Ide-Cel Improves PFS and ORR in Triple-Class Exposed, Early R/R Multiple Myeloma

Sergio Giralt, MD

Idecabtagene vicleucel (ide-cel; Abecma) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and objective response compared with standard of care approaches in patients with triple-class-exposed relapsed/refractory multiple myeloma, according to findings from the phase 3 KarMMa-3 trial (NCT03651128) presented at the 2023 Transplantation & Cellular Therapy Meetings.

“Karmma-3 is the first randomized phase 3 trial to evaluate the CAR T-cell therapy ide-cel vs standard regimens in patients with triple-class-exposed relapsed/refractory MM who had received 2 to 4 prior lines of therapy and disease refractory to the last regimen,” Sergio Giralt, MD, deputy division head, Division of Hematologic Malignancies; Melvin Berlin Family Chair in Multiple Myeloma; chief medical officer, MSK Direct, Memorial Sloan Kettering Cancer Center, said in a presentation of the data.

At the data cut-off, 158 patients were ongoing in the study–including 91 ongoing for PFS and 67 in survival follow-up–in the ide-cel arm, compared with 29 patients ongoing in the standard regimen arm, including 20 ongoing for PFS and 9 in the survival follow-up.

Efficacy of Ide-Cel

The BCMA-directed CAR T-cell therapy significantly reduced the risk for disease progression by 51% (HR, 0.49; 95% CI, 0.38-0.65; P < .0001), with a median PFS of 13.3 months (95% CI, 11.8-16.1), compared with 4.4 months (95% CI, 3.4-5.9) with a standard regimen. This PFS benefit with ide-cel was consistently observed across multiple patient subgroups in the study, Giralt noted.

Treatment with ide-cel also induced a superior ORR of 71% (95% CI, 66%-77%), compared with 42% (95% CI, 33%-50%). With ide-cel, the complete response (CR) was 39%, vs 5% with a standard regimen. Further, among patients who achieved a CR, 20% (95% CI, 15.2%-25.0%) in the ide-cel arm and 1% (95% CI, 0%-2.2%) were minimal residual disease (MRD) negative.

The median time to response (TTR) in the ide-cel and standard regimen arms was 2.9 months (95% CI, 0.5-13.0) and 2.1 months (95% CI, 0.9-9.4), respectively.

In addition, median duration of response (DOR) was longer in patients who received ide-cel (14.8 months; 95% CI, 12.0-18.6), vs a standard regimen (9.7 months; 95% CI, 5.4-16.3).

Giralt also noted that CAR-positive T cells underwent a rapid multi-log expansion, with a maximum expansion occurring at a median of 11 days. Further, he added that higher quartiles of ide-cel expansion measured by pharmacokinetic exposure (AUC0-28d) were associated with longer PFS.

Lastly, patient-reported outcomes improved significantly among patients treated with ide-cel. “There was significant improvements in fatigue, pain, and physical functioning that resulted in a significant improvement in global health status and quality of life,” Giralt said.

Safety of Ide-Cel

In total, 248 patients (99%) in the ide-cel arm and 123 patients (98%) in the standard regimen arm experienced any grade adverse events (AEs). Eighteen patients in the ide-cel arm and 3 patients in the standard regimen arm had grade 5 AEs that were consistent with progression of myeloma, including 6 patients in the ide-cel arm who never received treatment. The most common grade 5 AE was sepsis, occurring in 5 patients (2%) in the ide-cel group and 1 patient (1%) in the standard regimen group.

Hematologic AEs were the most common in the ide-cel and standard regimen arms, including grade 3/4 neutropenia (76% vs 40%, respectively), anemia (51% vs 18%), thrombocytopenia (42% vs 17%), lymphopenia (28% vs 18%), and leukopenia (28% vs 9%). Giralt noted that, among patients in the ide-cel group who developed grade 3/4 thrombocytopenia or anemia that persisted beyond 1 month, the median times to recovery were 1.9 months (95% CI, 1.5-2.1) and 1.7 months (95% CI, 1.5-1.9), respectively.

