Impact of Upfront Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma with Del(17) and t(4;14): A Report from the EBMT Chronic Malignancies Working Party
Authors: Gagelmann Nico , Eikema Dirk-Jan , Iacobelli Simona , Schoemans Helene , Koster Linda , Caillot Denis , Blaise Didier , Reményi Péter , Bulabois Claude-Eric , Passweg Jakob R. , Leleu Xavier , Zver Samo , Kobbe Guido , Rambaldi Alessandro , Chevallier Patrice , Ringhoffer Mark , Martin Alexander M , Salmenniemi Urpu , Poire Xavier , Lenhoff Stig , Pioltelli Pietro , Mordini Nicola , Nahi Hareth , Schönland Stefan , Garderet Laurent , Yakoub-Agha Ibrahim , Kroeger Nicolaus 
Published: October 2019

Abstract
Introduction
Current consensus identifies translocations t(4;14), t(14;16), t(14;20), and del(17/17p) as high-risk cytogenetics in newly diagnosed multiple myeloma (NDMM). However, evidence on outcome of specific abnormalities according to types of transplant as first-line treatment is limited. We analyzed NDMM patients with del(17) and/or t(4;14) reported to the European Society for Blood and Marrow Transplantation (EBMT) registry undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation.
Methods
Upfront transplantation was defined as first autologous transplant within 12 months from MM diagnosis and tandem transplant was defined as a second transplant (autologous or allogeneic) within 6 months from first transplant. Survival and cumulative incidence were calculated from date of first transplant (95% confidence interval) and analyses were performed using a landmark approach of patients who were alive and relapse-free by month 6. End points were progression-free survival (PFS), overall survival (OS), relapse and non-relapse mortality (NRM).
Results
Patients. Within the EBMT registry, 498 NDMM patients with del(17) (n=224), t(4;14) (n=229) or both (n=45) could be analyzed between 2000-2015. First-line auto was received by 337, auto-auto by 99 and auto-allo by 62 patients. Frequencies of del(17)/t(4;14)/or both were 39/51/10% in auto, 58/36/6% in auto-auto, and 55/35/10% in auto-allo (p=0.01). Median age was 60 years in auto and auto-auto, and 52 years in auto-allo (p<0.001) and more than half of patients were male (53% in auto, 63% in auto-auto, 52% in auto-allo). Median time from diagnosis to transplant was 5 months in all groups. 85% received at least 200mg/m2 melphalan conditioning for first autologous transplant. Most patients had IgG subtype (51% in auto, 60% in auto-auto, 58% in auto-allo). Disease stage according to ISS I/II/III was 23/55/22% in auto, 18/69/13% in auto-auto, and 14/63/23% in auto-allo. More patients receiving auto were in complete remission (CR) at time of first transplant (21%) compared with auto-auto (11%) and auto-allo (7%; p=0.01).
Posttransplant outcome and cytogenetics. The median follow-up of all patients was 57 months (55 months for auto, 57 months for auto-auto, and 64 months for auto-allo). 5-year PFS according to transplant was 18% (12-23) for auto, 32% (22-43) for auto-auto, and 32% (19-45) for auto-allo (p=0.11) and 5-year OS was 47% (41-54) for auto, 51% (40-63) for auto-auto, and 65% (51-78) for auto-allo (p=0.28). Relapse incidence was 82% (77-87) for auto, 63% (53-74) for auto-auto, and 58% (44-72) for auto-allo (p=0.002) while NRM was 1%, 4%, and 10%. PFS and OS according to cytogenetics was 24% and 58% for del(17), 22% and 42% for t(4;14), and 19% and 55% for presence of both. When stratified according to cytogenetics and transplant, PFS in del(17) was 21% (12-29) for auto, 26% (13-39) for auto-auto, and 30% (13-47) for auto-allo (p=0.78) while OS was 56% (45-67) for auto, 56% (41-70) for auto-auto, and 67% (50-84) for auto-allo (p=0.74). Relapse incidence and NRM were 79% and 1% for auto, 70% and 4% for auto-auto, and 64% and 6% for auto-allo. Single autologous transplant showed significantly worse PFS in t(4;14) resulting in 15% (8-22) compared with 45% (26-63) for auto-auto, and 39% (16-61) for auto-allo (p=0.05). OS was 39% (30-48) for auto, 37% (13-60) for auto-auto, and 63% (38-88) for auto-allo. Relapse incidence was also significantly higher in auto showing 84% (77-91) in comparison with 49% (30-67) for auto-auto and 52% (29-75) for auto-allo (p=0.004).
Multivariable analysis. A Cox regression was fitted to compare types of transplant after adjusting for cytogenetics, sex, age, ISS, and remission status. Subsequently, auto-auto (hazard ratio, 0.66) and auto-allo (hazard ratio, 0.58) were associated with better PFS while auto-allo appeared to result in better OS (hazard ratio, 0.71) in comparison with single autologous transplant. Both auto-auto and auto-allo were significantly associated with lower incidence of relapse after fitting a Fine and Gray model (p<0.001, respectively).
Conclusion
In NDMM patients undergoing upfront transplantation, PFS and relapse incidence were improved in patients specifically with del(17) and t(4;14) receiving tandem autologous or autologous/reduced-intensity allogeneic transplant.

Disclosures
Leleu: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Rambaldi:Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Omeros: Consultancy; Amgen Inc.: Consultancy. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kroeger:Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; JAZZ: Honoraria.