Nooka Dives into Data on Idecabtagene Vicleucel in R/R Multiple Myeloma

Idecabtagene vicleucel (ide-cel; Abecma) prolonged progression-free survival (PFS) and improved response compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma (RRMM), according to findings from the phase 3 KarMMa-3 trial (NCT03651128).¹

The KarMMa-3 study is a randomized phase 3 trial where investigators are evaluating the chimeric antigen receptor (CAR) T-cell therapy ide-cel compared with standard regimens for the treatment of patients with triple-class-exposed RRMM who had received 2-4 previous lines of therapy and who are disease refractory to the last regimen.²

In an interview with Targeted Oncology^TM, Ajay Nooka, MD, a professor and the director of the Myeloma Program, Department of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, Georgia, further discussed the results from the phase 3 KarMMa-3 trial and the rationale for using ide-cel for patients with RRMM.

Targeted Oncology: Can you discuss the mechanism of action of ide-cel and previous data on agent?

Nooka: Idecabtagene vicleucel s a B-cell maturation antigen-directed CAR T-cell therapy, approved for patients with relapsed/refractory multiple myeloma based on the results of a phase 2 trial among 127 patients conferring an overall response rate [ORR] of 72% and complete response [CR] in 28% among patients that received a median of 6 prior lines of therapy. Even, among this heavily pretreated patient population, close to two-thirds of patients who achieved CR remained in CR for at least 12 months. This approval for [patients with] RRMM that have received immunomodulatory agents [IMiDs], proteasome inhibitors [PIs], and CD38 monoclonal antibodies [mAbs] was based on a breakthrough therapy designation and orphan drug designation by the FDA.

Can you summarize the KarMMa-3 trial?

KarMMa-3, a phase 3 trial, involved adults with RRMM who had received 2 to 4 regimens previously, including IMiDs, PIs and CD38 mAbs, and who had disease refractory to the last regimen. Patients were randomly assigned in a 2:1 ratio to receive either ide-cel or 1 of the 5 standard-of-care [SOC] regimens of daratumumab [Darzalex], pomalidomide [Pomalyst], and dexamethasone, daratumumab, bortezomib [Velcade], and dexamethasone, ixazomib, lenalidomide [Revlimid], and dexamethasone, carfilzomib [Kyprolis] and dexamethasone, or elotuzumab [Empliciti], pomalidomide, and dexamethasone, per investigator discretion.

The primary end point is PFS. An ORR occurred in 71% of the patients in the ide-cel group and in 42% of those in the SOC group [P < .001]. At a median follow-up of 18.6 months, the median PFS was 13.3 months in the ide-cel group and 4.4 months in the SOC group (P < .001). The risk of progression with ide-cel compared to SOC regimens is decreased by 51%. This study used a cross-over method, which means that patients that progressed on the SOC therapies can still receive ide-cel on the trial. The overall survival data is immature but may not have a huge impact to assess the benefit of ide-cel given the nature of the study design.

What was the importance of KarMMa-3 and studying ide-cel in this patient population?

As with every drug that we have approved in myeloma, the optimal drug development involves evaluating the benefit of a known regimen, like ide-cel, in earlier lines of therapy [KarMMa-3 among patients that received median of 2-4 prior lines of therapy] that has demonstrated proven activity in later lines of therapy in the KarMMA-2 trial among patients received median of 6 prior lines of therapy. Myeloma is a disease where the benefit of a regimen is dependent on when it is administered. The same regimen administered as a first line of therapy will yield far better benefi compared with the regimen administered as a fifth line of therapy. Hence, choosing an optimal regimen that offers the most benefit as an earlier line of therapy is crucial in attaining better long-term results. In this context, ide-cel in KarMMa-3 had demonstrated a significant PFS benefit compared with SOC options [13.3 months v 4.4 months, P < .001) respectively, making a case that ide-cel should be a preferred option over the SOC regimens for early relapsed patent population.

What unmet needs still exist for patients with RRMM?

Unfortunately, despite the approval of multiple drugs with different mechanisms of action, myeloma remains an incurable disease for most patients. Alternate targets such as BCMA, GPRC5D, FCRH5 targeting antibody drug conjugates, bispecific antibodies, CAR T-cell therapies are currently being explored in various phases of clinical trials. Yet 'cure' as defined by the 'finite treatment duration followed by an indefinite treatment free period,' seems to be closer than ever, but farther than reach today.Novel targets with multimodal mechanisms of action that can bypass the current resistance mechanisms of the existing drugs and using these drugs and combinations as earlier lines of treatment seems to be the better answer to recheck cure. The results of KarMM-3 support this hypothesis.

At the same time, these newer treatments present with unique toxicities, which can be fatal or life-threatening. Cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, immune effector cell-associated neurotoxicity syndrome, and prolonged cytopenias occur in days to weeks following administration of bispecific antibodies or CAR T. Understanding how to recognize them early and how to treat them remains another major unmet need.

REFERENCES:

1. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614

2. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). ClinicalTrials.gov. Updated December 15, 2022. Accessed April 12, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03651128