Efficacy and Safety of Cilta-Cel in Patients with Progressive Multiple Myeloma after Exposure to Non-Cellular Anti-BCMA Immunotherapy

Introduction: With the availability of multiple therapy classes targeting BCMA for multiple myeloma (MM), data are needed to understand effective treatment (tx) sequencing. CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the efficacy and safety of cilta-cel, an anti-BCMA CAR-T therapy, in several MM patient populations. We present updated results with a longer follow-up on cohort C patients with previous exposure to a non-cellular anti-BCMA immunotherapy.

Methods: Cohort C patients had progressive MM after tx with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose: 0.75×10⁶ CAR+ viable T cells/kg) was administered 5–7 days post lymphodepletion. The primary endpoint was minimal residual disease (MRD) negativity at 10^-5. Secondary endpoints included overall response rate (ORR; assessed by IMWG criteria), duration of response (DOR), and adverse events (AEs).

Results: As of June 1, 2022, 20 patients (13-ADC exposed; 7 BsAb exposed; 1 patient in the ADC group also had prior BsAb exposure) were treated with cilta-cel. Four patients did not receive cilta-cel due to either low cellular yield (n=2, 1 patient in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 patient in each group). Six patients (30%) received anti-BCMA tx as their last line of therapy (LOT; n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included very good partial response (VGPR; 2 patients in ADC group, 1 patient in BsAb group), stringent complete response (sCR, 1 patient in ADC group), and complete response (CR; 1 patient in BsAb group); the rest had best response of stable disease (SD) or PD (1 patient was not evaluable [NE]). At baseline, median age was 62.5 y (range, 44–81), 60% were male, 3 (15%) had high risk cytogenetics (all del17p), and 5 (25%) had baseline extramedullary disease. Patients had received a median of 8 (range, 4–13) prior LOT; 18 (90%) were triple-class refractory, 11 (55%) penta-drug refractory, and 16 (80%) refractory to non-cellular anti-BCMA treatment (Figure 1A). The median time from last anti-BCMA agent to cilta-cel infusion was 195 d (range, 62–749). Median administered dose of cilta‑cel was 0.65x10⁶ (range, 0.21x10⁶– 1.11x10⁶) CAR+ viable T cells/kg; 1 patient received a below-target dose. At a median follow-up of 18.0 mo (range, 0.6–22.7), 7 of 10 evaluable patients (70%) were MRD-negative at 10^-5 (5 of 7 evaluable patients [71.4%] in the ADC group, and 2 of 3 evaluable patients [66.7%] in the BsAb group). The ORR was 60% (95% CI, 36.1 – 80.9) for the full cohort (61.5% [95% CI, 31.6–86.1] in the ADC group and 57.1% [95% CI, 18.4–90.1] in the BsAb group; Figure 1B). Median DOR (95% CI) was 12.8 mo (7.9–NE) in the full cohort, 12.8 mo (7.9–NE) in the ADC group, and 8.2 mo (4.4–NE) in the BsAb group. Median PFS (95% CI) was 9.1 (1.5–13.8) mo in the full cohort, 9.5 mo (1.0–15.2) in the ADC group, and 5.3 mo (0.6–NE) in the BsAb group. Patients who responded to cilta-cel had a shorter median duration of last anti-BCMA agent exposure (29.5 d, range 1–277) compared with non-responders (63.5 d, range 54–260). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d, range 26–695) than non-responders (56.5 d, range 40–77). The most common AEs were hematologic. CRS occurred in 12 (60%) patients (all grade 1/2), with median time to onset of 7.5 d (range, 2–10) and median duration of 6.0 d (3–10). ICANS occurred in 4 (20%) patients (2 grade 3/4), with median time to onset of 9.0 d (range, 4–13) and median duration of 7.0 d (range, 4–20). ICANS was recovered or resolved in 3 patients. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths: 8 due to PD, 2 due to COVID-19 pneumonia (not tx related), and 1 each due to subarachnoid hemorrhage (not tx related) and C. difficile colitis (tx related).

Conclusions: Heavily pretreated MM patients with previous exposure to a non-cellular anti-BCMA therapy had favorable responses following cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naïve patients treated with cilta-cel (at 27.7 mos, median DOR was not reached in heavily pre-treated but anti-BCMA naïve CARTITUDE-1 patients). These results may inform tx plans, including sequencing and washout period between BCMA-targeting agents.

Figure 1: (A) Patient Demographics and Disease Characteristics, (B) ORR