Miriam López-Parra

Chimeric antigen receptor (CAR)‐T‐cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long‐term disease control remains limited, with only 20% of patients remaining progression‐free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next‐generation flow cytometry to analyze T‐cell populations in blood at leukapheresis, before infusion, and post‐anti‐BCMA CAR‐T infusion, together with CAR‐T‐cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti‐BCMA CAR‐T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T‐helper (Th) 1 and Th1/2 CAR‐TCD4 ⁺ and CM CAR‐TCD8 ⁺ cells. Multivariate analyses revealed that higher frequencies of TCD4 ⁺ naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR‐T‐cell populations, were predictors of progression‐free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System‐Revised [ISS‐R]) independently predicted, before CAR‐T‐cell infusion, which RRMM patients were most likely to benefit from anti‐BCMA CAR‐T therapy. These findings suggest that long‐term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti‐BCMA CAR‐T‐cell properties.

We present the largest prospective real-world experience in 159 patients who received the triple combination of tacrolimus/sirolimus/mycophenolate mofetil after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) from matched-related (MRD), matched-unrelated (MUD) or mismatched-unrelated donors (MMURD). Despite the high-risk and elderly population, non-relapse mortality (NRM) at day +100 and 1 year was 5.1% and 8.6%. Grades 2-4 and 3-4 acute Graft-versus-host disease (GvHD) at day +180 was 30.3% and 13%, respectively. Chronic GvHD at 1 and 3 years was 23.2% and 41% and for moderate/severe was 13.2% and 26.6%, respectively. With a median follow-up of 20 months, the 1- and 3-year progression-free survival was 60% and 49%, the GvHD-free relapse-free survival was 44% and 32%, and the overall survival was 70.3% and 61%, respectively, for the entire cohort. Patients receiving allo-HSCT from MMURD showed a higher incidence of aGvHD with impact on survival endpoints. GvHD prophylaxis with the triple-drug combination tacrolimus/sirolimus/mycophenolate mofetil showed excellent results in terms of NRM, GvHD and survival in a high-risk, frail and elderly population in the context of RIC-HSCT from MRD and MUD. The subgroup of patients receiving RIC-HSCT from MMURD might probably benefit from other prophylaxis strategies.

The efficacies of chimeric antigen receptor T cells (CAR-Ts) and bispecific monoclonal antibodies (BiAbs) for triple-class refractory (TCR) myeloma have not previously been compared, and clinical data on how to rescue patients after relapse from these immunotherapies are limited. A retrospective study of 73 TCR patients included in trials was conducted: 36 received CAR-Ts and 37 received BiAbs. CAR-Ts produced a higher overall response rate (ORR) than BiAbs (97.1% vs 56.8%, P = .002). After a median of follow-up of 18.7 months, no significant difference in progression-free survival (PFS) was observed between the CAR-T and BiAbs groups (16.6 vs 10.8 months; P = .090), whereas overall survival (OS) was significantly longer in the CAR-T than in the BiAbs group (49.2 vs 22.6 months; P = .021). BiAbs after CAR-Ts yielded a higher ORR and longer PFS2 than did nonredirecting T-cell therapies after CAR-Ts (ORR: 87.5% vs 50.0%; PFS2: 22.9 vs 12.4 months). By contrast, BiAbs after BiAbs resulted in an ORR of 33% and PFS2 of 8.4 months, which was similar to that produced by the nonredirecting T-cell therapies (ORR: 28.6%; PFS2: 8.1 months). Although this is a pooled analysis of different trials with different products and the patient profile is different for CAR-Ts and BiAbs, both were effective therapies for TCR myeloma. However, in our experience, although the PFS was similar with the 2 approaches, CAR-T therapy resulted in better OS, mainly because of the efficacy of BiAbs as rescue therapy. Our results highlight the importance of treatment sequence in real-word experience.

Figure 13. Progression-free survival according to triple-refractoriness, high-risk cytogenetics, extramedullary involvement and ISS.

Figure 5. ARI0002h persistence according to baseline tumor burden measured as proportion of bone marrow plasma cells and soluble BCMA.

Table 6. Detection of CART antibodies at different timepoints.

Table 1. Representativeness of Study Participants.

Table 10. Multivariate analysis of the impact in progression-free survival of clinical variables at baseline.

Figure 7. Persistence of ARI0002h in the peripheral blood according to prior drug refractoriness and allogeneic stem cell transplantation