Maintenance after Autologous Hematopoietic Cell Transplantation Improves Overall Survival and Progression Free Survival Regardless of Disease Stage at Transplant in Newly Diagnosed Myeloma Patients: A Global, Real-World Analysis from the Worldwide Network for Blood and Marrow Transplantation Global Study

Background：

In eligible newly diagnosed myeloma patients, autologous hematopoietic cell transplantation (AHCT) is the standard of care. The most important prognostic factors are response status at the time of AHCT and receipt of maintenance therapy. Len maintenance post AHCT improves progression-free survival (PFS) and overall survival (OS). Using a global registry, we analyzed whether Len or Thal maintenance can overcome a suboptimal hematological response at AHCT.

Methods:

Data were provided by the Worldwide Network for Blood and Marrow Transplantation (WBMT) through the European Society for Blood and Marrow Transplantation (EBMT), the Center for International Blood and Marrow Transplantation (CIBMTR), the Asian Pacific Blood and Marrow Transplant Group (APBMT), the Eastern Mediterranean Blood and Marrow Transplant Group (EMBMT), the Latin American Bone Marrow Transplant group (LABMT), and the Ottawa hospital myeloma registry. The study included newly diagnosed myeloma patients receiving AHCT between 2013 and 2017 with data available on maintenance treatment. The primary endpoint was OS and secondary endpoints were PFS, Multivariable 6-month landmark analyses were performed using Cox proportional hazards models including a random effect for country. Apart from maintenance post AHCT (Len vs. Thal vs no maintenance) and hematological response at AHCT, models included patient sex, year of AHCT, Karnofsky score at AHCT, myeloma subclassification, conditioning dosage, interval between diagnosis and AHCT, HCT comorbidity index, ISS at diagnosis, and cytogenetic risk score.

Results:

Among the 61,797 patients in the WBMT study, 11% had information on maintenance. Fifty-one percent had Len (3460 pts), 38% other than Len (2640 pts, including 672 with Thal) and 11% none (767 pts). We report characteristics of the 4903 patients with Len, Thal or no maintenance (47.0% EBMT, 33.9% CIBMTR, 10.4% APBMT, 0.9% EMBMT, 4.4% LABMT, 3.4% Canada) and include 4555 of these who were alive at 6 months post-AHCT in the OS and 4334 who additionally were without relapse in the PFS analysis. The median age at AHCT was 60.0 (IQR: 53.7-65.5) years. Response status at AHCT was: complete response (CR) (19%), very good partial response (VGPR) (39%), partial response (PR) (36%), stable disease/minor response (SD/MR) (5%), relapse/progression (Prog) (1%).

Median follow-up after AHCT was 45 months. In univariable analyses, Len and, to a lesser extent, Thal maintenance was associated with improved OS, PFS, lower RI and NRM (all p<0.001) compared to no maintenance. Improvements were observed regardless of disease status at HCT. OS at 3 years for CR, VGPR, PR and SD/MR/Prog patients was 82%, 80%, 81% and 72% in those without maintenance and was 92 (+10)%, 89 (+9)%, 88 (+7)%, 84 (+12)%, respectively for those with Len, (log-rank p<0.001). PFS at 3 years ranged from 61, 54, 45 and 35% without maintenance to 72 (+11)%, 68 (+14)%, 63 (+18)%, 58 (+23)% with Len for CR, VGPR, PR and SD/MR/Prog patients, respectively (log-rank p<0.001).

In the MVA, better response status at AHCT, and Len maintenance were significantly associated with better OS and PFS. The OS and PFS HR (95% CI) comparing no maintenance vs Len were 1.92, (1.52-2.43), p=0.0004 and HR 1.74 (1.51-2.02) p<0.0001, respectively. The OS HR (95% CI) for VGPR, PR, SD/MR and Rel/Prog vs CR at AHCT was 1.07 (0.82-1.40), 1.23 (0.94-1.61), 1.79 (1.18-2.72) and 2.71 (1.55-4.74), respectively, (overall p=0.0003). For PFS, these estimates were 1.12 (0.95-1.32), 1.43 (1.21-1.68), 1.78 (1.37-2.32) and 2.10 (1.40-3.15), respectively (overall p<0.0001). In the MVA for OS, the benefit of Len maintenance decreased with longer time after AHCT (non-proportional hazards p=0.0002). The HR for no maintenance vs. Len decreased from 3.89 (95% CI 2.55-5.93) at 6 months to 1.02 (95% CI 0.67-1.54) at 36 months. For PFS, a less strong decrease in the HR over time was observed (p=0.05). The HR comparing no maintenance vs Thal for OS was 1.38 (0.98-1.95) and for PFS was 1.21 (0.98-1.49), p=0.06 and 0.07, respectively.

Conclusions:

In this global study of myeloma patients who underwent upfront AHCT, Len maintenance improved PFS and OS, as shown in other studies. Patients with CR as well as those with suboptimal response at AHCT benefit from Len maintenance. Thal, more broadly available globally than Len, was associated with a lesser non-significant trend towards improvement in OS and PFS compared to no maintenance.

Cowan:Sanofi: Consultancy, Research Funding; Regeneron: Research Funding; IgM biosciences: Research Funding; Nektar: Research Funding; HopeAI: Consultancy, Current holder of stock options in a privately-held company; Adaptive Biotechnologies: Consultancy, Research Funding; Caelum: Research Funding; Juno/Celgene: Research Funding; Harpoon: Research Funding; Abbvie: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sebia: Consultancy. Takamatsu:Ono: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen: Honoraria; SRL: Consultancy. D'Souza:Novartis: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Caelum: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Takeda: Research Funding. Hari:Obsidian Therapeutics: Current Employment; Obsidian Biotherapeutics: Ended employment in the past 24 months. Bazarbachi:Amgen: Honoraria; Roche: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Research Funding; Jansen: Honoraria, Research Funding; Caribou: Honoraria; Biologix: Research Funding. Mian:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. Snowden:Jazz: Other: Advisory board; Medac: Other: Advisory board; Vertex: Other: Advisory board; Jazz: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; BMS: Other: Advisory board; Kiadis: Other: IDMC membership for clinical trial. McLornan:Imago Biosciences: Research Funding; Abbvie: Honoraria; Jazz Pharma: Honoraria; Novartis: Honoraria. De La Camara:MSD: Membership on an entity's Board of Directors or advisory committees. Ciceri:ExCellThera: Membership on an entity's Board of Directors or advisory committees. Rondelli:Vertex Pharmaceuticals: Honoraria. Greinix:Sanofi: Honoraria, Speakers Bureau; Stemline: Honoraria, Speakers Bureau; Neovii: Honoraria; Novartis: Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Therakos: Honoraria, Speakers Bureau; BMS: Honoraria. Atsuta:Meiji Seika Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Janssen Pharmaceutical K.K.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Consultancy. Garderet:Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria.