous system, PNET=Primitive neuroectodermal tumor, TED=Transplant essential data, CRF=Comprehensive report form.

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TO: Plasma Cell Disorders and Adult Solid Tumors Working Committee Members FROM: Parameswaran Hari, MD, MS; Scientific Director and Anita D’Souza, MD; Assistant

Scientific Director for the Plasma Cell Disorders and Adult Solid Tumors Working Committee

RE: Studies in Progress Summary MM14-03: Trends in survival outcomes among patients relapsing early after autologous stem cell transplantation for multiple myeloma (S Kumar/ A Dispenzieri) The study proposed to determine if overall survival from the time of relapse has improved over time among patients relapsing early after autologous stem cell transplantation for multiple myeloma. Manuscript is underway. The goal of the study is to submit manuscript by July 2017. MM15-02: Post-relapse Survival Rates after Tandem Auto-HSCT vs. Auto/Allo-HSCT in Multiple Myeloma (M Sharma/A Krishnan/B Bruno/N Tank) The primary purpose of this study is to ompare Tandem Auto-HSCT and AUTO/ALLO HSCT for post-relapse patients and determine TRM, relapse/progression progression-free survival and overall survival in patients with MM who underwent PB autologous stem cell transplant. Manuscript is underway and we expect to submit to JCO by the emd of April. The goal of the study is to submit manuscript after 2017 BMT Tandem meeting. MM14-01: Characteristics and Outcomes of patients with refractory germ cell tumor undergoing autologous hematopoietic stem cell transplantation (M Qayed/D Kilari/ T Olson/ KY Chiang/P Hari) The primary aim of the study is to determine the overall outcomes of patients with testicular and extragonadal GCT (excluding intracranial tumors) who underwent high-dose chemotherapy and autologous SCT. This was a combined study of ST1301 and proposal1311-09. We looked into our database in Aug 2014 and realized that the newer version of research level disease from (version 2008) needs to be updated among 200 records. The protocol is in progress. The goal of the study is to submit manuscript after 2017 BMT Tandem meeting. MM16-01 Validation of R-ISS in real world population of MM undergoing HDM and evaluate outcomes of autologous hematopoietic cell transplantation in patients with high risk multiple myeloma using the international myeloma working group 2014 and 2015 criteria (S Kumar/E Scott). This study will assess the newly recommended R-ISS based outcome from CIBMTR database and validate the prognostic significance (response rate, progression free and overall survival) of the 2014 and 2015 international myeloma working group high risk models in patients that received an autologous hematopoietic cell transplant for multiple myeloma registered with the CIBMTR. Protocol development is in progress. The goal of the study is to finalize data file by July 2017. MM16-02 Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Multiple Myeloma in Adult Patients: Comparing Umbilical Cord Blood versus Haploidentical Related Donor Transplantation (A Kanate/N Shah/Q Bashir/S Ciurea) Protocol Development is underway. This study will compare the post-transplantation outcomes in patients with MM undergoing UCB versus

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haploidentical allo-HCT. Protocol development is in progress. The goal of the study is to finalize data file by July 2017. MM16-03 Third Stem Cell Transplant (SCT) for Multiple Myeloma: An analysis from the CIBMTR database (R Nath). This study hypothesize the evaluation of the frequency, disease and transplant characteristics and outcomes of patients undergoing third SCT for multiple myeloma will help define its role in myeloma management in the era of novel agents. Protocol development is in progress. The goal of the study is to finalize protocol by July 2017.

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Proposal 1611-50 Title: Outcomes of Patients with t(11;14) Genetic Abnormalities in Multiple Myeloma Liana Nikolaenko: City of Hope, Duarte, CA Amrita Krishnan: City of Hope, Duarte, CA Hypothesis: Multiple myeloma (MM) with t(11;14) is considered a standard-risk disease (1,2); however, emerging data suggests that the t(11;14) may be an adverse prognostic indicator and is associated with poor survival. Scientific impact: Small single-institution studies have shown that patients with MM carrying t(11;14), in fact, have inferior survival after induction treatment followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) (3,4). This is in contradiction to current thinking that these patients have standard risk disease (1). If this study in a large multi-institution cohort confirms the inferior prognosis, it would provide further evidence for alternate therapeutic approaches. This could include a clinical trial evaluating targeted therapy, such as venetoclax, a selective BCL-2 inhibitor, which has shown activity in t(11;14) myeloma cells expressing high levels of BCL2 (5,6), as a post-transplant maintenance therapy in this patient population. Specific aims:

• To investigate a true impact of t(11;14) genetic abnormality in MM and possibly re-stratify disease risk with this translocation utilizing a large database to encompass a diverse population.

• To assess effects of novel agents on outcomes of MM with t(11;14). • To evaluate outcomes with t(11;14) post autologous transplantation. • To use this data to develop a clinical trial involving targeted therapy, such as venetoclax, which

has shown activity in t(11;14) myeloma. Scientific justification: Cytogenetic abnormalities, determined by conventional cytogenetics or fluorescence in situ hybridization (FISH), in MM have become significantly more important with respect to determining patient’s prognosis, responses to treatment and identifying targeted therapies. Frequently occurring genetic abnormalities include hyperdiploidy, hypodiploidy, and chromosomal aberrations, such as abnormalities on chromosome 1, 7, 13, 14 and 17. The most common abnormality involving chromosome 14 is reported to be t(11;14)(q13;q32) (7). The studies have shown an association between del(13q), t(4;14), or del(17p) with worse outcome and overall survival (OS). These chromosomal abnormalities are considered to be high risk features in MM. The poor prognosis is more pronounced in patients harboring more than one cytogenetic abnormality (8). Multiple studies have shown that patients with t(11;14)(q13;q32) in MM represent a subset of population with standard risk and considered to have a favorable prognosis (1,2). Frequency of t(11;14) is reported to be 15-20% of newly diagnosed MM cases. This translocation can be seen in association with other chromosomal aberrations (9). Most recently, inferior outcomes were reported when additional cytogenetic abnormalities were present together with t(11;14) as compared with t(11;14) alone. Presence of at least two additional abnormalities was seen in 35% of patients. Coexisting

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chromosomal abnormalities and t(11;14) reported to exert a deleterious effect on OS and might represent a high risk population (10). However, we need larger studies assessing this translocation as a sole abnormality. Management of MM involves an induction therapy with multi-agent regimen, followed by early HDT with ASCT in transplant-eligible patients. Outcomes of patients with t(11;14) after HDT and ASCT were evaluated by Kaufman et al., showing inferior OS when compared to standard risk patients. The use of maintenance therapy with bortezomib or lenalidomide after ASCT improved the negative prognostic value of high-risk cytogenetic group, which included del(17p), t(4;14), t(14;20) or t(14;16), with 5-year OS approaching that of standard risk group (3). Similar inferior outcomes were reported by Sasaki et al. Patients undergoing HDT and ASCT who harbor t(11;14)(q13;q32) with or without additional high risk cytogenetic abnormalities did worse as compared to patients with normal cytogenetics but had better outcomes than patients with high risk cytogenetics only (chromosomes 13 and 17 abnormalities, t(4;14), t(14;16), t(14;20), and hypoploidy) (4). Moreover, Shin et al. showed that t(11;14) represents a poor prognostic parameter for ASCT and was associated with higher rates of extramedullary plasmacytoma relapse (11). Therefore, patients with t(11;14) might need to be re-classified to represent an intermediate risk disease, rather than standard risk group. Recent trials evaluating a selective, orally available anti-apoptotic protein BCL-2 inhibitor, venetoclax, showed activity in MM cell lines, particularly with t(11;14). Phase 1 studies using single agent venetoclax or in combination with bortezomib and dexamethasone in relapsed/refractory MM are showing promising response rates, including complete responses, especially in patients harboring t(11;14) mutation (5,6). Most of these studies have been single institution studies. We propose to look at the outcome of t(11;14) in general and by era to assess the effects of novel agents on progression-free survival and overall survival. In addition we will assess the effects of t(11;14) and presence of other concurrent cytogenetic abnormalities and patterns of relapse. Study population: Adult patients with diagnosis of multiple myeloma, who had evaluation by genetic analysis (cytogenetics or FISH) that would contribute to the risk stratification of their disease. Especially of interest are t(11;14) genetic abnormalities and standard risk population. Data points to be collected would include:

• age (18 years or older) • gender • International Staging System (ISS) stage • Karnofsky Performance Status (KPS) • cytogenetics and FISH • time from diagnosis to transplant • date of transplant • prior therapies (include novel agents) • melphalan dose at conditioning • post-transplant maintenance • date of relapse • date of death • cause of death • beta-2 microglobulin, LDH, and creatinine

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Data requirements: CIBMTR Data Collection Forms 2016: Plasma Cell Disorders Pre-HCT Data and 2116: Plasma Cell Disorders Post-HCT Data. Study design:

• Study Design: Observational analysis • Statistical Methods: Factors significant in univariate analysis will be considered for multivariate

analyses. Estimation of progression-free survival and overall survival using Kaplan-Meier analysis.

