Cilta-cel a new Soc for lenalidomide-refractory MM?

In patients with lenalidomide-refractory multiple myeloma (MM), a single infusion of ciltacabtagene autoleucel (cilta-cel), a dual-binding BCMA*-directed chimeric antigen receptor (CAR) T-cell therapy, improved progression-free survival (PFS) compared with standard of care** (SoC), according to the phase III CARTITUDE-4 trial.

“The primary endpoint was met,” reported Dr Hermann Einsele from the Universitätsklinikum Würzburg, Germany, at EHA 2023. “In patients with lenalidomide-refractory MM and 1–3 prior lines of therapy (LOT), cilta-cel significantly prolonged PFS and had a favourable benefit-risk profile across patient populations.”

The 12-month PFS rate was higher with cilta-cel vs SoC (76 percent vs 49 percent). Median PFS with SoC was 11.8 months, whereas with cilta-cel, it was not reached (NR; hazard ratio [HR], 0.26; p<0.0001). [EHA 2023, abstract S100]

Subgroup analysis consistently favoured cilta-cel over SoC across all key*** subgroups, with HRs ranging between 0.15 and 0.40.

Overall response rate was higher with cilta-cel vs SoC (85 percent vs 67 percent; odds ratio [OR], 3.0; p<0.0001), which was primarily driven by the higher ≥CR^# rate (73 percent vs 22 percent; OR, 10.3; p<0.0001). Cilta-cel also trumped SoC in terms of median DoR^# (NR vs 16.6 months) and 12-month DoR rate (85 percent vs 63 percent).

Cilta-cel improved rates of overall MRD^## negativity at 10^-5, both in the intention-to-treat cohort (61 percent vs 16 percent; OR, 8.7; p<0.0001) and among those evaluable for MRD (88 percent vs 33 percent).

Albeit immature, there was a positive trend for overall survival with cilta-cel vs SoC (HR, 0.78; p=0.26). There were 39 deaths in the cilta-cel arm as opposed to 47 in the SoC arm.

In the as-treated cilta-cel cohort (n=176), 12-month PFS rate was 90 percent, ORR was 99 percent (86 percent ≥CR), and 72 percent were MRD-negative at 10^-5.

Safety

The most common treatment-emergent adverse events (TEAEs) were haematologic events, with up to 90 percent of participants experiencing high-grade neutropenia. Cilta-cel was tied to more grade 3/4 anaemia (36 percent vs 14 percent), thrombocytopenia (41 percent vs 19 percent), and lymphopenia (21 percent vs 12 percent) events than SoC, but most high-grade cytopenias resolved to grade ≤2 by day 30.

“CAR T-cell-specific AEs were manageable with the appropriate supportive care,” said Einsele.

There were 10 deaths in the cilta-cel arm due to TEAEs, seven of which were due to COVID-19. Of the five TEAE-related deaths in the SoC arm, only one was attributed to COVID-19. “This highlights the need for strict prevention measures and aggressive treatment of COVID-19 in patients receiving CAR T-cell therapies,” noted Einsele.

In the as-treated population, 76 percent had cytokine release syndrome (CRS) and 20 percent had CAR T-cell-related neurotoxicities (both any-grade). None of the neurotoxicities were fatal. ICANS^### was reported in eight patients, while 30 had non-ICANS neurotoxicities (cranial nerve palsy, peripheral neuropathy, MNT^###).

Of note, the incidence and severity of CRS, ICANs, MNTs, and some cytopenias were lower in this study compared with the phase Ib/II CARTITUDE-1 trial, which looked at heavily pretreated MM patients with ≥3 prior LOT. “[This underlines] the improved tolerability of cilta-cel when used earlier in treatment,” said Einsele.

 

A population with clear unmet need

The investigators sought to evaluate cilta-cel against effective SoC treatments in earlier LOT, as “T-cell function/CAR T-cell activity is better in less heavily pretreated patients,” noted Einsele.

A total of 419 patients (median age 61 years, 57 percent male) were randomized 1:1 to receive cilta-cel (target dose 0.75 × 10⁶ CAR+ viable T cells/kg) or SoC. Those on cilta-cel initially received bridging therapy with PVd or DPd ≥1 cycle, followed by cilta-cel infusion 5–7 days after lymphodepletion.

“[The CARTITUDE-4 cohort] represents a patient population with clear unmet need commonly seen in clinical practice,” noted Einsele.

“The 74-percent reduction in progression/death and high rates of CR and MRD-negativity highlight the potential for cilta-cel to become a new SoC for patients with lenalidomide-refractory MM after first relapse,” Einsele concluded.