Clinical InsAIghts: The KarMMa 3 Trial

Study Overview

Study Acronym: KarMMa-3

Study Design: International, open-label, phase 3 trial

Study Phase: Phase 3

Population Under Investigation: Adults with relapsed and refractory multiple myeloma, having received 2-4 previous regimens including immunomodulatory agents, proteasome inhibitors, and daratumumab, and disease refractory to the last regimen.

Intervention Under Investigation: Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy

Control Group: Standard regimens (daratumumab pomalidomide dexamethasone, daratumumab bortezomib dexamethasone, ixazomib lenalidomide dexamethasone, carfilzomib dexamethasone, or elotuzumab pomalidomide dexamethasone)

Number of Patients: 386 (254 to ide-cel and 132 to standard regimen)

Duration of Follow-Up: Median follow-up of 18.6 months

Main Efficacy Outcomes: Median progression-free survival was 13.3 months in the ide-cel group vs. 4.4 months in the standard-regimen group. Response rate was 71% in the ide-cel group and 42% in the standard-regimen group, with complete response rates of 39% and 5% respectively.

Main Safety Outcomes: Grade 3 or 4 adverse events occurred in 93% in the ide-cel group and 75% in the standard-regimen group. Cytokine release syndrome occurred in 88% (ide-cel), with 5% having an event of grade 3 or higher.

The KarMMa-3 trial presents significant findings in the context of treating relapsed and refractory multiple myeloma (RRMM) (1). To assess its impact, we must consider the current treatment landscape, the trial's findings in comparison to existing treatments, the magnitude of its results, and its implications for clinical practice.

The current standard treatment for RRMM, according to the latest clinical guidelines available up to April 2023, includes a range of regimens involving proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, such as daratumumab. Notably, the control arm in the KarMMa-3 trial reflects this standard, employing combinations like daratumumab with pomalidomide and dexamethasone, or elotuzumab with pomalidomide and dexamethasone.

The KarMMa-3 study introduces idecabtagene vicleucel (ide-cel), a novel CAR T-cell therapy, in this therapeutic area. The trial demonstrates a substantial improvement in median progression-free survival (PFS) — 13.3 months with ide-cel versus 4.4 months with standard regimens. This is a notable leap, considering that in the ELOQUENT-3 trial that investigated elotuzumab combined with pomalidomide and dexamethasone, the median PFS was 10.3 months in the elotuzumab group, which was already an improvement from 4.7 months in the control group (2). Likewise, in the SIRIUS trial evaluating daratumumab monotherapy, the median PFS was 3.7 months (3). Thus, ide-cel demonstrates a remarkable increase in PFS compared to these therapies.

Furthermore, the response rate with ide-cel was 71%, with a complete response rate of 39%. This is significantly higher than the response rates observed in the control treatments of the aforementioned studies and the earlier phase 2 KarMMa trial. The phase 2 KarMMa trial, which also involved ide-cel, showed a response rate of 89% in the Japanese cohort with a stringent complete response in 56%, indicating consistency in ide-cel's efficacy across different patient groups (4).

However, the safety profile of ide-cel needs careful consideration. Grade 3 or 4 adverse events were high (93%), and cytokine release syndrome occurred in 88% of patients, although most were of lower grade. This contrasts with the lower incidence of severe adverse events in the control regimens and calls for a vigilant approach in clinical practice, especially considering the management of these side effects.

In clinical practice, the findings from the KarMMa-3 trial could be transformative for patients with RRMM who have limited options after failing multiple lines of therapy. Ide-cel's efficacy in extending PFS and achieving higher response rates offers a new avenue of hope. However, its safety profile necessitates a structured approach in its administration, potentially limiting its use to specialized centers with experience in managing CAR T-cell therapy-associated toxicities.

Overall, the KarMMa-3 trial marks a significant advancement in the treatment of RRMM, positioning ide-cel as a potent therapeutic option. Its introduction into clinical practice will require careful patient selection and management strategies, but its potential to improve outcomes in this challenging patient population is undeniable.

References

  1. Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023;388(11):1002-14.

  2. Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. J Clin Oncol. 2023;41(3):568-78.

  3. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-60.

  4. Minakata D, Ishida T, Ando K, Suzuki R, Tanaka J, Hagiwara S, et al. Phase 2 results of idecabtagene vicleucel (ide-cel, bb2121) in Japanese patients with relapsed and refractory multiple myeloma. Int J Hematol. 2023;117(5):729-37.