References: 1. Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma:

updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88(4):360-76.

2. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007;109(8):3489-95.

3. Kaufman GP, Gertz MA, Dispenzieri A, et al. Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma. Leukemia. 2016;30(3):633-9.

4. Sasaki K, Lu G, Saliba RM, et al. Impact of t(11;14)(q13;q32) on the outcomes of autologous hematopietic cell transplantation in multiple myeloma. Biol Blood marrow Transplant. 2013;19(8):1227-32.

5. Kumar S, Vij R, Kaufman JL, et al. Phase 1b venetoclax monotherapy for relapsed/refractory multiple myeloma. J Clin Oncol. 2016; 34 (suppl; abstr 8032).

6. Moreau P, Chanan-Khan AAA, Roberts AW, et al. Phase 1b venetoclax combined with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2016; 34 (suppl; abstr 8011).

7. Li S, Lim HH, Woo KS, et al. A retrospective analysis of cytogenetic alterations in patients with newly diagnosed multiple myeloma: a single center study in Korea. Blood Res. 2016;51(2):122-6.

8. Sergentanis TN, Kastritis E, Terpos E, et al. Cytogenetics and survival of multiple myeloma: isolated and combined effects. Clin Lymphoma Myeloma Leuk. 2016;16(6):335-40.

9. Segges P, Braggio E, Minnicelli C, et al. Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context. Braz J Med Biol Res. 2016;49(5):e5034.

10. Leiba M, Duek A, Amariglio N, et al. Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable? Genes Chromosomes Cancer. 2016;55(9):710-8.

11. Shin H, Kim K, Lee J, et al. The t(11;14)(q13;q32) translocation as a poor prognostic parameter for autologous stem cell transplantation in myeloma patients with extramedullary plasmacytoma. Clinical Lymphoma, Myeloma & Leukemia. 2015;15(4):227-35.

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Characteristics of ≥18 years of age US patients who underwent melphalan based regimen autologous HCT with t(11;14) genetic abnormality for MM reported to CIBMTR between 2008-2015

N (%)

Number of patients 345 Number of centers 76

Patient age, years Median (range) 60 (30-79) 20-29 1 (<1)

30-39 12 (3) 40-49 47 (14) 50-59 119 (34)

60-69 140 (41) >70 26 (8)

Gender Male 193 (56) Female 152 (44)

Race/Ethnicity Non-Hispanic, Caucasian 225 (65) Non-Hispanic, African-American 94 (27)

Non-Hispanic, Asian 6 (2) Non-Hispanic, Pacific islander 2 (<1) Non-Hispanic, Native American 1 (<1)

Hispanic, Caucasian 11 (3) Hispanic, African-American 2 (<1) Missing 4 (1)

Karnofsky score < 90 187 (54) 90-100 154 (45)

Missing 4 (1) Conditioning regimen Melphalan only (not TBI) 332 (96)

Melphalan + others (not TBI) 12 (3) Melphalan + TBI only 1 (<1)

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N (%)

Disease status prior to HCT SCR/CR/ NCR near CR 44 (13) VGPR 84 (24)

PR 171 (50) SD 37 (11) PD/REL from CR 9 (3)

Time from diagnosis to transplant <6 months 97 (28) 6-12 months 169 (49)

12-18 months 38 (11) 18-24 months 13 (4) >24 months 28 (8)

Type of transplant One auto only 288 (83) Auto/auto planned 27 (8)

Auto/allo planned 6 (2) Salvage auto 18 (5) Salvage allo 6 (2)

Year of transplant 2008 55 (16) 2009 24 (7)

2010 17 (5) 2011 34 (10)

2012 28 (8) 2013 58 (17) 2014 61 (18)

2015 68 (20) Planned treatment No 124 (36)

Yes 219 (63) Missing 4 (1) Median follow-up of survivors (range), months 27 (3-102)

Data source: CRF (Auto) *Additional patients might be added after review of the “other specify” cytogenetic fields

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Proposal 1611-106 Title: Prevalence of cytogenetic abnormalities by patient race in multiple myeloma and outcomes after stem cell transplant Sikander Ailawadhi: Mayo Clinic in Florida Shaji Kumar: Mayo Clinic in Minnesota Parmeswaran Hari: Medical College of Wisconsin Objectives: This study will evaluate the prevalence of various cytogenetic abnormalities in patients with multiple myeloma (MM) belonging to different racial subgroups and compare the outcomes of patients with different cytogenetic myeloma risk categories from various races after an autologous stem cell transplant (ASCT). The data collected in the CIBMTR database will be utilized. The study objective is:

• To examine the prevalence of various cytogenetic abnormalities seen in patients with MM belonging to different racial subgroups.

• To examine if survival outcomes across various cytogenetic risk categories are similar for MM patients belonging to different racial subgroups.

Scientific justification: MM Outcomes Over Years: MM is a heterogeneous disease with some patients progressing rapidly despite treatment, and others not requiring therapy for a number of years. Several studies, both institutional as well as population-based, have shown that outcomes in MM patients have markedly improved over the past decade with the introduction of new therapeutic agents.1,2 MM Outcomes by Race: Significant survival differences exist in MM patients belonging to different races. While several studies have reported that African-American (AA) cancer patients have worse outcomes as compared to Whites,3 MM is rather unique where outcomes of AA patients have been reported superior to Whites in several reports.4 Furthermore, differences in outcomes exist in races even beyond Whites and AA, with Hispanics noted to have the worst median overall survival (OS) and Asians the best, in a large population-based analysis representing the current US demographics.1 MM Outcomes with ASCT and the Role of Cytogenetics: A significant benefit has been reported with the widespread utilization of ASCT in MM patients as compared to the pre-ASCT era,1 as well as in patients who received transplant as a part of their MM treatment vs. those who did not, especially in those >65 years of age.2 Yet, patients with high-risk disease [t(14;16), t(14;20), or del17p13] have a median overall survival (OS) of approximately two to three years despite standard treatment.5,6 It seems that the duration of therapy with novel therapeutic agents has made some improvement in such patients in recent years.7 In a pooled analysis, patients who received bortezomib-based induction and were randomized to either 1 or 2 transplants were evaluated from several different large European cooperative group studies.8 This data showed the benefit for tandem ASCT, with the greatest benefit among those who failed to achieve a complete response (CR) following bortezomib-based induction, suggesting the importance of depth of response initially with high-risk patients. These results focused on del (17p) and t (4;14) only as the high-risk cytogenetic abnormalities. Despite the presence of this data and the importance of risk stratification to determine therapeutic options as well as eventual patient outcomes, there is no data to specifically show the outcomes of patients with various cytogenetic abnormalities separately in a systematic way. In today’s era of widespread use of several novel therapeutic drugs and ASCT, as well as the universal utilization of cytogenetics to define risk groups for

27


MM patients, a better understanding of the effect of ASCT on MM patients with different cytogenetic abnormalities is needed. Biologic Differences Among Races: While outcomes among MM patients of different races may be different due to a multitude of causes including healthcare utilization, access and awareness among others, differences in disease biology have also been postulated. Studies have suggested that the presence of biologically indolent disease subtypes in AA patients, may be the cause of improved outcomes in these patients when compared with Whites.4,9,10 Yet, a systematic analysis of the prevalence of various cytogenetic abnormalities and hence, disease risk groups has not been formally undertaken for MM patients belonging to different racial subgroups, with no such data available for Hispanics and Asians, the two fastest growing racial subgroups in the United States. Current Data on Cytogenetic Risk Groups and Outcomes After ASCT in Patients from Different Races: Despite a federal mandate more than 2 decades ago, clinical trial participation of racial minorities has lagged significantly and the knowledge gained from reported clinical trials is disproportionately representative of relatively younger Caucasian patients.11 As such, the current data available on the outcomes of patients with various cytogenetic risk categories in MM is derived from clinical trials or single-institution experiences and thus, are not representative of racial/ethnic minorities in the United States. The CIBMTR database provides a unique opportunity where the prevalence of risk categories in MM as well as their prognostic significance with currently utilized therapeutic modalities for patients of different races can be determined and compared. Study population: The study will use patient, treatment and outcome data collected on the existing data collection forms (will use TED and CRFs already submitted). No additional information would be required from the transplant centers. Outcomes:

