KarMMa-2 Cohort 2c: Efficacy and Safety of Idecabtagene Vicleucel in Patients with Clinical High-Risk Multiple Myeloma Due to Inadequate Response to Frontline Autologous Stem Cell Transplantation

Abstract

**Co-lead authors Introduction Patients (pts) with multiple myeloma (MM) who do not achieve a deep response post-autologous stem cell transplantation (ASCT) have an increased risk of progressive disease (PD) death (van de Velde Eur J Haematol 2017) and a high unmet medical need. 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) led to 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. The efficacy and safety of ide-cel in cohort 2c pts with MM who had an inadequate response to frontline therapy with ASCT are presented. Methods Eligible pts in cohort 2c had newly diagnosed MM (NDMM), received ≥3 cycles of induction therapy (including a proteasome inhibitor, immunomodulatory agent, and dexamethasone), and had an inadequate response to ASCT (single or tandem), defined as less than very good partial response (VGPR) at 70-110 days after last ASCT, without use of consolidation or maintenance therapy. Pts had ECOG performance status (PS) ≤1. After lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 × 3), pts received a single infusion of ide-cel at dose range 150-450 × 106 CAR+ T cells. At investigator discretion, pts could receive maintenance therapy post-infusion. The primary endpoint was complete response (CR) rate (CRR; CR and stringent CR) per investigator and IMWG Uniform Response Criteria. Secondary endpoints included overall response rate (ORR; ≥ partial response), VGPR rate (VGPRR), time to response (TTR), duration of response, PFS, overall survival, safety, and pharmacokinetics (PK). Exploratory endpoints included assessment of soluble BCMA (sBCMA) level, and minimal residual disease negativity (MRD-) by aggregation of next-generation sequencing and EuroFlow (<10-5 nucleated cells) data with interpolation to reduce missing/indeterminate data points. Efficacy and safety were analyzed in all pts who received ide-cel; PK, sBCMA, and MRD- were analyzed in evaluable pts. Results Ide-cel was successfully manufactured and infused in 31/32 enrolled pts. Median age was 64 y; 67.7% of pts had ECOG PS 0. At study entry, 41.9% pts had R-ISS stage I disease, 16.1% had stage II, and none had stage III; 9.7% pts had high-risk cytogenetics, 3.2% had bone marrow biopsy-determined high tumor burden (≥50% bone marrow CD138+ plasma cells), and 6.5% had extramedullary disease. At data cut-off (14 Mar 2022), median follow-up was 27.5 mo (range 22-31). CRR was 74.2% (95% CI 55.4-88.1), and ORR was 87.1% (95% CI 70.2-96.4) (Table 1). Median TTR was 1 mo (range 0.9-2.8). Time to event endpoint results are in Table 1. Grade (Gr) 3-4 adverse events (AEs) on or after ide-cel infusion were reported in 29 (93.5%) pts, most commonly, neutropenia in 25 (80.6%) pts, leukopenia in 9 (29.0%), and anemia in 7 (22.6%). No Gr 5 AEs were reported. Grade 1 CRS occurred in 14 (45.2%) pts, Gr 2 in 4 (12.9%), and no pts had ≥Gr 3 (Table 1). Investigator-identified neurotoxicity (NT) occurred in 2 (6.5%) pts, one had Gr 1 and one had Gr 3. Robust cell expansion was seen in 31 evaluable pts (Table 2) despite low tumor burden, as assessed by sBCMA level (range 6.5-154.0 ng/mL at infusion, n = 30). Ide-cel cellular expansion was higher in pts who achieved ≥CR vs <CR with ide-cel (Table 2). sBCMA was cleared within 2 mo post-ide-cel infusion in 24/31 (77.4%) evaluable pts, including in 22 who had ≥CR. Among 23 pts with ≥CR, 16 (69.6%; 95% CI, 49.1-84.4) pts had MRD− at 6 mo post-ide-cel infusion. At 12 mo, MRD− was seen in 17/27 (62.9%; 95% CI 44.2-78.5) evaluable pts, regardless of CR status and in 16/23 (69.6%; 95% CI 49.1-84.4) evaluable pts who had ≥CR. Of note, of the 16 pts, 11 sustained MRD− at 24 mo, 2 pts did not have 24 mo data available, and data for 3 pts were indeterminate. Conclusions Ide-cel treatment resulted in frequent, deep, and durable responses in pts with an inadequate response to frontline ASCT. Early deep clearance of tumor was seen in pts with ≥CR after ide-cel treatment and was sustained at 2 y. Lower incidence of CRS and NT were seen in these pts vs those treated with ide-cel in later lines. These results support a favorable clinical benefit-risk profile of ide-cel in NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal