Ide-Cel Leads to Extended PFS, Increased Response Rates in R/R Multiple Myeloma

Paula Rodriguez-Otero, MD, PhD

Patients with relapsed/refractory multiple myeloma who received idecabtagene vicleucel (ide-cel; Abecma) experienced a significant survival benefit with an improved response rate compared with those treated with standard regimens, according to findings from the phase 3 KarMMa-3 trial (NCT03651128) published in The New England Journal of Medicine.¹

Data from the study showed that, at a median follow-up of 18.6 months (range, 0.4-35.4), patients who were treated with the B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy (n = 254) experienced a median progression-free survival (PFS) of 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) among 132 patients who received a standard regimen (HR, 0.49; 95% CI, 0.38-0.65; P < .001). Six-month PFS rates were 73% and 40%, respectively; 1-year PFS rates were 55% and 30%, respectively. Study authors noted that overall survival (OS) data were immature at this time.

“In this patient population with hard-to-treat disease, ide-cel therapy resulted in significantly longer progression-free survival than standard regimens, with a 51% lower risk of disease progression or death,” Paula Rodriguez-Otero, MD, PhD, a hematologist with la Clínica Universidid de Nevarra, in Madrid, Spain, and co-investigators, wrote in the study.

“Treatment with ide-cel resulted in a significantly higher percentage of patients with a response and with deeper responses than were observed in the standard-regimen group,” they added. “The efficacy of ide-cel therapy was striking considering that 65% of patients had triple-class–refractory disease in a short time from diagnosis (4 years), with disease relapse at a median of approximately 7 months during the last previous regimen.”

Ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma when the agency gave the agent the go ahead for the treatment of adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, on March 26, 2021.² The regulatory decision was largely supported by findings from the phase 2 KarMMa trial (NCT03361748).

The phase 3 KarMMa-3 enrolled adult patients with multiple myeloma who had previously received 2 to 4 prior therapies including daratumumab (Darzalex), an immunomodulatory agent, and a proteasome inhibitor for a minimum of at least 2 consecutive cycles who experienced disease progression within 60 days of completion of their last therapy.¹ Patients were then randomly assigned 2:1 to receive either ide-cel or 1 of 5 standard regimens. To be eligible for the international, open-label trial, patients needed to have an ECOG performance status of 1 or less and measurable disease. Patients were stratified based on age (< 65 years vs ≥ 65 years), number of previous regimens (2 vs 3 or 4), and high-risk cytogenetic profile (present vs absent or unknown).

In the investigational arm, patients were treated with ide-cel at a dose range of 150 x 10⁶ to 450 x 10⁶ CAR-positive T cells. Prior to receiving ide-cel, patients underwent lymphodepletion with fludarabine and cyclophosphamide for 3 consecutive days, followed by 2 days of no treatment before infusion. For patients in the control arm, the standard regimens were chosen by investigator’s discretion and consisted of: daratumumab, pomalidomide, and dexamethasone; daratumumab, bortezomib (Velcade), and dexamethasone; ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone; carfilzomib (Kyprolis) and dexamethasone; or elotuzumab (Empliciti), pomalidomide, and dexamethasone.

The primary end point was PFS. Secondary end points included overall response rate (ORR) and OS. Investigators also assessed safety.

Baseline patient characteristics were generally well-balanced between the 2 arms; the median age was 63 years (range, 30-81) in the ide-cel arm and 63 years (range, 42-83) in the standard regimen arm. Most patients in both arms were younger than 65 years (59% vs 59%), White (68% vs 59%), had R-ISS stage II disease (59% vs 62%), and had undergone haematopoietic stem cell transplantation (84% vs 86%).

The median time from initial diagnosis to screening was 4.1 years (range, 0.6-21.8) and 4.0 years (range, 0.7-17.7) in the investigational and control arms, respectively. The median time to progression during last previous antimyeloma therapy was 7.1 months (range, 0.7-67.7) vs 6.9 months (range, 0.4-66.0), respectively. Patients in both arms underwent a median of 3 prior regimens (range, 2-4).

Most patients in both the ide-cel and standard therapy arms were refractory to an immunomodulatory agent (88% vs 94%), such as lenalidomide (73% vs 79%) or pomalidomide (50% vs 53%); a proteasome inhibitor (74% vs 72%; or an anti-CD38 monoclonal antibody (95% vs 94%), such as daratumumab (95% vs 93%). A majority of patients in both arms had double-class-refractory (67% vs 69%) and triple-class-refractory (65% vs 67%) disease.

Additional findings from the trial showed that the ORR was 71% (95% CI, 66%-77%) compared with 42% (95% CI, 33%-50%) in the investigational and control arms, respectively (Odds ratio [OR], 3.47; 95% CI, 2.24-5.39; P < .001). Complete response rates were 39% (95% CI, 33%-45%) vs 5% (95% CI, 2%-9%), respectively. The median duration response was 14.8 months (95% CI, 12.0-18.6) vs 9.7 months (95% CI, 5.4-16.3), respectively.

In the ide-cel arm, 35% of patients experienced a stringent complete response, 22% had a very good partial response, 11% had a partial response, 2% had a minimal response, 12% had stable disease, 9% experienced disease progression, and 6% were not evaluable for response. These respective figures were 5%, 10%, 27%, 7%, 36%, 8%, and 8% in the control arm.

In terms of safety, any-grade adverse effects (AEs) occurred in 99% of patients in the ide-cel arm. The most common any-grade AEs included neutropenia (78%), anemia (66%), infection (58%), and thrombocytopenia (54%). Grade 3 or 4 AEs consisted of neutropenia (76%), anemia (51%), thrombocytopenia (42%), lymphopenia (28%, and leukopenia (28%), among others and occurred at a rate of 93% overall. Any-grade cytokine release syndrome (CRS) was present in 88% of patients in this arm.

Among patients who received a standard regimen, any grade AEs occurred at a rate of 98% and grade 3 or 4 AEs were present in 75%. Common any grade AEs included infection (54%), neutropenia (44%), and anemia (36%). Grade 3 or 4 AEs included neutropenia (40%), infection (18%), and anemia (18%). CRS did not occur in any patients in the control arm.

Serious AEs were reported in 52% of patients in the ide-cel arm compared with 38% of patients in the standard regimen arm. Grade 5 AEs occurred in 2% and 1% of patients, respectively. In the intention-to-treat population, 30% vs 26% died, respectively. The most common cause of death was disease progression (17% vs 17%).

Editor's Note. This article was updated on February 27, 2023.

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. Published online February 10, 2023. doi:10.1056/NEJMoa2213614
2. FDA approves idecabtagene vicleucel for multiple myeloma. News release. March 26, 2021. Accessed February 14, 2023. bit.ly/3E3NEkg