• Prevalence of different cytogenetic abnormalities, and hence, disease risk categories in MM patients belonging to different racial subgroups (Non-Hispanic Whites, African American, Hispanics, Asians and Native Americans)

• Presence of disease subtypes (IgA vs. IgG vs. light chain only) in MM patients belonging to different racial subgroups (Non-Hispanic Whites, African American, Hispanics, Asians and Native Americans)

• Overall and disease free survival after ASCT for MM in different cytogenetic subgroups by race over time (2000-2014)

Variables: Descriptive outcome: Prevalence of cytogenetic abnormalities by race Main Effect: Outcomes (PFS/OS) by race stratified by cytogenetic risk group Patient related:

• Age: continuous, categorical by decade • Gender: male vs. female • Race: non-Hispanic Whites (NHW), non-Hispanic African-Americans (AA), non-Hispanic

Asians/Pacific Islanders (Asians), Hispanic Whites (Hispanics) and Native Americans (NA) [self identified]

• Karnofsky performance score at transplant: ≥ 90 vs. < 90 • US Geographic regions (Northeast vs. Midwest vs. South vs. West)

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Disease related: • Disease type: MM only • Disease status at the time of transplant • Cytogenetics: Individual abnormalities collected and then categorized separately into: • High risk: t(14;16), t(14;20), del17p13, 1q+ • Intermediate risk: t(4;14), del13/hypodiploidy • Standard risk: All others

(Classification is NOT final) • Disease subtype: IgA vs. IgG vs. light chain only vs. non-secretor vs. other

Transplant related: • Conditioning regimen: single-agent MEL • Type of autologous transplant – single vs. tandem

Study design: The current study will use the data from CIBMTR to determine the incidence of various cytogenetic abnormalities seen in MM patients across various racial subgroups. We will assess the absolute numbers as well as proportion of all individual cytogenetic abnormalities as well as risk categories (high vs. intermediate vs. standard) in the 5 racial subgroups (NHW, AA, Asian, Hispanic and NA) of MM patients undergoing ASCT. The absolute numbers as well as proportion of disease subtype categories (IgA vs. IgG vs. light chain only vs. non-secretor vs. other) will be assessed for the different racial subgroups as well. Follow-up data at day 100, 6 months, 1 year and annually thereafter will be reviewed and additional predictor variables will be included to construct a model in order to assess overall and disease-free survival. References: 1. Ailawadhi S, Aldoss IT, Yang D, et al. Outcome disparities in multiple myeloma: a SEER-based

comparative analysis of ethnic subgroups. Br J Haematol. 2012;158(1):91-98. 2. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma:

changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128. 3. Bach PB, Schrag D, Brawley OW, Galaznik A, Yakren S, Begg CB. Survival of blacks and whites after a

cancer diagnosis. JAMA. 2002;287(16):2106-2113. 4. Waxman AJ, Mink PJ, Devesa SS, et al. Racial disparities in incidence and outcome in multiple

myeloma: a population-based study. Blood. 2010;116(25):5501-5506. 5. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management.

American journal of hematology. 2012;87(1):78-88. 6. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk

cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962.

7. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955.

8. Cavo M, Salwender H, Rosiñol L, al. e. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase European III studies. Blood. 2013;122(21):767 (Abstract).

9. Rohatgi N, Du XL, Coker AL, Moye LA, Wang M, Fang S. Chemotherapy and survival for patients with multiple myeloma: findings from a large nationwide and population-based cohort. Am J Clin Oncol. 2007;30(5):540-548.

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10. Baker A, Braggio E, Jacobus S, et al. Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach. Blood. 2013;121(16):3147-3152.

11. Fisher JA, Kalbaugh CA. Challenging assumptions about minority participation in US clinical research. Am J Public Health. 2011;101(12):2217-2222.

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Demographic table of U. S. adult patients underwent 1st autoPB MM transplant from 2008-2015 and reported with CIBMTR

Variable Caucasian African American Other

Number of patients 2537 1025 353

Number of centers 120 101 80 Patient age, years

Median 61 (23-80) 58 (20-77) 58 (30-82) 20-29 4 (<1) 2 (<1) 0 30-39 57 (2) 33 (3) 19 (5)

40-49 286 (11) 190 (19) 68 (19) 50-59 857 (34) 395 (39) 125 (35)

60-69 1095 (43) 342 (33) 114 (32) ≥70 238 (9) 63 (6) 27 (8) Gender

Male 1527 (60) 512 (50) 204 (58) Female 1010 (40) 513 (50) 149 (42)

Race/Ethnicity Non-Hispanic, Caucasian 2537 0 0

Non-Hispanic, African-American 0 1025 0 Non-Hispanic, Asian 0 0 96 (27) Non-Hispanic, Pacific islander 0 0 9 (3)

Non-Hispanic, Native American 0 0 20 (6) Hispanic, Caucasian 0 0 204 (58)

Hispanic, African-American 0 0 19 (5) Hispanic, Asian 0 0 1 (<1) Hispanic, Pacific islander 0 0 1 (<1)

Hispanic, Native American 0 0 3 (<1) Missing 0 0 0

Karnofsky score < 90 1439 (57) 459 (45) 205 (58)

90-100 1030 (41) 545 (53) 141 (40) Missing 68 (3) 21 (2) 7 (2)

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Conditioning regimen Melphalan + TBI only 6 (<1) 6 (<1) 0 Melphalan + TBI + others 4 (<1) 0 0

Melphalan only (not TBI) 2382 (94) 990 (97) 333 (94) Melphalan + others (not TBI) 117 (5) 16 (2) 13 (4) Missing – will be checked 28 (1) 13 (1) 7 (2)

Cytogenetic risk High Risk 338 (13) 144 (14) 64 (18) Intermediate Risk 289 (11) 97 (9) 34 (10)

Standard risk 586 (23) 276 (27) 84 (24) No abs/no metaphase 868 (34) 353 (34) 105 (30) Cytogenetics tested but results missing 129 (5) 28 (3) 12 (3)

Missing 327 (13) 127 (12) 54 (15) Disease status prior to HCT SCR/CR/ NCR near CR 391 (15) 147 (14) 73 (21)

VGPR 705 (28) 304 (30) 101 (29) PR 1147 (45) 456 (44) 145 (41)

SD 182 (7) 78 (8) 23 (7) PD/REL from CR 109 (4) 36 (4) 10 (3) Missing 3 (<1) 4 (<1) 1 (<1)

Time from diagnosis to transplant <6 months 819 (32) 210 (20) 89 (25) 6-12 months 1131 (45) 501 (49) 176 (50)

12-18 months 229 (9) 135 (13) 37 (10) 18-24 months 92 (4) 60 (6) 15 (4) >24 months 266 (10) 117 (11) 36 (10)

Missing 0 2 (<1) 0 Tandem trasnplant One auto only 2041 (80) 891 (87) 302 (86)

Auto/auto planned 227 (9) 63 (6) 26 (7) Auto/allo planned 45 (2) 6 (<1) 3 (<1) Salvage auto 168 (7) 54 (5) 18 (5)

Salvage allo 56 (2) 11 (1) 4 (1) Year of transplant 2008 669 (26) 144 (14) 60 (17)

2009 238 (9) 62 (6) 18 (5)

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2010 150 (6) 80 (8) 16 (5) 2011 236 (9) 61 (6) 30 (8) 2012 248 (10) 61 (6) 20 (6)

2013 399 (16) 135 (13) 77 (22) 2014 277 (11) 211 (21) 64 (18) 2015 320 (13) 271 (26) 68 (19)

Median follow-up of survivors (range), months 47 (3-104) 24 (3-100) 25 (3-98) *Additional patients might be added after path report and “other specify” field review

