Subsequent Anti-Myeloma Therapy after Idecabtagene Vicleucel (ide-cel, bb2121) Treatment in Patients with Relapsed/Refractory Multiple Myeloma from the KarMMa Study
Authors: Rodriguez-Otero Paula , San-Miguel Jesús F. , Anderson Larry D. , Lonial Sagar , Truppel-Hartmann Anna , Sanford Jill , Rowe Everton , Campbell Timothy B. , Munshi Nikhil C. 
Published: November 2021

Abstract
Introduction
Outcomes for patients (pts) with relapsed/refractory multiple myeloma (RRMM) previously treated with immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 antibodies are poor; novel treatments that prolong survival in pts with RMMM are essential. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy, showed frequent, deep, and durable responses in triple-class exposed pts with RRMM in the pivotal phase 2 KarMMa study (NCT03361748; Munshi et al. N Engl J Med 2021). Two updates of ide-cel in RRMM (phase 1 CRB-401 [NCT02658929] and the KarMMa study) demonstrated an overall survival (OS) of 34.2 and 24.8 months and median progression-free survival (PFS) of 8.8 and 8.6 months, respectively (Lin et al. ASH 2020 Abstract 131; Anderson et al. ASCO 2021 Poster 8016). The effect on median PFS and median OS was observed in all dose ranges, including in pts who received 450 x 10 6 CAR+ T cells (12.2 and 24.8 months, respectively). The difference between median PFS and OS in these studies prompted additional analyses examining outcomes for pts enrolled in KarMMa, including time to second disease progression (PFS2), duration of subsequent anti-myeloma therapy (sAMT), and OS in pts who received sAMT. Additionally, the subset of pts who received subsequent anti-BCMA therapy was analyzed.
Methods
Pts with MM, ≥ 3 prior lines of therapy (including an immunomodulatory agent, PI, and anti-CD38 antibody), and disease refractory to their last regimen per IMWG criteria received ide-cel infusion (target dose range 150-450 x 10 6 CAR+ T cells) after lymphodepletion (fludarabine 30 mg/m 2/day + cyclophosphamide 300 mg/m 2/day for 3 days). After ide-cel treatment, pts who relapsed could receive sAMT, ide-cel re-treatment (RT), or both. Baseline characteristics were collected prior to initial ide-cel transfusion. PFS2, type and duration of sAMT, and OS were assessed.
Results
Among 128 pts who received ide-cel, 104 (81%) had progressive disease or death after receiving ide-cel (median follow-up 24.8 months). Of the 128 ide-cel-treated pts, 68 received sAMT alone or with RT (of whom 11 received subsequent anti-BCMA therapy); 33 did not receive sAMT and relapsed after, or did not respond to, ide-cel; and 27 were not included in this analysis due to having received RT alone (n = 8) or continuing in remission after ide-cel at time of analysis. Baseline demographics and clinical characteristics of pts receiving sAMT, anti-BCMA, and no sAMT/RT were generally similar; median age (63, 55, 57 years), male (60%, 55%, 64%), and ECOG PS 0-1 (97%, 91%, 97%). However, a greater proportion of pts who did not receive sAMT/RT had revised International Staging System stage III disease compared with pts who had sAMT or anti-BCMA therapy (33%, 9%, 9%, respectively). The most frequent sAMT classes were corticosteroids (n = 58) and PIs (n = 47), while the most frequent sAMT agents were dexamethasone (n = 56) and carfilzomib (n = 32). Anti-BCMA agents included antibody-drug conjugate belantamab mafodotin (GSK2857916; n = 10) and inducible T-cell co-stimulator feladilimab (GSK3359609; n = 1). In pts who received sAMT, median PFS and OS to ide-cel was 6.1 and 24.8 months (Table). Median duration of first sAMT was 44 days and duration of all sAMT was 215 days, with a PFS2 of 13.6 months (inclusive of time on ide-cel). Among pts who received anti-BCMA therapy, median PFS and OS to ide-cel was 12.1 and 31.0 months. The median duration of first sAMT was 48 days and PFS2 was 15.5 months.
Conclusions
Pts who relapsed after ide-cel were able to successfully receive sAMT with a PFS2 longer than 13 months. No consistent drug class was used for sAMT. Although the number of pts who received anti-BCMA as sAMT was small, this subset of pts had overall favorable outcomes, including OS, after ide-cel and sAMT. BCMA loss has been noted as a potential mechanism of immune escape (Da Vià et al. Nat Med 2021); however, in KarMMa, it was suspected in just 3 of 71 pts who could be evaluated at progression (Munshi et al. N Engl J Med 2021). As such, pts who relapsed after initial ide-cel infusion may benefit from subsequent anti-BCMA therapy. Further exploration into the tumor microenvironment before and after ide-cel and how it relates to favorable PFS2 and OS in these subgroups is ongoing.
Study support
bluebird bio and Celgene, a Bristol-Myers Squibb Company.
Figure 1 Figure 1.

Disclosures
Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial: Merck: Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding. Truppel-Hartmann: bluebird bio: Current Employment. Sanford: Bristol Myers Squibb: Current Employment. Rowe: Bristol Myers Squibb: Current Employment. Campbell: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Munshi: Abbvie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Adaptive Biotechnology: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Takeda: Consultancy; Novartis: Consultancy; Legend: Consultancy.