Safety and efficacy of pomalidomide, bortezomib and dexamethasone for the treatment of RRMM

On 7^th September, study results were published in Blood assessing the use of pomalidomide, bortezomib and dexamethasone (PVD) with relapsed Multiple Myeloma (MM) patients who are refractory to lenalidomide. Jonas Paludo from the Division of Hematology at the Mayo Clinic in Rochester, and colleagues, determined the maximum tolerated dose (MTD) and the efficacy and safety of PVD in phase I and II trials.

The study was prospective, non-randomized, multicenter, open-label and investigator-initiated. The phase I study determined the MTD of PVD and the efficacy and safety were evaluated in the phase II study. Phase II study endpoints included: Partial Response (PR), Objective Response Rate (ORR), Very Good Partial Response (VGPR) and Complete Response (CR). Secondary endpoints included: Overall Survival (OS), Progression-Free Survival (PFS), Duration of Response (DOR) and toxicity.

 Key Findings

• Backbone dosing: pomalidomide (4 mg orally on days 1 and 21) and dexamethasone (40 mg orally on days 1, 8, 15 and 22) every 28 days
• Two dose levels (DL) for bortezomib were determined in phase I:
  • DL 1: IV or S/C bortezomib (1.0 mg/m² on days 1, 8, 15 and 22)
  • DL 2 (MTD): IV or S/C bortezomib (1.3 mg/m² on days 1, 8, 15 and 22)
• Number of patients (pts) n = 50, pts receiving DL 1 (n = 3) and pts receiving DL 2 (n = 47)
• Results for all patients:
  • Median follow-up = 42 months (range 13-59)
  • ORR = 50 pts 86% (95%; CI, 73-94)
  • CR = 5 pts (10%)
  • VGPR = 14 pts (28%)
  • PR = 18 pts (36%)
• Results for DL 2 (MTD):
  • ORR = 41 pts (87%), (95%; CI, 75-94)
• Results for standard-risk pts:
  • Median PFS = 15.4 months; (95% CI, 9.5-19.1); P = 0.5
  • Median OS = not reached
  • ORR = 83%, P = 0.68
• Results for high-risk pts:
  • Median PFS = 12.3 months (95%; CI, 5.2-24.6)
  • Median OS = not reached
  • ORR = 100%

Safety

• Grade ≥3 hematologic toxicities = 74%
• Grade ≥3 non-hematologic toxicities = 26%; Most common grade ≥3 toxicities included: neutropenia (70%), leukopenia (36%) and lymphopenia (20%), deep vein thrombosis (n = 5 pts)
• Peripheral sensory neuropathy toxicity = 68%
• Dose reductions = 8 pts (16%), death = 17 pts (34%), and disease progression = 40 pts (80%)

Conclusion

The results of this study showed good efficacy for the use of PVD in RRMM patients who are refractory to lenalidomide treatment. Safety profiles were shown to be acceptable, and dose reductions of bortezomib limited the major AE of neuropathy. Thus PVD is a convenient and well-tolerated regimen for use as a second line therapy for patients previously treated with lenalidomide. Given that the lower dose of 1 mg of bortezomib was only tested in 3 patients in the phase I portion of the trial, little conclusion can be drawn and it would be interesting to see if smaller dose reductions can retain efficacy whilst limiting resulting AEs.