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Proposal 1611-34 Title: Exploring the Transplant Center Volume-Outcomes relationship in MM Saurabh Chhabra: Medical College of Wisconsin Binod Dhakal: Institution Name: Medical College of Wisconsin Hypothesis: OS of myeloma patients is longer if they receive autologous transplant at a higher volume center compared to a lower volume center. This is mediated by superior survival post-relapse after autologous HCT at higher volume centers. Specific aims:

• To evaluate OS in myeloma patients receiving autologous transplantation as a function of the volume of the transplant center

• To evaluate PFS after the first autologous transplant in patients with myeloma as a function of the volume of the transplant center

Scientific justification: The last 10 years have seen rapid and remarkable progress in the field of multiple myeloma. We have four new classes of drugs that did not exist before 2005 and the median survival has continued to increase for patients with myeloma. Autologous transplantation has remained a widely established treatment for the treatment of myeloma. There has been evidence from the field of Surgery that higher volume center are associated with improved outcomes [1]. More recently, there is evidence based on registry studies (observational and retrospective) that in patients with acute myeloid leukemia (AML), inpatient mortality is increased at lower volume centers (<75th percentile) (5% vs. 2%) compared to higher volume centers (above 75th percentile) [2]. Similarly, a recently published study from Mayo Clinic where the authors evaluated mortality of patients with myeloma based on the volume of the treating center utilizing the National Cancer Database demonstrated clearly that patients treated at higher volume centers have a longer overall survival (OS) [3]. The disparity seemed to be increasing in more recent times than 10 years ago. The investigators speculated multiple arguments for the difference in OS seen in the study: myeloma care is becoming increasingly complex with the explosion of biological and clinical information and the availability of new drugs not only in the field of myeloma but in other malignancies such that the Oncologists at low volume centers who probably cater to a broader cancer patient population find the more common cancers and their management may take priority and compete for their time with the myeloma management. The care processes and multidisciplinary support systems in place at the higher volume centers may also play a role in lowering the mortality. Better access to clinical trials of novel agents, fewer practice variations by following institution-based care pathways, higher adherence to national clinical practice guidelines may be other features of high volume centers that result in improved outcomes. Studies in hematopoietic cell transplantation have also suggested that center effect may be more important: for example, availability of physicians (as opposed to non-physician providers) to answer after-office or emergency calls and center accreditations by the Foundation for the Accreditation of Cellular Therapy (FACT) and the Clinical Trial Network (CTN) [4, 5]. In the proposed CIBMTR observational study, we aim to evaluate the OS (from diagnosis) and PFS of myeloma patients (from the onset of first-line therapy until first relapse post-transplant) as a function of the volume of the transplanting center.

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Study population: The study population includes patients over the age of 18 years who underwent a first autologous HCT for multiple myeloma and were reported to CIBMTR between 2008-2015. All the patients received melphalan-based conditioning regimen for autologous HCT. Patients who received transplant at one center but then moved to another center would be categorized under the first center. Patients receiving first allogeneic or tandem autologous-allogeneic transplant would be excluded. Second and subsequent transplants, however, would be allowed (autologous and allogeneic). Primary plasma cell leukemia patients would be excluded. The transplant centers will be divided into four quartiles groups for comparative analysis depending on the volume at the transplant centers. Outcomes: For multivariate analysis:

• Overall survival: Events are death by any cause. Surviving patients are censored at the time of last contact.

• 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.

• 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.

• Post Relapse Survival: Events are death by any cause occurring after first relapse or at any time due to myeloma progression after HCT. Surviving patients are censored at the time of last contact and deaths prior to relapse from any other are ignored.

Descriptive only: Hematopoietic recovery: The primary measures for hematopoietic recovery will be:

• Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution.

• Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 7 consecutive days, and (b) >50 x 109/L independent of platelet transfusions for 7 consecutive days.

Variables to be described: Patient related:

• Age: continuous; 18-49 vs. 50-59 vs. 60-69 • Gender: male vs. female • Race: white vs. black vs. others • Karnofsky performance score at transplant: <90% vs. ≥90%

Disease-related: • Stage at diagnosis (ISS or DS Stage III): yes vs. no • Beta 2 microglobulin at diagnosis: <3.5 vs. ≥3.5 mg/l • Immunochemical subtype: IgG vs. IgA vs. light chain vs. non-secretory/others • Albumin at diagnosis: ≤3.5 g/dl vs. >3.5 g/dl • Hemoglobin at diagnosis, g/dl: continuous • Creatinine at diagnosis: <2 mg/dl vs. ≥2 mg/dl • Serum calcium at diagnosis: ≤10.5 mg/dl vs. >10.5 mg/dl • HCT-CI: 0 vs. 1-2. Vs. ≥3

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• Cytogenetics at initial diagnosis: high risk vs standard risk • Disease status at autoHCT1: CR vs. PR vs. SD vs. REL/PD • Disease response after autoHCT1: CR/VGPR vs. PR vs SD vs PD

Treatment-related: • First-line induction chemotherapy regimen: PI vs. IMiD vs. PI + IMiD vs. others • Maintenance therapy after first transplant: Yes vs No • Melphalan Dose: 140-180 mg/m2 vs. >180 mg/m2 • Sensitivity to chemotherapy prior to transplant: sensitive vs resistant • Total No. of CD34+ cells infused, ×106/kg: continuous • Time from diagnosis to transplant: <6 months vs. 6-12 months vs. 12-24 months vs. >24

months • Year at transplant: by years

Variables to be analyzed: Main effect: High volume center vs Low volume center (such as Q4 vs Q3 vs Q2 vs Q1) Patient related:

• Age: continuous; 18-49 vs. 50-59 vs. 60-69 • Gender: male vs. female • Race: white vs. black • Karnofsky performance score at transplant: <90% vs. ≥90% • HCI-CI: 0 vs. 1-2. Vs. ≥3

Disease related: • Stage at diagnosis (ISS or DS Stage III): yes vs. no • Immunochemical subtype: IgG vs. IgA vs. light chain vs. non-secretory/others • Hemoglobin at diagnosis, g/dl: continuous • Creatinine at diagnosis: <2 mg/dl vs. ≥2 mg/dl

Treatment related: • First-line induction chemotherapy regimen: PI vs. IMiD vs. PI + IMiD vs. others • Melphalan Dose: 140-180 mg/m2 vs. >180 mg/m2 • Disease status at autoHCT1: CR vs. PR vs. SD vs. REL/PD • Disease response after autoHCT1: CR/VGPR vs. PR vs SD vs PD • Sensitivity to chemotherapy prior to autoHCT1: sensitive vs resistant • Time from diagnosis to transplant: <6 months vs. 6-12 months vs. 12-24 months vs >24 months • Time to relapse/progression after autoHCT1: <12 months vs 12-24 months vs >24 months • Planned post-autoHCT1 therapy: PI vs. IMiD vs. None

Study design: The goal of this study is to compare the clinical outcomes of myeloma patients depending on the transplant center where they receive their first autologous transplant, while adjusting for significant patient-, disease-, and transplant-related variables. The transplant centers will be divided into four quartiles groups for comparative analysis depending on the volume at the transplant centers. Overall and progression-free survivals will be calculated by Kaplan-Meier, and univariate comparisons will be made by the log-rank test for binary or categoric variables and by Cox proportional hazard regression for continuous and ordered categoric variables and for multivariable analyses.

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References: 1. Halm, E.A., C. Lee, and M.R. Chassin, Is volume related to outcome in health care? A systematic

review and methodologic critique of the literature. Ann Intern Med, 2002. 137(6): p. 511-20. 2. Giri, S., et al., Impact of hospital volume on outcomes of patients undergoing chemotherapy for

acute myeloid leukemia: a matched cohort study. Blood, 2015. 125(21): p. 3359-60. 3. Go RS, B.A., Crowson CS, et al. , Association Between Treatment Facility Volume and Mortality of

Patients With Multiple Myeloma. J Clin Oncol, 2016. DOI: 10.1200/JCO.2016.68.3805 epub ahead of print.

4. Marmor, S., et al., The impact of center accreditation on hematopoietic cell transplantation (HCT). Bone Marrow Transplant, 2015. 50(1): p. 87-94.

5. Loberiza, F.R., Jr., et al., Association of transplant center and physician factors on mortality after hematopoietic stem cell transplantation in the United States. Blood, 2005. 105(7): p. 2979-87.

