Chimeric Antigen Receptor-T (CAR-T) Cell Therapy Targeting BCMA in Patients with Prior Allogeneic Transplantation (allo-HCT) in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background: Chimeric antigen receptor T-cell (CAR-T) treatment against BCMA has shown impressive efficacy and safety profile in patients with relapsed/refractory multiple myeloma (RRMM) leading to the approval of two BCMA-targeted CAR-Ts, designated idecabtagene vicleucel (ide-cel, ABECMA®) and ciltacabtagene autoleucel (cilta-cel, CARVYKTI®), in patients with 4 or more lines of prior therapy. The role of allogenic stem cell transplant (allo-HCT), despite being a potentially curative option in MM, is limited to selective young high-risk patients preferably in the context of clinical trials. Limited data exist on the safety and efficacy of CAR-T cells in the post allo-HCT setting where apheresed T-cell products are donor-derived.

Methods: In this single center retrospective study, we analyzed the safety and efficacy of RRMM patients treated with BCMA CAR-T cell therapy and prior history of allo-HCT from January 1, 2019, to July 20, 2022. Safety outcomes included the incidence and severity of adverse events (AEs). AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0). Cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) were graded as per the ASTCT criteria. Efficacy outcomes included overall response rates as per the IMWG criteria. Descriptive statistics were used to assess the outcomes.

Results: Twelve RRMM patients with history of prior allo-HCT received BCMA CAR-T cell therapy. Five patients received ABECMA®, and seven received investigational product. The median age was 64 years (range, 47-70 years), 67% were males and 8% Black (Table 1). Three patients (25%) had an R-ISS III and 56% had high-risk cytogenetics at diagnosis (Table 1). The median time from MM diagnosis to allo-HCT was 534 days (range, 219-1,966). All patients had undergone at least one prior autologous transplant (auto-HCT); one patient had two prior auto-HCT. The median number of prior lines of therapy before allo-HCT was 2.5 (range, 1-5). All patients had full donor T-cell chimerism after allo-HCT. Seven patients (58%) had history of GVHD (liver, skin, oral and/or ocular involvement), none active at the time of CAR-T treatment. The median number of lines of therapy prior to CAR-T was 7 (range, 3-12). Eleven (92%) patients had CRS after CAR-T administration, 8 were Grade 1 and 3 were Grade 2, all of which resolved with tocilizumab use (67%). Two (17%) patients had ICANS, one was Grade 3 and the other with Grade 4 and both were treated with tocilizumab and steroids. The patient with Grade 3 ICANS died of ICANS-related complications, COVID-19 infection, and disease progression at day 39 post infusion. The patient with Grade 4 ICANS resolved completely and was still alive at last follow up. The overall response rate (ORR) at day 28 after CAR-T was 92% (11). Nine patients achieved CR (75%) and 2 VGPR (17%). As of last follow up, only 2 patients (17%) had relapsed after 155- and 975-days post-infusion respectively. Median duration of response, progression-free survival and overall survival were not reached in this cohort. No exacerbation of acute or chronic GVHD occurred post CAR-T infusion. No cases of delayed movement and neurocognitive disorders and other Grade 3 or higher AEs were observed. One other patient died at day 445 post CAR-T due to preexisting portal fibrosis and ascites.

Conclusions: These data suggest that BCMA directed CAR-T after prior allo-HCT does not lead to GVHD and may provide deep and durable disease control in heavily treated MM. Further studies looking at the functional and phenotypic attributes of these donor-derived CAR-T products are needed to better understand and harness their potential benefit.

Pasquini:Novartis: Research Funding; Kite: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Chhabra:Janssen: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Honoraria. Mohan:BMS/Celgene: Research Funding; GSK: Research Funding; Takeda: Research Funding; Novartis: Research Funding. D'Souza:Takeda, Sanofi, TeneoBio, Prothena, Caelum Biosciences, Janssen Oncology, Regeneron, Abbvie: Research Funding; Pfizer, Janssen Oncology, Bristol-Myers Squibb/Celgene, Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hari:Takeda: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pharmacyclics: Consultancy; GlaxoSmithKline: Honoraria; Incyte: Honoraria; Millennium: Research Funding; Spectrum Pharmaceuticals: Research Funding; Iovance: Current Employment. Dhakal:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Natera: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; BMS: Honoraria, Research Funding; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees.