Benefit of ide-cel versus standard regimens maintained across patient populations with high-risk relapsed/refractory multiple myeloma
Results of the KarMMa-3 study indicate that patients treated with idecabtagene vicleucel (ide-cel) had a lower risk of disease progression or death and higher odds of achieving an overall response, with higher complete response rates, compared with patients who received standard regimens, regardless of baseline high-risk disease. Overall, these results support the use of ide-cel in patients with triple-class exposed RRMM, including patients with difficult-to-treat, high-risk disease.
Despite therapeutic improvements in the treatment landscape of patients with relapsed or refractory multiple myeloma (RRMM), the introduction of immunomodulatory agents (IMiDs), proteasome inhibitors (PI) and anti-CD38 monoclonal antibodies in frontline and in early relapse settings results in patients becoming triple-class exposed earlier in their treatment course. In addition, outcomes in patients with high-risk disease characteristics such as cytogenetic abnormalities, advanced-disease stage, high tumour burden, presence of extramedullary plasmacytoma (EMP) and triple-class refractory (TCR) disease remain poor. Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR-T cell therapy that significantly improved median progression-free survival (PFS) and objective response rate (ORR) versus standard regimens in the overall population of patients with triple-class exposed RRMM in the KarMMa-3 study. At EHA 2023, Dr. Krina Patel discussed the efficacy and safety of ide-cel versus standard regimens in patients with high-risk disease characteristics in KarMMa-3.
Study design
In total, 386 patients were randomised 2:1 to ide-cel (target dose range: 150–450 x 106 CAR-T cells) or standard regimens (DPd, DVd, IRd, Kd or EPd). Patients were required to be at least 18 years old, have an ECOG performance status of 0 or 1, have received 2-4 previous lines of treatment (including an IMiD, a PI and daratumumab) and were refractory to their last line of therapy. Efficacy (PFS, ORR, and complete response rate [CRR]) was assessed in high-risk groups including patients with cytogenetic abnormalities (del[17p], t[4;14], or t[14;16]), R-ISS stage III disease, high tumour burden (≥50% CD138-positive plasma cells in bone marrow), EMP (soft-tissue–only and soft-tissue bone-related plasmacytomas), and TCR (refractory to ≥1 each of an IMiD agent, a PI, and an anti-CD38 antibody).
Results
In this analysis, efficacy and safety were assessed in high-risk subgroups, including high-risk cytogenetics, R-ISS stage III disease, high tumour burden, EMP or TCR disease. Baseline demographics and disease characteristics were generally well balanced between treatment arms and high-risk subgroups. In terms of prior treatment, the median time to progression on the last prior regimen was less than 7 months in all high-risk subgroups. After a median follow-up of 18.6 months, median PFS in the overall population was 13.3 months for patients in the ide-cel arm and 4.4 months in the standard regimen arm (HR[95%CI]: 0.49[0.38-0.65], p< 0.0001). The 12-month PFS rates were respectively 55% and 30%. mPFS was longer in patients treated with ide-cel vs. standard regimens in all high-risk subgroups; cytogenetic abnormalities (11.9 vs. 4.2 months; HR[95%CI]: 0.61[0.41-0.90]), R-ISS stage III disease (5.2 vs. 3.0 months; HR[95%CI]: 0.86[0.39-1.93]), high tumour burden (11.0 vs. 4.9 months; HR[95%CI]: 0.60[0.37-0.97]), EMP (7.2 vs. 2.0 months; HR[95%CI]: 0.40[0.25-0.65]), and TCR disease (11.2 vs. 3.5 month; HR[95%CI]: 0.46[0.34-0.62]). However, interpretation in patients with R-ISS stage III disease was limited due to small subgroup size. ORRs were improved with ide-cel vs. standard regimens, regardless of the presence of high-risk disease characteristics. Similarly, complete response rates were improved in patients treated with ide-cel vs. standard regimens in all high-risk subgroups: cytogenetic abnormalities (32% vs. 5%), R-ISS stage III (16% vs. 7%), high tumour burden (31% vs. 9%), EMP (23% vs. 3%), and TCR disease (34% vs. 1%). Tumour clearance, as measured by soluble BCMA, was deeper with ide-cel versus standard regimens in all high-risk subgroups.
Safety data were generally consistent between treatment arms and high-risk subgroups. The most common side effects were haematologic, and their frequency was consistent between high-risk subgroups. Incidence of high-grade (grade ≥3) CRS and neurotoxicity was low in all high-risk subgroups and resolved within a median of 3-4 and 2-3 days, respectively. No parkinsonism was reported.
Conclusion
The KarMMa-3 study enrolled a high-risk triple-class exposed and highly refractory population of patients with RRMM. In this subgroup analysis, a single infusion of ide-cel treatment consistently demonstrated clinically meaningful improvements in PFS and ORR versus standard regimens regardless of baseline high-risk disease characteristics. Nadir levels of soluble BCMA, a pharmacodynamic marker of tumour clearance, were lower in the ide-cel arm versus the standard regimen arm in all high-risk subgroups. The toxicity profile of ide-cel in high-risk subgroups was manageable and consistent with the overall population and previous studies.
Reference
Patel K, et al. IDECABTAGENE VICLEUCEL (IDE-CEL) VS STANDARD REGIMENS IN PATIENTS WITH TRIPLE-CLASS–EXPOSED (TCE) RELAPSED AND REFRACTORY MULTIPLE MYELOMA (RRMM): A KARMMA-3 ANALYSIS IN HIGH-RISK SUBGROUPS. Presented at EHA 2023; Abstract S195.