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Characteristics of US adult patients, divided into quartiles (Q) by center volume of transplants, who underwent melphalan-based conditioning regimen first Autologous HCT for MM from 2008-2015 and

reported with CIBMTR

Q1 N=1-53

Q2 N=54-123

Q3 N=124-260

Q4 N=261+

Number of patients 842 3416 7539 21326 Is recipient on Ted or on CRF CRF* 66 (8) 489 (14) 886 (12) 2795 (13) Number of centers 40 41 39 40 Age 61 (28-79) 61 (22-81) 61 (23-83) 61 (19-84) Median (range) 10-19 0 0 0 2 (<1) 20-29 1 (<1) 4 (<1) 17 (<1) 44 (<1) 30-39 19 (2) 64 (2) 147 (2) 398 (2) 40-49 79 (9) 362 (11) 929 (12) 2489 (12) 50-59 272 (32) 1124 (33) 2498 (33) 7045 (33) > 60 471 (56) 1862 (55) 3948 (52) 11348 (53) Gender Male 488 (58) 2044 (60) 4272 (57) 12313 (58) Female 354 (42) 1372 (40) 3267 (43) 9013 (42) Race/Ethnicity Caucasian, non-Hispanic 547 (65) 2426 (71) 5166 (69) 15633 (73) African-American, non-Hispanic 227 (27) 565 (17) 1500 (20) 3356 (16) Asian, non-Hispanic 7 (<1) 62 (2) 120 (2) 441 (2) Pacific islander, non-Hispanic 0 8 (<1) 10 (<1) 31 (<1) Native American, non-Hispanic 7 (<1) 10 (<1) 27 (<1) 63 (<1) Hispanic, Caucasian 40 (5) 249 (7) 562 (7) 1261 (6) Hispanic, African-American 5 (<1) 23 (<1) 23 (<1) 34 (<1) Hispanic, Asian 0 1 (<1) 2 (<1) 5 (<1) Hispanic, Parcific islander 0 2 (<1) 2 (<1) 7 (<1) Hispanic, Native American 0 1 (<1) 7 (<1) 8 (<1) Missing 9 (1) 69 (2) 120 (2) 487 (2) Karnofsky score < 90 552 (66) 2053 (60) 4483 (59) 11570 (54) 90-100 270 (32) 1305 (38) 2750 (36) 9173 (43) Missing 20 (2) 58 (2) 306 (4) 583 (3) Sorrorscore 0 350 (42) 1355 (40) 2650 (35) 7042 (33) 1 126 (15) 461 (13) 968 (13) 3078 (14) 2 121 (14) 509 (15) 1174 (16) 3488 (16) >2 244 (29) 1085 (32) 2745 (36) 7693 (36) TBD review needed 0 1 (<1) 0 3 (<1) Missing 1 (<1) 5 (<1) 2 (<1) 22 (<1)

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Q1 N=1-53

Q2 N=54-123

Q3 N=124-260

Q4 N=261+

Disease status prior to HCT SCR/CR/NCR near CR 147 (17) 575 (17) 1252 (17) 3076 (14) VGPR 258 (31) 1000 (29) 2074 (28) 6569 (31) PR/MR 329 (39) 1360 (40) 3426 (45) 9330 (44) SD 57 (7) 313 (9) 514 (7) 1400 (7) PD/REL near CR 42 (5) 131 (4) 228 (3) 897 (4) Missing 9 (1) 37 (1) 45 (<1) 54 (<1) Conditioning regimen TBI + melphalan 1 (<1) 17 (<1) 0 12 (<1) Melphalan (only)±other(not TBI) 489 (58) 2195 (64) 4760 (63) 14915 (70) Missing 352 (42) 1204 (35) 2779 (37) 6399 (30) Time from diagnosis to transplant <6 months 180 (21) 879 (26) 1756 (23) 6316 (30) 6-12 months 364 (43) 1511 (44) 3494 (46) 9224 (43) 12-18 months 118 (14) 394 (12) 934 (12) 2158 (10) 18-24 months 57 (7) 200 (6) 396 (5) 997 (5) >24 months 122 (14) 426 (12) 948 (13) 2609 (12) Missing 1 (<1) 6 (<1) 11 (<1) 22 (<1) Graft type Bone marrow 0 2 (<1) 13 (<1) 9 (<1) Peripheral blood 842 3414 7525 21317 Cord blood 0 0 1 (<1) 0 Type of transplant One auto only 712 (85) 2978 (87) 6700 (89) 18481 (87) Auto/auto planned 48 (6) 175 (5) 347 (5) 1053 (5) Auto/allo planned 10 (1) 27 (<1) 43 (<1) 281 (1) Salvage auto 58 (7) 200 (6) 365 (5) 1145 (5) Salvage allo 14 (2) 36 (1) 84 (1) 366 (2) Year of transplant 2008 75 (9) 320 (9) 566 (8) 1542 (7) 2009 91 (11) 371 (11) 724 (10) 1972 (9) 2010 89 (11) 383 (11) 833 (11) 2429 (11) 2011 96 (11) 411 (12) 875 (12) 2880 (14) 2012 95 (11) 432 (13) 1014 (13) 3077 (14) 2013 91 (11) 428 (13) 1139 (15) 3098 (15) 2014 145 (17) 540 (16) 1133 (15) 3141 (15) 2015 160 (19) 531 (16) 1255 (17) 3187 (15) Planned treatment No 210 (25) 653 (19) 1938 (26) 5213 (24) Yes 343 (41) 1581 (46) 3477 (46) 9584 (45) Missing 289 (34) 1182 (35) 2124 (28) 6529 (31) Median follow-up of survivors (range), months 34 (3-102) 37 (3-102) 36 (3-105) 37 (3-102)

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Proposal 1609-02/1611-40/1611-53/1611-133 Title: Hematopoietic Cell Transplantation for Primary Plasma Cell Leukemia in the Era of Novel Agents Saulius Girnius, MD, [email protected], University of Cincinnati Sagar S. Patel, MD, [email protected], Cleveland Clinic - Taussig Cancer Institute Lohith S. Bachegowda, MD, [email protected], MD Anderson Cancer Center Binod Dhakal, MD, MS, [email protected], Medical College of Wisconsin Hypothesis: We hypothesize that in the era of novel agents and improved supportive care, overall survival has improved in those treated with hematopoietic cell transplantation (HCT) for primary plasma cell leukemia (pPCL). Specific aims: This study will evaluate transplant outcomes of patients aged ≥ 18 years with pPCL who underwent autologous HCT (auto-HCT) and allogeneic (allo-HCT). Our specific aims are: Primary

• To determine the overall survival (OS), progression free survival (PFS), relapse, and non-relapse mortality (NRM) in patients with pPCL after HCT.

Secondary • To determine the incidence and severity of acute and chronic graft-versus-host disease

(GVHD) after allo-HCT • To determine engraftment outcomes • To determine the cause of death • To compare the OS, PFS and NRM in those receiving a single auto-HCT, a tandem auto-HCT,-

allo-HCT and allo-HCT Scientific impact and justification: pPCL is an aggressive and rare proliferative plasma cell disorder with a very poor prognosis and limited effective treatment options. It is diagnosed by high levels of circulating plasma cells (absolute plasma cell of >2x106 cells/l or relative plasmacytosis of >20% of blood leucocytes) (1, 2). pPCL presents de novo and comprises 60-70% of PCL cases; the remainder progress from multiple myeloma (MM) (secondary PCL) (3, 4). Patients with PCL are known to harbor multiple high-risk cytogenetic abnormalities leading to high proliferative rates and rapidly progressive disease (3). Historically, some 28% of patients die within the first month after diagnosis (5). Previous studies have shown that even with autologous HCT, median OS is around 12 months (6). Treatment of pPCL is derived from management of MM, with induction treatment followed by auto-HCT or allo-HCT. Bortezomib-based induction is generally preferred based on a number of retrospective studies showing its benefit (7, 8). At present, there remains controversy given limited data on optimal transplant approaches as both autologous and allogeneic options have been utilized (9-11). The role of HCT in PCL is less well established as most of these patients were excluded in the prospective randomized trials in MM. The largest retrospective report comes from the European Group for Blood and Marrow Transplantation’s (EBMT) analysis of 272 patients with PCL undergoing auto-HCT from 1980-2006 compared to 20,844 patients with MM (9). PCL patients had inferior PFS (median 14 months vs. 27 months) and OS (median 26 months vs. 62 months) compared to those with MM. Given the timing of the study, novel agents were rarely used. A previous Center for International Blood and Marrow Transplant

