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Cilta-cel in earlier lines improves outcomes over SoC in LEN-refractory MM patients

29 Jul 2023

STUDY DESIGN

For patients with heavily pretreated lenalidomide (LEN)-refractory multiple myeloma (MM) who have received ≥3 lines of therapy (LoT), the efficacy of ciltacabtagene autoleucel (cilta-cel) has been demonstrated in previous studies.¹ Cilta-cel is a dual-binding, B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapy, which has achieved a median progression-free survival (PFS) of around 3 years.¹

A phase 3 CARTITUDE-4 study was conducted to evaluate the clinical benefits of cilta-cel in the LEN-refractory MM population with earlier LoT (i.e., 1-3 LoT).¹ A total of 419 eligible patients were randomized 1:1 to receive either the cilta-cel arm (n=208) or the standard of care (SoC) therapy (n=211).¹ The SoC was either the daratumumab + pomalidomide + dexamethasone (DPd) regimen or the pomalidomide + bortezomib + dexamethasone (PVd) regimen, while the cilta-cel arm received 1 cilta-cel infusion at a target of 0.75x10⁶ CAR-T cells/kg.¹ The primary efficacy endpoint was PFS.¹ The secondary endpoints included overall response rate (ORR), complete response (CR) or more, minimal residual disease (MRD) negativity, overall survival (OS), and safety.¹

The results demonstrated that cilta-cel achieved significant PFS benefits in the overall population with a 12-month PFS rate of 76% vs. 49% in the SoC arm and a relative risk reduction of 74% (HR=0.26; 95% CI: 0.18-0.38; p<0.0001).¹ The PFS benefit was consistent across different subgroups.¹ The cilta-cel arm also obtained a significantly higher ORR of 84.6% vs. 67.3% with SoC (OR=3.0; 95% CI: 1.8-5.0; p<0.0001).¹ In addition, significantly more patients who received cilta-cel achieved the duration of response for 12 months (84.7% vs. 63.0%).¹ Cilta-cel also improved the rates of overall MRD-negativity at 10^-5 vs. SoC (60.6% vs. 15.6%; OR=8.7; p<0.0001).¹

FINDINGS

Primary endpoints:

The primary efficacy endpoint was PFS¹

The 12-month PFS rates were 76% with cilta-cel and 49% with SoC, demonstrating a 74% risk reduction in disease progression (HR=0.26; 95% CI: 0.18-0.38; p<0.0001) in the intention-to-treat (ITT) population¹

PFS benefits were seen across different patient subgroups, including those with ≥2 high-risk cytogenetics, soft-tissue plasmacytomas, International Staging System (ISS) stage III, and prior exposure to anti-cluster of differentiate (CD) 38 antibodies and proteasome inhibitor (PI)¹

Secondary endpoints:

Secondary endpoints included ORR, ≥CR, MRD negativity, OS, patient-reported outcomes (PROs)¹

The ORR of patients treated with cilta-cel vs. SoC was 84.6% vs. 67.3%, with 73.1% vs. 21.8% of patients reaching ≥CR, respectively (OR=3.0; 95% CI: 1.8-5.0; p<0.0001)¹

MRD negativity was significantly higher (OR=8.7; p<0.0001) with the cilta-cel arm at 60.6% compared with 15.6% in the SoC arm¹

At the time of analysis, OS data were immature with 39 deaths in the cilta-cel arm vs. 47 deaths in the SoC arm (HR=0.78; 95% CI: 0.5-1.2; p=0.26)¹

In the as-treated population (n=126), 12-month PFS was at 90% with an ORR of 99.4%, an MRD negative at 10^-5 of 72% and a ≥CR rate of 86.4%¹

Safety:

In the safety population of the cilta-cel arm (n=208), serious adverse events (SAEs) of any grade were reported in 44.2%, which were similar to those in the safety population of the SoC arm (n=208) at 38.9%¹

Neutropenia was the most common hematological adverse event (AE), occurring in 89.9% of patients in the cilta-cell arm, which was similar to that in the SOC arm (85.1%)¹

Overall, CAR-T-specific AEs were manageable with appropriate supportive care¹

The incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), movement and neurocognitive treatment-emergent adverse event (MNT) of cilta-cell were lower when used in earlier lines, suggesting improved tolerability among LEN-refractory MM patients when it is used earlier in the treatment¹

“Cilta-cel has the potential to be a new SoC for patients with LEN-refractory MM after first relapse”

^{Dr. Binod Dhakal

Medical College of Wisconsin,

Milwaukee, Wisconsin, United States}

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