Phase 3 CARTITUDE-4 Results Show Superiority of Cilta-Cel in MM

The first phase 3 results from the CARTITUDE-4 trial of ciltacabtagene autoleucel (cilta-cel) vs standard of care (SOC) in lenalidomide-refractory multiple myeloma (MM) demonstrated the former’s convincing superiority in several key outcomes.

Presented during the plenary session at the European Hematology Association 2023 Congress by Hermann Einsele, MD, FRCP of Universität Würzburg in Germany, the data could position the chimeric antigen receptor (CAR) T-cell therapy as the new SOC. They extend the findings of the phase 1b/2 CARTITUDE-1 trial, which showed cilta-cel’s efficacy in extending progression-free survival (PFS) for patients with MM who had received at least 3 prior lines of therapy.

Cilta-cel, sold as Carvykti, was approved for treatment of relapsed or refractory MM in March 2022 based on the results of CARTITUDE-1, including an objective response rate of 98%.

CARTITUDE-4 (NCT04181827) compared cilta-cel’s efficacy and safety vs that of SOC (pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory MM who had 1 to 3 prior lines of therapy. The primary end point was PFS; secondary end points included safety, patient-reported outcomes, and efficacy as measured by complete response, overall response rate, overall survival, and minimal residual disease (MRD) negativity.

Of the 419 patients randomly assigned to a study arm, 208 were in the cilta-cel arm and 211 were in the SOC arm, representing the intent-to-treat population. Baseline demographics and disease characteristics were similar across arms, Einsele said.

The median PFS was 11.8 months in the SOC arm and not reached in the cilta-cel arm, thus meeting the study’s primary end point; 49% and 76% of patients in each arm, respectively, achieved PFS at 12 months. Cilta-cel had the edge on PFS whether patients had 1 or 2 to 3 prior lines of therapy, and even those who received cilta-cel after 2 or 3 other therapies had better PFS than those who received SOC after just 1 prior line. The CAR T therapy also had a significantly higher overall response rate (odds ratio, 3.0) and MRD negativity rate (odds ratio, 8.7) vs the SOC.

Moving into the safety data, Einsele showed that most treatment-emergent adverse events in the cilta-cel arm were hematological, often neutropenias. Of note, there were 7 deaths due to COVID-19 in the cilta-cel arm and just 1 in the SOC arm.

“The issue of COVID-19 really indicates the need for strict prevention measures and aggressive treatment for COVID-19 in patients who are receiving CAR T-cell therapy,” Einsele said. “When safety measures consistent with the international guidelines were introduced, there were no further COVID-19–related deaths in the cilta-cel arm.”

Drawing comparisons between CARTITUDE-1 and CARTITUDE-4, he noted a lower incidence and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, movement and neurocognitive treatment-emergent adverse events, and some cytopenias in the newer trial, suggesting improved tolerability of cilta-cel when used in earlier lines of therapy.

“In conclusion, cilta-cel has the potential to be a new [SOC] for patients with lenalidomide-refractory [MM] after first relapse,” Einsele said.

Plenary moderator Brian Huntly, MB ChB, PhD, of the University of Cambridge in England, posed a question to Einsele: With results this impressive, why qualify that prediction with “potential” or “probably”?

Einsele said that he would like to see longer follow-ups, but so far, “this extremely high overall response rate in the patients who were treated with cilta-cel speaks for using CAR T cells in early lines of therapy.”

Reference

Einsele H, Yong K, Harrison S, et al. First phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. Presented at: European Hematology Association 2023 Congress; June 8-11, 2023; Frankfurt, Germany. Session S100.