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Research (CIBMTR) study established the safety and feasibility of auto-HCT after initial induction therapy in pPCL (10). In this study, 147 patients with primary PCL underwent auto-HCT (N= 97) or allo-HCT (N=50) within 18 months of diagnosis from 1995-2006. The 3-year PFS with auto-HCT vs. allo-HCT was 34% vs. 20%; 3-year OS was 64% vs. 39% indicating an inferior survival with allo-HCT. Amongst the allo-HCT MAC, allo-HCT RIC, and auto-HCT cohorts, thalidomide use was only 6%, 25%, and 25%, while bortezomib use was only 6%, 0%, and 5%, respectively. In another multi-center retrospective review, 73 patients with pPCL in which 46 (63%) of patients received bortezomib or thalidomide or both during the first or second line treatment (11). In this highly-selected group, patients who survived initial therapy and received HCT had superior survival and response durations when compared with those who did not receive HCT. Furthermore, the patients receiving novel agents at any stage of treatment had a decreased risk of death in respect to those having never received them, with a borderline statistical significance (HR for death 0.47, 95% CI 0.21–1.03). In a phase II trial of 40 patients with pPCL, bortezomib based induction followed by either tandem auto-HCT or auto-allo HCT resulted in high response rates and improved PFS (median PFS and OS 15 and 16 months, respectively) (12). The Arkansas group, in juxtaposition, was unable to demonstrated improved OS or PFS in persons with pPCL, even as novel agents were introduced in Total Therapy 2 and 3 (13). Likewise, the Japanese Society of Myeloma demonstrated a doubling in OS when using novel agents, but advanced age, not the lack of use of novel agents, was prognostic for inferior OS(14). During the time periods 1973-1995 and 2006-2009, population-based studies have shown a median OS improvement from 5 to 12 months, respectively (6). Due to ongoing paucity of large-scale prospective studies, as well as conflicting findings with novel agents, we propose to study the efficacy of HCT in the era of novel. The results of our study could identify the utility of HCT with newer drugs and also offer insights to design future post HCT studies aimed at incorporating maintenance therapy. Additionally, this study would highlight the impact improved supportive care, GVHD prophylaxis, and expanded use of reduced-intensity conditioning regimens have on NRM and OS in allo-HCT. Thus, an updated analysis to reflect these developments is needed. Study population: Inclusion Criteria:

• Patients ≥ 18 years of age with pPCL as per the International Myeloma Working Group (IMWG) undergoing the first auto-HCT or allo-HCT between 1/2007-12/2015

• For allo-HCT, HLA matched sibling, matched unrelated, haplo-identical donor, and cord blood sources

• Myeloablative and reduced-intensity transplants • Bone marrow, peripheral blood, and umbilical cord graft sources • Single or tandem HCTs • All disease stages

Exclusion Criteria: • Secondary plasma cell leukemia

Data requirements: Data will be analyzed from the CIBMTR Report forms. No supplemental data will be required. Outcomes:

• Non-relapse mortality (NRM): Cumulative incidence of NRM at day 100 and 1, 3, and 5 years. Defined as death without preceding disease relapse/progression. Relapse/progression are competing events.

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• Relapse/Progression: Cumulative incidence of disease relapse/progression at 1, 3, and 5 years, with NRM as competing event.

• Progression-free survival (PFS): Survival without relapse/progression or death. Relapse or progression of disease and death are competing events. Those who survive without relapse/progression are censored at last follow-up.

• Overall survival (OS): Time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

• Acute Graft-versus-host disease (aGVHD): Severity as grades II-IV; time from transplant to first grade 2-4 and 3-4 aGVHD.

• Chronic Graft-versus-host disease (cGVHD): Severity as limited and extensive; time from transplant to first limited chronic GVHD and time from transplant to first extensive cGVHD.

• Neutrophil engraftment: Time to neutrophils (ANC) > 0.5 x109/L sustained for 3 consecutive days.

• Platelet engraftment: Time to achieve a platelet count >20 x 109/L independent of platelet transfusions for 7 consecutive days.

Variables: Patient-related:

• Age at HCT, years: 18-29; 30-39; 40-49, 50-59, ≥60 years and continuous • Gender: male vs. female • Karnofsky performance score: ≥80% vs. <80% • Race: White vs. Black vs. Asian/pacific islander vs. Hispanic vs. others • Hematopoietic cell transplantation co-morbidity index (HCT-CI) (≥3 vs. <3)

Disease-related: • Date of diagnosis • International staging system (ISS)/ Durie Salmon Stage: I vs. II vs. III • Immunochemical subtype: IgG vs. IgA vs. light chain vs. non-secretory/others • Hemoglobin at diagnosis: g/dL, continuous • Creatinine at diagnosis: <2 mg/dL vs. ≥2 mg/dL • Albumin at diagnosis: g/dL, (<3.5 g/dL vs. >3.5 g/dL) • Beta-2-microglobulin at diagnosis: mcg/mL, continuous \ • Cytogenetics: High risk vs. standard risk • Gene Expression Profiling • Induction therapy: Doublet vs. triplet • First line induction chemotherapy: IMID/PI, non-IMID/PI, non-PI/IMID vs. others • Time from diagnosis to transplant (<12 months vs 6-12 months vs. 12-18 months) • Disease status at transplant: sCR/CR/NCR near CR vs. VGPR vs PR vs. MR vs. SD vs. REL/PD

Transplant-related: • Date of transplant • HCT-CI (0, 1-2, >3) • Autologous vs. allogeneic transplant • Melphalan Dose: 140-180 mg/m2 vs. >180mg/m2 • Conditioning regimen for allo-HCT: RIC vs. MA • GVHD prophylaxis regimen for allo-HCT • Donor Type • Graft source: BM vs. PBSC vs. UCB

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• HLA matching status • Donor-recipient CMV status • Time from diagnosis to HCT: <6 months vs. 6-12 months vs. 12-18 months • Planned upfront transplant (Yes vs. No) • Planned tandem transplant (Yes vs. No) • Post-transplant maintenance therapy (Yes vs. No; if Yes – PI vs. IMiD vs. both)

Study design: This is a retrospective analysis examining HCT outcomes for those with pPCL in the novel agent era. The analysis will be restricted to 2007 to 2015. Patient-, disease-, and transplant-related factors will be compared between groups (auto-HCT vs. allo-HCT) using the Chi-square test for categorical variables and the Wilcoxon two sample test for continuous variables. Specific response criteria for pPCL are not defined and thus we will utilize the IMWG criteria for MM. Kaplan-Meier product limit estimates will be used to calculate the probabilities of OS and PFS. The cumulative incidence of NRM, disease progression, and acute and chronic GVHD will be estimated accounting for competing risks. Cox proportional hazards regression will be used to compare the two HCT types for: NRM, relapse/progression, PFS, OS, neutrophil and platelet engraftment. The variables to be considered in the multivariate models will include patient-, disease-, and transplant-related factors as described previously. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. A forward stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main effect for the type of HCT. Factors which are significant at a 5% level will be kept in the final model. The potential interactions between main effect and all significant covariates will be tested. If the number of censored observations before the specific day is not ignorable, the pseudo-value approach will be performed. References 1. Kyle RA, Maldonado JE, Bayrd ED. Plasma cell leukemia. Report on 17 cases. Arch Intern Med. 1974

May;133(5):813-8. 2. Noel P, Kyle RA. Plasma cell leukemia: an evaluation of response to therapy. Am J Med. 1987

Dec;83(6):1062-8. 3. Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA, et al.

Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008 May;22(5):1044-52. 4. Fernandez de Larrea C, Kyle RA, Durie BG, Ludwig H, Usmani S, Vesole DH, et al. Plasma cell

leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013 Apr;27(4):780-91.

5. Ramsingh G, Mehan P, Luo J, Vij R, Morgensztern D. Primary plasma cell leukemia: a Surveillance, Epidemiology, and End Results database analysis between 1973 and 2004. Cancer 2009; 115(24): 5734-9.

6. Gonsalves WI, Rajkumar SV, Go RS, Dispenzieri A, Gupta V, Singh PP et al. Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood 2014; 124(6): 907-12.

