Outcomes of Patients with Relapsed Multiple Myeloma Treated with Pomalidomide, Cyclophosphamide, and Dexamethasone Based on Prior Resistance to Anti-CD38 Monoclonal Antibodies
Authors: Hidalgo-Soto Marta , Martín-Rodríguez Lucía , Abella Montreal Eugenia , Fernández-Camacho Inmaculada , Gironella Mesa Mercedes , González-Montes Yolanda , Cibeira López M Teresa , Rosinol Dachs Laura , Mateos Pérez José Miguel , Tovar Natalia , Fernández de Larrea Carlos , Rodríguez-Lobato Luis Gerardo 
Published: December 2024

Background
The combination of pomalidomide, cyclophosphamide, and dexamethasone (PomCyDex) has been used in the treatment of patients with relapsed/refractory multiple myeloma (RRMM) particularly among those with lenalidomide refractoriness. However, after the introduction of novel therapies such as anti-CD38 monoclonal antibodies (mAbs), even as standard first-line treatment, many patients are now presenting as refractory to these drugs. The effectiveness of the PomCyDex regimen in patients who are triple class refractory [defined as refractory to anti-CD38 mAbs, immunomodulatory drugs (IMiDs), and proteasome inhibitors (PIs)], remains to be elucidated.
Methods
Patients with RRMM who received the PomCyDex regimen [pomalidomide at a dose of 4 mg on day 1 through 21 of 28-day cycles, cyclophosphamide 50 mg/day on D1 through 21 of 28-day cycles, and dexamethasone 40 mg or 20 mg weekly (if subjects aged 75 years or older, or presence of severe comorbidities)], were included in a retrospective, multicenter study within the Catalan Myeloma and Amyloidosis Group (GEMMAC). Baseline characteristics were collected at the start of treatment. Responses were evaluated according to the international myeloma working group (IMWG) 2016 criteria. Overall survival (OS) and covariates were assessed using a Cox proportional hazard model. A nominal p-value from the Cochran-Mantel-Haenszel test was used to evaluate the effect of covariates on OS.
Results
A total of 77 patients with RRMM were identified, with a median age of 67 years (IQR: 64-70), and a median of 3 previous lines of treatment. In this cohort, 81% were refractory to lenalidomide and 57% to anti-CD38 mAbs. All patients who received previously anti-CD38 mAbs were triple refractory (anti-CD38 mAbs + IMIDs + PIs). The median follow-up was 69 months (IQR 47-91), and the global cohort received a median of 6 cycles (range: 2-9).
The overall response rate (ORR) was 62%, with 58.7% in lenalidomide-refractory patients (double-refractory) and 45.8% in triple-refractory patients. Therapy was discontinued in 27% of cases due to primary progression, 40% due to relapse, and 12% due to intolerance. The median overall survival (OS) was 13 months (95% CI: 9-16), and progression-free survival (PFS) was 7 months (95% CI: 4-9).
Lenalidomide-refractory patients did not show a significantly lower OS (hazard ratio [HR]: 1.2; 95% CI: 0.6-2.4, p=0.5) or PFS [6 months (CI 95%:3-8),p=0.2]. However, anti-CD38 mAbs refractory patients had significantly worse OS compared to anti-CD38 naïve patients, regardless of prior treatment exposure (OS: 11 months [95%CI: 8-12] vs. 22 months [12-31], p=0.03; HR: 1.7, 95% CI: 1.1-3). No significant differences in progression-free survival (PFS) were observed between both groups (PFS: 6 months [95% CI: 3-8] vs. 7 months [95% CI: 4-9], p=0.9), respectively.
Multivariate analysis demonstrated that refractoriness to anti-CD38 mAbs (HR: 1.7, 95% CI: 1.1-3) and not achieving at least a partial response (PR) or better (HR: 2.4, 95% CI: 1.4-4.2) were associated with lower OS.
Conclusion:
The PomCyDex regimen is an effective salvage therapy, demonstrating efficacy regardless of lenalidomide refractoriness. However, patients previously refractory to anti-CD38 mAbs experience poorer outcomes. In the context of evolving first-line treatments and with the near approval of daratumumab for maintenance, these results are of interest as they could impact outcomes in a commonly used relapse strategy.