Comparative Effectiveness of Ciltacabtagene Autoleucel vs Physician’s Choice of Therapy for Relapsed or Refractory Multiple Myeloma

Most patients with multiple myeloma (MM) experience relapses marked by worsening disease and progressively lower rates and durations of response with each successive line of therapy. No clear standard of care exists for patients with relapsed or refractory MM who have been exposed to three classes of treatment, immunomodulatory drugs (IMiDs), proteasome inhibitors (Pis), and monoclonal antibodies (mAbs). However, treatment with the anti-CD28 mAb ciltacabtagene autoleucel (cilta-cel) is being studied in patients with relapsed or refractory MM in the open-label, single-arm CARTITUDE-1 trial, although no randomized clinical trials have compared cilta-cel directly with currently used treatments.

Nevertheless, long-term follow-up data from 3 clinical trials of another anti-CD28 mAb, daratumumab, may provide an external control arm useful for establishing the comparative efficacy of cilta-cel and currently used treatments in patients with triple-class exposed RRMM. In these 3 trials, CASTOR, POLLUX, and EQUULEUS, patients received the physician’s choice of treatment after trial treatment was discontinued. To determine the comparative efficacy of cilta-cel vs. physician’s choice of treatment from long-term follow-up data from these 3 trials, an international team of researchers created an external control arm for CARTITUDE-1 from patients in the 3 daratumumab trials who satisfied the eligibility criteria of CARTITUDE-1 (Clin Drug Investig. 2021;42:29-41. Doi:10.1007/s40261-01100-y).

The researchers Used inverse probability of treatment weighting to align the external control and CARTITUDE-1 populations on important baseline characteristics and assessed overall response rate, rate of complete response or better, progression-free survival (PFS), time to next treatment, and overall survival (OS) for each treatment. They also did several sensitivity analyses to assess the effect of varying the population, statistical methods, covariates, and outcome definitions used.

After propensity score weighting, the researchers found that the baseline characteristics of the cohorts were comparable and that results of cilta-cel were superior when compared to to those of physician’s choice of treatment, which included IMiDs (pomalidomide, thalidomide, and lenalidomide), PIs (carfilzomib, bortezomib, and ixazomib), and mAbs (daratumumab, elotuzumab, and isatuximab). “Patients in the physician’s choice cohort received 151 unique treatment combinations after becoming triple-class exposed,” wrote first author Katja Weisel, M.D., Section of Pneumology, Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and colleagues.

After comparing the results of cilta-cel with those of physician’s choice of treatment, the researchers found that, for the overall response rate, the relative risk (RR) was 2.95 (95% confidence interval [CI], 2.27 to 3.84), and for complete response or better, the RR was 111.7 (95% CI, 29.08 to 429.06). For PFS, the hazard ratio (HR) was 0.24 (95% CI, 0.15 to 0.37), for time to next treatment, the HR was 0.14 (95% CI, 0.09 to 0.22), and for OS, the HR was 0.21 (95% CI, 0.13 to 0.35). All comparisons were significant at the level of P<.0001, and the researchers also considered cilta-cel to be superior in clinical efficacy to the physician’s choice of treatment. Moreover, the researchers found consistent results for all of their sensitivity analyses.

“These findings suggest that cilta-cel may represent an important new treatment option for patients with triple-class exposed RRMM,” Dr. Weisel and team concluded.