7. Gertz MA. Managing plasma cell leukemia. Leuk Lymphoma. 2007 Jan;48(1):5-6. 8. Katodritou E, Terpos E, Kelaidi C, Kotsopoulou M, Delimpasi S, Kyrtsonis MC, et al. Treatment with

bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group. Am J Hematol. 2014 Feb;89(2):145-50.

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9. Drake MB, Iacobelli S, van Biezen A, Morris C, Apperley JF, Niederwieser D, et al. Primary plasma cell leukemia and autologous stem cell transplantation. Haematologica. 2010 May;95(5):804-9.

10. Mahindra A, Kalaycio ME, Vela-Ojeda J, Vesole DH, Zhang MJ, Li P, et al. Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research. Leukemia. 2012 May;26(5):1091-7.

11. Pagano L, Valentini CG, De Stefano V, Venditti A, Visani G, Petrucci MT, et al. Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. Ann Oncol. 2011 Jul;22(7):1628-35.

12. Royer B, Minvielle S, Diouf M, Roussel M, Karlin L, Hulin C, et al. Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2016 Jun 20;34(18):2125-32.

13. Usmani SZ, Nair B, Qu P, et al. Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling and clinical outcome with Total Therapy protocols. Leukemia. 2012;26(11):2398-2405

14. Iriuchishima H, Ozaki S, Konishi J, et al. Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma. Acta Haematol. 2016;135(2):113-121

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Characteristics of patients >18yrs of age with PCL undergoing auto or allo HCT registered to the CIBMTR between 2008-2015

AlloHCT AutoHCT Number of patients 156 421 CRF (research level only)* 33 (21) 46 (11) Number of centers 75 128 Patient age at HCT, years Median (range) 53 (22-71) 59 (25-77) 20-29 6 (4) 2 (<1) 30-39 12 (8) 16 (4) 40-49 43 (28) 64 (15) 50-59 69 (44) 148 (35) > 60 26 (17) 191 (45) Patient Gender Male 78 (50) 208 (49) Female 78 (50) 213 (51) Race/Ethnicity Caucasian, non-Hispanic 111 (71) 286 (68) African-American, non-Hispanic 20 (13) 80 (19) Asian, non-Hispanic 8 (5) 8 (2) Pacific islander, non-Hispanic 2 (1) 0 Hispanic, Caucasian 6 (4) 14 (3) Hispanic, African-American 1 (<1) 1 (<1) Missing 8 (5) 32 (8) Karnofsky score 90-100 95 (61) 226 (54) < 90 58 (37) 189 (45) Missing 3 (2) 6 (1) Sorror score

0 56 (36) 127 (30) 1 11 (7) 46 (11) 2 25 (16) 62 (15) >2 54 (35) 164 (39) Missing 10 (6) 22 (5) Disease status prior to HCT SCR/CR/NCR near CR 48 (31) 96 (23) VGPR 36 (23) 114 (27) PR/MR 43 (28) 142 (34) SD 10 (6) 25 (6) PD/REL near CR 19 (12) 29 (7) Missing 0 15 (4)

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AlloHCT AutoHCT Conditioning intensity / TBI based Myeloablative-TBI based 25 (16) NA Myeloablative-non TBI 32 (21) NST/RIC-TBI based 43 (28) NST/RIC-non TBI 28 (18) Missing** 28 (18) Conditioning regimen

TBI + melphalan 10 (6) 0 TBI(only) ± other (not melphalan) 58 (37) 1 (<1) Melphalan only ± other(not TBI) 33 (21) 270 (64) No TBI nor melphalan 28 (18) 2 (<1) Missing – will be checked 27 (17) 148 (35) Time from diagnosis to transplant

<6 months 41 (26) 215 (51) 6-12 months 59 (38) 149 (35) 12-18 months 23 (15) 15 (4) 18-24 months 8 (5) 11 (3) >24 months 25 (16) 31 (7) Graft type

Bone marrow 17 (11) 1 (<1) Peripheral blood 129 (83) 420 Cord blood 10 (6) 0 Type of donor

HLA-matched sibling 65 (42) NA Other relative 14 (9) Unrelated 77 (49) CMV match

NA

Positive/positive 39 (25) Positive/negative 9 (6) Negative/positive 35 (22) Negative/negative 39 (25) Missing 34 (22) Sex match

NA

Male/male 42 (27) Male/female 46 (29) Female/male 34 (22) Female/female 30 (19) Missing 4 (3)

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AlloHCT AutoHCT Donor gender

NA

Male 88 (56) Female 64 (41) Missing 4 (3) Type of transplant

One allo only 51(33) 0 One auto only 0 278 (66) Auto/auto planned 0 54 (13) Auto/allo planned 43 (28) 43 (10)

Allo/allo planned 5 (3) 0

Salvage Auto 0 32 (8)

Salvage Allo 57 (37) 14 (3) Year of transplant 2008 19 (12) 37 (9) 2009 23 (15) 45 (11) 2010 19 (12) 53 (13) 2011 14 (9) 54 (13) 2012 21 (13) 46 (11) 2013 18 (12) 55 (13) 2014 17 (11) 64 (15) 2015 25 (16) 67 (16) GVHD prophylaxis

NA

T-cell depletion 1 (<1)

CD34 selection 2 (1)

Post-Cyclophosphamide 13 (8)

FK506+-other 80 (51) CSA+-other 50 (32) Other GVHD Prophylaxis 7 (4) Missing 3 (2) Median follow-up of survivors (range), months 48 (3-92) 36 (3-83) *The CIBMTR collects data at two levels: Transplant Essential Data (TED) level and Comprehensive Report Form (CRF) level. The TED-level data contains a limited number of key variables for all consecutive transplant recipients. When a transplant is registered with the CIBMTR, a subset of patients are selected for the CRF level of data collection. The CRF-level captures additional more in-depth patient, disease and treatment-related data. **MA=11, NonMA=6, RIC=10

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Proposal 1611-153 Title: The Impact of Bortezomib Based Induction Therapy vs No Induction Therapy on Outcomes for Light Chain Amyloidosis Robert F. Cornell: Vanderbilt University Medical Center Luciano Costa: University of Alabama-Birmingham Stacey A. Goodman: Vanderbilt University Medical Center Specific aims: To compare pre-transplant bortezomib-based induction therapy with no induction therapy prior to autologous hematopoietic cell transplantation (AHCT) and determine pre-transplant disease status, mortality rates, day-100 post-transplant disease status, TRM, hematopoietic recovery rates, relapse/progression progression-free survival and overall survival in patients with light chain (AL) amyloidosis. Scientific justification: AL amyloidosis is a monoclonal plasma disorder that can result in multi-organ dysfunction from amyloid fibril deposition.1 Amyloid fibrils are misfolded immunoglobulin light chains produced from plasma cell clones.2 Common sites of involvement include cardiac, renal, gastrointestinal and the peripheral and autonomic nervous systems.3

Management of AL amyloid involves optimal medical management of end-organ damage while instituting therapy to target the amyloid fibril producing plasma cells.4 Currently, there are three treatment strategies for targeting plasma cells in AL. The first option is treatment with chemotherapy alone. Historically, melphalan-based regimens were used, but recently use bortezomib-based therapies have become standard practice at many institutions.5 In some cases (option two) patients are able to proceed with consolidative AHCT based on end-organ damage (cardiac in particular), age, performance status and institutional practice. The third management option is to proceed with AHCT without induction therapy. Historically, routine use of AHCT was limited by high transplant related mortality (TRM).3 In recent years, TRM has decreased 3-5% as a result of better patient selection and improved supportive care measures, including stem cell collection technique, melphalan dose adjustments, post-high dose melphalan growth factor support, and infective prophylaxis.3, 6 It remains unclear if pre-AHCT induction therapy is superior to proceeding directly AHCT without induction in eligible patients. The goal of this study to evaluate the outcome differences with these two approaches.

Study population: The study population includes all the patients in US and Canada who underwent autologous stem cell transplant with melphalan-based conditioning for AL amyloidosis and reported to CIBMTR between 2008 and 2015 in the era of bortezomib-based therapy for AL. Analysis will be limited to patients who either proceeded directly to AHCT without induction and those receiving bortezomib-based induction therapy prior to AHCT. Patients with concurrent myeloma evidenced by attributable end-organ damage (hypercalcemia, lytic lesions) will be excluded.

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Outcomes: 1. For multivariate analysis

• Mortality rate @ 30-days and 100-days: events are death by any cause. To be evaluated at day-30 and day-100 from transplant.

