Ide-cel vs Standard Regimens in Triple-Class–Exposed Relapsed and Refractory Multiple Myeloma: Updated KARMMA-3 Analyses

Oncology Medicine Life Sciences Hematology Immunology
multiple myeloma relapsed and refractory ide-cel KARMMA-3 trial CAR-T cell therapy progression-free survival overall survival

Latest Research Report: Idecabtagene Vicleucel (ide-cel) Significantly Extends Progression-Free Survival in Triple-Class Exposed (TCE) Relapsed or Refractory Multiple Myeloma – Results from the KARMMA-3 Clinical Trial

Academic Background and Research Question

Patients with Multiple Myeloma (MM) often relapse after multiple lines of therapy, with progressively worsening prognoses. This is especially true for those whose disease has been exposed to proteasome inhibitors, immunomodulatory agents, and CD38 antibodies, referred to as Triple-Class Exposure (TCE). For these patients, treatment options are extremely limited, with poor disease control and significantly shortened survival. Historical data show that in this patient population, standard therapies result in a progression-free survival (PFS) of approximately 3-5 months and an overall survival (OS) of only 9-22 months. Meanwhile, Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated potential efficacy, yet its integration into treatment strategies alongside standard regimens (SRS) remains unclear due to insufficient research.

In light of this, the authors conducted the KARMMA-3 international randomized phase 3 clinical trial to compare a B-cell maturation antigen (BCMA)-targeted CAR T-cell product—idecabtagene vicleucel (ide-cel)—with standard regimens (SRS) in patients with TCE relapsed or refractory multiple myeloma (R/RMM). The study also explored the impact of multi-line therapies and long-term follow-up on patient survival and quality of life (QoL).

Study Source

This research was a collaborative effort among researchers from institutions such as Mayo Clinic, MD Anderson Cancer Center, and Bristol Myers Squibb. Results were published under the title “Updated KARMMA-3 Analyses” in Blood on December 5, 2024, and were also presented at the 2023 American Society of Hematology (ASH) Annual Meeting.

Study Design and Methods

KARMMA-3 was an international, multi-center, open-label, randomized phase 3 trial. A total of 386 patients aged 18 years or older, who had received 2-4 prior lines of therapy and were refractory to their most recent regimen, were enrolled. Patients were randomized 2:1 to receive ide-cel or one of five investigator-selected standard regimens (SRS), comprising conventional treatments such as daratumumab.

Experimental Workflow:

  1. Patient Recruitment and Grouping:

    • 254 patients were placed in the ide-cel group, and 132 in the SRS group.
    • Patients in the ide-cel arm underwent leukapheresis, bridging therapy (limited to one cycle), lymphodepleting chemotherapy, and a single infusion of ide-cel.
    • The SRS arm patients received standard therapy directly.

  2. Follow-Up and Assessments:

    • The primary endpoint was PFS, assessed by an Independent Review Committee (IRC) following International Myeloma Working Group (IMWG) standards.
    • Secondary endpoints included overall response rate (ORR), overall survival (OS), minimal residual disease (MRD) negativity, and health-related quality of life (HRQoL).
    • Sensitivity analyses, such as accelerated failure time models and rank-preserving structural failure time models, were pre-specified to adjust for the potential confounding effect of crossover between study arms.

  3. Data Analysis Approaches:

    • Kaplan-Meier (KM) estimates and Cox proportional hazards models were used to evaluate PFS and OS.
    • Multiple sensitivity analyses, including inverse probability-weighted models, were employed to control for crossover effects between treatment groups.

Core Study Results

After a 30.9-month median follow-up, the key findings were as follows:

  1. Significant Extension in PFS:

    • Median PFS was significantly longer with ide-cel (13.8 months [95% CI, 11.8-16.1]) compared to SRS (4.4 months [95% CI, 3.4-5.8]), representing a 51% reduction in the risk of progression or death (HR, 0.49; 95% CI, 0.38-0.63).
    • Subgroup analyses by the number of prior therapy lines demonstrated greater benefits for ide-cel in earlier lines of treatment. For instance, patients with 2 prior lines of therapy achieved a median PFS of 16.2 months with ide-cel versus 4.8 months with SRS.

  2. Higher ORR and Deeper Responses:

    • Ide-cel achieved an ORR of 71% versus 42% for SRS. Complete response (CR) rates were also superior at 44% compared to 5%.
    • The MRD-negative rate was 35% with ide-cel versus 2% with SRS.

  3. OS Evaluation:

    • Median OS was not statistically different between the groups (ide-cel: 41.4 months; SRS: 37.9 months). However, sensitivity analyses suggested a trend favoring ide-cel (HR, 0.72; 95% CI, 0.49-1.01).

  4. Improved QoL Outcomes:

    • Ide-cel led to significant and sustained improvements in patient-reported outcomes (PROs), including fatigue, physical functioning, and pain scores, compared to SRS.

  5. Safety and Adverse Events:

    • The most common grade 3⁄4 adverse events with ide-cel included neutropenia (79%), anemia (45%), and thrombocytopenia (42%). These were consistent with known CAR T-cell therapy profiles, without new safety signals.

Implications and Clinical Significance

The study demonstrated that BCMA-targeted CAR T-cell therapy ide-cel significantly improved PFS and ORR compared to standard treatments for patients with TCE R/RMM, while also enhancing QoL. The findings underscore the potential of ide-cel as a transformative treatment in this highly refractory patient population. Early intervention with CAR T-cell therapy may further improve outcomes, highlighting the importance of patient-specific bridging therapy during CAR T-cell production to maximize treatment benefits.

In addition to its significant efficacy, ide-cel’s one-time infusion and manageable safety profile support long-term disease management and may reduce the burden of continuous treatment.

Study Limitations and Future Directions

While this trial was multi-center and robust, crossover between the study arms confounded OS comparisons. Additionally, further research is needed to explore ide-cel’s potential in earlier treatment lines and assess long-term safety and efficacy over extended follow-up periods.

This study provides pivotal data to advance CAR T-cell therapy for multiple myeloma, offering new hope for patients and potentially setting a new standard of care in this difficult-to-treat population.