KarMMa-2 Cohort 2a: Efficacy and Safety of Idecabtagene Vicleucel in Clinical High-Risk Multiple Myeloma Patients with Early Relapse after Frontline Autologous Stem Cell Transplantation

Abstract

**Co-lead author Introduction Patients with multiple myeloma (MM) who relapse early after frontline therapy with autologous stem cell transplant (ASCT) have a poor prognosis. Novel therapies are needed to improve outcomes (Paiva Blood 2012; Bygrave Br J Haematol 2020). In the pivotal phase 2 KarMMa study (NCT03361748), treatment with the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel) resulted in frequent, deep, and durable responses in pts with relapsed and refractory MM (RRMM) who were triple-class exposed and refractory to last treatment (Munshi N Engl J Med 2021). KarMMa-2 is a multicohort, phase 2, multicenter trial (NCT03601078) of ide-cel in RRMM and in clinical high-risk MM, defined as early relapse after frontline therapy (cohorts 2a, 2b) or inadequate response after frontline ASCT (2c). The efficacy and safety of ide-cel in cohort 2a are presented. Methods Eligible pts in cohort 2a had early relapse after frontline therapy, defined as progressive disease (PD) <18 mo from starting treatment containing induction, ASCT (single or tandem), and lenalidomide-containing maintenance. After lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 × 3), pts received a single infusion of ide-cel at 150-450 × 106 CAR+ T cells. The primary efficacy endpoint was complete response (CR) rate (CRR; CR and stringent CR) by investigator per IMWG criteria. Secondary endpoints included overall response rate (ORR; ≥ partial response), time to response (TTR), duration of response (DOR), PFS, OS, safety, and pharmacokinetics (PK). Exploratory endpoints included assessment of soluble BCMA (sBCMA) level and minimal residual disease negativity (MRD-) by next-generation sequencing (<10-5 nucleated cells). Efficacy and safety were analyzed in all pts who received ide-cel; PK and sBCMA were analyzed in evaluable pts. MRD- is reported for evaluable pts with ≥CR. Results Ide-cel was successfully manufactured and infused in 37/39 pts. Median age was 57 y; median time since diagnosis was 1.6 y. A total of 62.2% pts had ECOG PS 0, and 70.3% received bridging therapies (corticosteroids, alkylating agents, immunomodulatory agents, proteasome inhibitors [PI], and/or anti-CD38 antibodies) for MM. At study entry, 13.5%/51.4%/5.4% pts had R-ISS stage I/II/III disease, 32.4% had high-risk cytogenetics, 18.9% had bone marrow biopsy-determined high tumor burden (≥50% bone marrow CD138+ plasma cells), and 8.1% had extramedullary disease. Most pts had disease refractory to an immunomodulatory agent (86.5%) or PI (89.2%); 86.5% had double refractory disease. At data cut-off (14 Mar 2022), median follow-up was 21.5 mo (range 2-31). CRR was 45.9% (95% CI 29.5-63.1), and ORR was 83.8% (95% CI 68.0-93.8) (Table 1). At 6 mo post-ide-cel, MRD− was observed in 11/13 (85%; 95% CI 57.8-95.7) pts. At 12 mo, MRD− was observed in 7/10 (70%; 95% CI 39.7-89.2) pts; of the 7 pts, 1 had PD at 20.8 mo, 5 sustained MRD− at ≥18 mo, and >12 mo data was unavailable for 1 pt. Median TTR was 1 mo (range 0.9-2.9). Median DOR was 15.7 mo (95% CI 7.62-19.81). Median PFS was 11.4 mo (95% CI 5.55-19.58); median OS was not reached. Time to event endpoint results for DOR, PFS, and OS are shown in Table 1. Grade (Gr) 3-4 AEs on or after ide-cel infusion occurred in all pts, most commonly neutropenia in 35 (94.6%) pts, anemia in 17 (45.9%), and thrombocytopenia in 14 (37.8%). Two pts died due to pneumonia and pseudomonal sepsis. Gr 1/2 cytokine release syndrome (CRS) occurred in 30 (81.1%) pts; 1 (2.7%) pt had a Gr 3 event (Table 1). Gr 1/2 investigator-identified neurotoxicity (NT) occurred in 8 (21.6%) pts; no pts had ≥Gr 3 NT. Robust cell expansion was seen in 36 evaluable pts (Table 2). Ide-cel cellular expansion levels were higher in pts who had ≥CR vs those who had <CR with ide-cel (Table 2). sBCMA (range 15.0-737.0 ng/mL at infusion, n = 36) was cleared within 2 mo post-ide-cel infusion in 25/37 (67.6%) pts, including all pts who had ≥CR. Conclusions Ide-cel treatment demonstrated frequent, deep responses in pts who experienced an early relapse after frontline therapy with ASCT. MRD− was sustained in a subset of pts >18 mo. The incidence of CRS and NT were similar in these pts vs those treated with ide-cel in later lines. These results support a favorable clinical benefit-risk profile of ide-cel and its potential use in earlier lines of treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal