Pembrolizumab, pomalidomide and low-dose dexamethasone in RRMM patients

In May 2017, Ahraf Badros from the University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA and colleagues published a paper in Blood, reporting results from a single-center Phase II study to assess the efficacy of pembrolizumab in combination with pomalidomide and low-dose dexamethasone. Pembrolizumab is a humanized monoclonal antibody that binds programmed death receptor 1 (PD-1) blocking interaction with its ligands PD-L1 and PD-L2. PD-L1 appears to be over-expressed on myeloma cells, especially in the relapsed setting, and has also been linked to risk of progression to MM from the precursor state. Expression of PD-L1 on myeloma cells drives immunosuppressive signaling and drug resistance via the PI3K/Akt pathway. Therefore, blocking this pathway in MM, along with the use of pomalidomide to drive immune stimulation, is a rational approach in this patient setting.

Study Design:

• Patients (pts) with relapsed and refractory (RR) MM were enrolled, n=48
• All drugs were administered in a 28-day cycle
• Pembrolizumab was administered intravenously (200 mg dose) every 2 weeks
• Pomalidomide = 4 mg daily for 21 days and dexamethasone = 40 mg weekly
• The study was powered (82%) to detect a 25% improvement in overall response rate (ORR) between the study population and a historical control regimen of pomalidomide plus dexamethasone alone (ORR = 30%)
• Median pt age = 64 (35-83 years); Median no. of prior therapies = 3 (range: 2-5)
• High risk cytogenetics (deletion of 17p, t(14:16), t(14:20), t(4:14)and/or 1q+ in CD138-selected myeloma samples) = 62% (30 pts)
• All pts had been pre-treated with a range of PIs and IMiDs, 73% (35 pts) were refractory to both; previous transplant = 72% (31)

 Key Findings:

• ITT population = 48
• Median follow-up = 15.6 months (95% CI 9.2-17.5)
• PFS = 17.4 months (95% CI 11.7-18.8); ORR = 60%
• Stringent complete response sCR/CR = 4 pts (8%)
• VGPR = 19% (9pts); PR = 33% (16 pts)
• Median duration of response = 14.7 months (95% CI 7.9-17.5)
• Overall Survival = was not reached (95% CI 18.9-NR)
• Dose reductions = 49% (22 pts) across all three drugs
• Discontinuation = 11% (5 pts)
• Adverse Effects (AEs) ≥ grade 3 = 42% (20 pts)
• Most common AEs = fatigue, hyperglycemia, dizziness and constipation
• Comparable trials of pomalidomide plus dexamethasone alone:
  • NIMBUS: ORR = 32%; PFS = 4 months
  • STRATUS: ORR = 32.6%; PFS = 4.6 months
  • In 50 high-risk pts: ORR = 22% and DOR = 5.5 months
• Patient responses (in terms of VGPR) appeared to correlate with expression of PD-L1 on bone marrow biopsies, although there was no correlation with PFS and such measurements are not yet standardized for clinical use
• PFS did correlate with higher levels of bone marrow infiltrate, suggesting that cross-talk between infiltrating cells may be a factor

Overall, initial data from this trial is promising, particularly in comparison with two trials using pomalidomide and dexamethasone alone (STRATUS and NIMBUS). However, when making direct comparisons between these two trials it must be noted that the patient set in both trials was heavily pre-treated, with a median of 5 lines of prior therapy compared to 3 in this study. Nevertheless, this study indicates a favorable safety profile for this triplet regimen, although in light of the pause put on the KEYNOTE- 183 Phase 3 trial (also assessing pembrolizumab in combination with pomalidomide and low-dose dexamethasone), the success of this regimen may depend more on prior-treatment exposure and particular characteristics of the patient set than originally thought.