PCD in RRMM: Improved Outcomes and Manageable Safety

Patients (pts) experiencing relapse or refractory status in multiple myeloma (RRMM) with prior resistance to lenalidomide and bortezomib face a survival prognosis of less than one year. Pomalidomide (pom), an immunomodulatory drug, has demonstrated enhanced survival benefits in this subgroup. However, the optimal combination with pom remains uncertain, as pts often become triple-class refractory when requiring pom.

Yang Song and other researchers compared the efficacy of pom, cyclophosphamide, and dexamethasone (PCD) with pom and dexamethasone (PD), specifically in Asian RRMM pts.

In the phase 3 trial, researchers conducted a two-arm randomized, multicenter, and multinational prospective study. This trial enrolled RRMM pts with prior exposure to proteasome inhibitors (bortezomib, carfilzomib, or ixazomib) and lenalidomide. Inclusion criteria were measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, satisfactory organ function (neutrophil count ≥ 1,000/mm³, platelet count ≥ 50,000/mm³, bilirubin ≤ 1.5 x upper limit of the normal range (ULN), alanine aminotransferase, and aspartate aminotransferase ≤ 3 x ULN, and creatinine clearance ≥ 30 ml/min). The exclusion criteria involved plasma cell leukemia, more than 6 lines of prior treatment, or previous exposure to pom.

In the interventional study, the enrolled pts were randomly assigned in a 1:1 ratio to receive either PCD or PD. The dosing schedule was 4-weekly, including pom 4mg on days 1-21, dexamethasone 40 mg twice a week, and, for PCD pts, cyclophosphamide 400 mg weekly for 3 weeks. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The analysis included a modified intention-to-treat population comprising all randomized pts who received at least 1 dose of the study drug.

The primary endpoint was progression-free survival (PFS), defined as the time from the start of treatment to disease progression or death. Secondary endpoints included overall response rate (ORR), overall survival (OS), duration of response (DOR), and safety, assessed by the frequency and percentage of adverse events (AEs) by severity.

With Kaplan-Meier curves, they presented PFS, OS, and DOR. A Cox proportional hazard model was employed to compare the two arms in terms of PFS, OS, and DOR, while a generalized linear model with binomial distribution was used for ORR.

Among the 124 recruited pts, 122 received at least 1 dose of the study drug (62 PCD, 60 PD). The baseline characteristics were comparable between arms. Median age was (range 47 – 88) years in the PCD arm and 67.2 (range 48 – 85) years in the PD arm, with both groups having a median of 3 prior lines of treatment.

At a median follow-up of 13.5 (IQR 8.7 – 24.0) months, the median PFS was 10.9 months (95% CI, 7.1 – 27.7) in the PCD arm versus 5.8 months (95% CI, 4.4 – 6.9) in the PD arm (HR 0.43, 95% CI, 0.27-0.69; P < 0.001). The ORR was 55.4% (95% CI, 41.0 – 69.7) in the PCD arm and 32.0% (95% CI, 19.5 – 44.5) in the PD arm; a difference of 23.3% (95% CI, 6.5 – 40.2, P = 0.007).

The median DOR was 12.0 months (95% CI, 7.2 – NR) in the PCD arm and 5.7 months (95% CI, 3.7 – 9.7) in the PD arm (HR 0.41, 95% CI, 0.20 – 0.87). Although not statistically significant, the median OS was numerically greater in the PCD arm (41.5 months, 95% CI, 24.5 – NR) compared to the PD arm (27.5 months, 95% CI, 27.5 – NR).

The median treatment duration for pom was 7.8 (IQR 4.4 – 13.4) months in the PCD arm and 5.1 (IQR 2.8 – 8.7) months in the PD arm. Adverse event (AE) rates were similar in both arms. In the PCD arm, 51 pts (82.3%) experienced 346 treatment-emergent adverse events (TEAEs), with 164 (47.4%) related to study treatment. In the PD arm, 49 pts (81.7%) had 241 TEAEs, and 136 (56.4%) were related to study treatment. The most common grade ¾  treatment emergent AEs (TEAEs) in both arms were neutropenia, anemia, and pneumonia. About 34 deaths occurred during the study (17 in PCD, 17 in PD), with 12 (35.2%) attributed to disease progression and 3 deaths (1 in PCD, 2 in PD) were deemed related to study treatment (2 infections, 1 fluid overload).

The result concluded that PCD significantly extends PFS, enhances the ORR, and prolongs the DOR when compared to PD in pts with RRMM who have previously been exposed to both a proteasome inhibitor and lenalidomide. The findings suggested that PCD treatment represents a viable therapeutic option for this specific patient population, characterized by an acceptable and manageable safety profile. These results contributed valuable insights into improving treatment strategies for individuals with RRMM and a history of prior exposure to specific agents.

This study is sponsored by the National University Hospital, Singapore.

Source: https://ash.confex.com/ash/2023/webprogram/Paper184723.html

Clinical Trial: https://clinicaltrials.gov/study/NCT03143049

Song Y, Kim JS, Chim CS, et al. “Randomized Phase 3 Study of Pomalidomide Cyclophosphamide Dexamethasone (PCD) Versus Pomalidomide Dexamethasone (PD) in Relapse or Refractory Myeloma: An Asian Myeloma Network (AMN) Study”. Presented at ASH 2023. (Abstract: 1009).