Among gastrointestinal AEs in the ide-cel and standard regimen arms, the most common grade 3/4 were nausea (2% vs 0%, respectively) and diarrhea (2% vs 3%).

Other grade 3/4 AEs of interest in the ide-cel and standard regimen arms were infections (24% vs 18%, respectively), hypophosphatemia (20% vs 2%), hypokalemia (5% vs 1%), fatigue (2% vs 2%), pyrexia (1% vs 1%), headache (0% vs 1%), hypomagnesemia (1% vs 1%), and dyspnea (2% vs 2%).

Second primary malignancies occurred in 6% of patients in the ide-cel arm, vs 4% in the standard regimen arm.

Among patients treated with ide-cel, any grade cytokine release syndrome (CRS) occurred in 88% of patients (n = 197), 4% being grade 3/4 and 1% being grade 5. The median time to first onset of CRS was 1.0 day (range, 1.0-14.0), for a median duration of 3.5 days (range, 1.0-51.0). Further, any grade neurotoxicity occurred in 15% of patients (n = 34), with 3% being grade 3/4and no grade 5 events. The median time to first onset of neurotoxicity was 3.0 days (range, 1.0-317.0), for a median duration of 2.0 days (range, 1.0-37.0).

Giralt noted that the safety profile of ide-cel was consistent with previous findings.

Karmma-3 Trial Background

Giralt explained that although the treatment landscape for relapsed/refractory MM has evolved, relapse can be common and patients can become triple-class-exposed earlier in their disease, with limited treatment options. “In the absence of an established standard of care for triple-class-exposed relapsed/refractory multiple myeloma, therapies with novel mechanisms of action that provide deeper and more durable responses are needed in earlier lines of treatment,” he explained.

The international, open-label, phase 3 trial evaluated ide-cel (n = 254), compared with a standard regimen (n = 312), in patients with relapsed and refractory MM who had received 2 to 4 regimens previously—including immunomodulatory agents, proteasome inhibitors, and daratumumab (Darzalex)—and who had disease refractory to the last regimen. Patients were randomized 2:1 to receive either ide-cel (dose range, 150 × 106 to 450 × 106 CAR-positive T cells) or 1 of 5 standard regimens (daratumumab, pomalidomide [Pomalyst], and dexamethasone [DPd]; daratumumab, bortezomib [Velcade], and dexamethasone [DVd]; ixazomib [Ninlaro], lenalidomide [Revlimid], and dexamethasone [IRd]; carfilzomib [Kyprolis; Kd]; or elotuzumab [Empliciti], pomalidomide, and dexamethasone [EPd]).

Key inclusion criteria was comprised of 18 years of age or older, an ECOG performance status of 0-1, having had 2 to 4 prior regimens, and refractory disease to last regimen received.

PFS served as the primary end point. Secondary end points included ORR and overall survival (OS). Other secondary end points were CR rate, DOR, TTR, MRD status, and safety.

Patients were stratified by age (<65 vs 65 and older), number of prior regimens (2 vs 3 or 4), and high-risk cytogenetics (t[4;14], t[14;16], or del[17p]).

Patient characteristics were generally well balanced between treatment arms, Giralt noted.

Data cut-off was April 18, 2022, and the median duration of follow-up was 18.6 months (range, 0.4-35.4).

This second interim analysis was performed in 242 of 289 planned PFS events. OS data were immature and remained blinded at data cut-off.

“These results support the use of ide-cel, and patients with early-line relapse in triple-class-exposed relapsed/refractory multiple myeloma, a patient population with poor survival outcomes,” Giralt concluded.

References

1. Giralt S, Ailawadhi S, Arnulf B, et al. Idecabtagene Vicleucel (ide-cel) Versus Standard Regimens in Patients with Triple-Class–Exposed Relapsed and Refractory Multiple Myeloma: Karmma-3, a Phase 3 Randomized Controlled Trial. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract LBA1.
2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. New Eng J Med. 2022. doi:10.1056/NEJMoa2213614.