• Non-relapse mortality >100-days (NRM): time to death occurring in continuous complete remission, partial response, minimal response or stable disease beyond 100 days from transplant. This event is summarized by the cumulative incidence estimate with relapse as the competing risk.

• Hematologic relapse/progression: time to first evidence of laboratory recurrence or progression of amyloidosis based on the 2004 uniform consensus criteria proposed at the 10th International Symposium on Amyloidosis.

• Hematologic 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, no response or stable disease are censored at time of last follow-up.

• Overall survival: events are death by any cause. Surviving patients are censored at the time of last contact.

2. Descriptive only • Hematopoietic recovery: The primary measures for hematopoietic recovery will be: • Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days. This endpoint does

not specify whether recovery is engraftment of donor cells or autologous reconstitution. • Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 7

consecutive days, and (b) >50 x 109/L independent of platelet transfusions for 7 consecutive days.

3. Response rate • Hematologic response: the best hematologic response to the transplant based on the 2004

uniform consensus criteria proposed at the 10th International Symposium on Amyloidosis. • Renal response: the best renal response achieved after transplant. Renal response was defined

as at least a 50% decrease (at least 0.5 g/day) of 24-hour urine protein with less than 25% decrease in renal function.

Variables: Patient related:

• Age, continuous; by decades • Gender (male vs. female) • Race (White vs. Africa America vs. others) • Karnofsky performance score (<80% vs. ≥80%) • HCT co-morbidity score (0 vs. 1-2 vs. 3+)

Disease related: • Serum monoclonal immunoglobulin at diagnosis (only for Electroporesis), g/dl, (continuous) • Involved serum free light chain at diagnosis, continuous; (Kappa vs. Lambda) • Serum creatinine at diagnosis (≥2 mg/dl vs. <2 mg/dl) • Serum creatinine prior to transplant (≥2 mg/dl vs. <2 mg/dl) • Serum creatinine at any time pre-transplant (≥2 mg/dl vs. <2 mg/dl) • Serum albumin at diagnosis (≥3 g/dl vs. 2.5-3 g/dl vs. <2.5 g/dl) • Serum albumin prior to transplant (≥3 g/dl vs. 2.5-3 g/dl vs. <2.5 g/dl) • Serum albumin at any time pre-transplant (≥3 g/dl vs. 2.5-3 g/dl vs. <2.5 g/dl)

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• Bone marrow plasma cells at diagnosis (>10% vs. ≤10%) • Bone marrow plasma cells prior to transplant (>10% vs. ≤10%) • Cardiac involvement at diagnosis (yes vs. no) • Liver involvement at diagnosis (yes vs. no) • Renal involvement at diagnosis (yes vs. no) • Autonomic nervous system involvement at diagnosis (yes vs. no) • Organs involved at diagnosis (1 vs. 2 vs. 3 vs. ≥4) • Type of organ involvement (Cardiac vs. Predominant Renal vs. Others)

Transplant related: • Total No. of CD34+ cells infused (×106/kg), continuous • Melphalan dose, mg/m2 (<140 vs. 140-180 vs. ≥180) • Lines of chemotherapy (0 vs. 1 vs. 2 vs. 3) • Chemotherapy (Yes vs No) • Disease status at HCT (Untreated vs. CR/PR vs. MR/NR/SD vs. Rel/Prog) • Time from diagnosis to transplant (<6 months vs. 6-12 months vs. 12-24 months) • Year of transplant, by years • Experience of transplant center

Post-transplant related: • Length of inpatient days, continuous • Median follow-up of patients from the time of diagnosis, months • Median follow-up of patients from the time of transplant, months

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. 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 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. Kastritis, E. & Dimopoulos, M. A. (2015) Recent advances in the management of AL

Amyloidosis. British Journal of Haematology, doi: 10.1111/bjh.13805 2. D'souza, A., A. Dispenzieri, B. Wirk, M.-J. Zhang, J. Huang, M. A. Gertz, R. A. Kyle, S. Kumar, R. L.

Comenzo, R. Peter Gale, H. M. Lazarus, B. N. Savani, R. F. Cornell, B. M. Weiss, D. T. Vogl, C. O. Freytes, E. C. Scott, H. J. Landau, J. S. Moreb, L. J. Costa, M. Ramanathan, N. S. Callander, R. T. Kamble, R. F. Olsson, S. Ganguly, T. Nishihori, T. L. Kindwall-Keller, W. A. Wood, T. M. Mark, and P. Hari. "Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study." Journal of Clinical Oncology 33.32 (2015): 3741-749. Web.

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3. Merlini, G. & Bellotti, V. (2003) Molecular Mechanism of Amyloidosis.New England Journal of Medicine, 349, 585-596.

4. Gertz, M.A., Landau, H.J., Comenzo, R., Seldin, D.C., Weiss, B.M., Zonder J.A., Walling, J., Kinney, G., Koller, M. & Liedtke, M. (2015) Cardiac and renal biomarker response in a phase 1/2 study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction. Journal of Clinical Oncology, 33, supplement, abst 8514.

5. Cornell, R.F., Zhong, X., Arce-Lara, C., Atallah, E., Blust, L., Drobyski, W.R., Fenske, T.S., Pasquini, M.C., Rizzo, J.D., Saber, W., & Hari, P.N. (2015) Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. Bone Marrow Transplantation, 50, 914-917.

6. Dhakal, B., Strouse, C., D'souza, A., Arce-Lara, C., Esselman, J., Eastwood, D., Hamadani, M. (2014). Plerixafor and Abbreviated-Course Granulocyte Colony–Stimulating Factor for Mobilizing Hematopoietic Progenitor Cells in Light Chain Amyloidosis. Biology of Blood and Marrow Transplantation, 20(12), 1926-1931. doi: 10.1016/j.bbmt.2014.08.002

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Characteristics of U.S. patients who underwent a melphalan-based conditioning and Bortezomib based induction PB autoHCT for Amyloidosis reported to the CIBMTR from 2008-2015*

Variable Bort No-Bort

Number of patients 208 220 Number of centers 59 53 Patient age

Median (range) 60 (35-78) 60 (26-75) 20-29 0 1 (<1) 30-39 8 (4) 8 (4)

40-49 26 (13) 22 (10) 50-59 74 (36) 87 (40)

60-69 82 (39) 84 (38) >70 18 (9) 18 (8) Gender

Male 119 (57) 137 (62) Female 89 (43) 83 (38) Karnofsky Score

< 90 99 (48) 111 (50) 90-100 104 (50) 105 (48) Missing 5 (2) 4 (2)

Race/ethnicity Non-Hispanic, Caucasian 162 (78) 185 (84) Non-Hispanic, African-American 26 (13) 21 (10)

Non-Hispanic, Asian 3 (1) 4 (2) Non-Hispanic, Pacific islander 1 (<1) 0 Hispanic, Caucasian 8 (4) 7 (3)

Hispanic, African-American 0 1 (<1) Missing 8 (4) 2 (<1) Conditioning regimen

No preparative regimen 1 (<1) 2 (<1) BEAM 3 (1) 0 LPAM alone 203 (98) 217 (99)

LPAM±others 1 (<1) 1 (<1)

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Variable Bort No-Bort

Lines of chemotherapy 0 0 185 (84)

1 171 (82) 31 (14) 2 33 (16) 3 (1) 3 4 (2) 1 (<1)

Disease status prior to transplant Stringent Complete Remission 3 (1) 0 Complete Remission 22 (11) 4 (2)

Very Good Partial Remission 27 (13) 4 (2) Partial Remission 60 (29) 25 (11)

Stable Disease 43 (21) 49 (22) Progression 5 (2) 7 (3) REL from CR 0 4 (2)

Never treated 0 81 (37) Not evaluable 48 (23) 43 (20) Missing 0 3 (1)

Year of transplant 2008 9 (4) 68 (31) 2009 15 (7) 39 (18)

2010 0 3 (1) 2011 3 (1) 0 2012 2 (<1) 1 (<1)

2013 12 (6) 6 (3) 2014 81 (39) 62 (28) 2015 86 (41) 41 (19)

Median follow-up of survivors (range), months 13 (3-89) 25 (3-99) Data source: CRF *Patients with a time from diagnosis to transplant ≥24 were excluded (n=17 patients). US only selected (Canada with Bortezomib=1 excluded).

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