Pembrolizumab in Combination with Pomalidomide and Dexamethasone (PEMBRO/POM/DEX) for Pomalidomide Exposed Relapsed or Refractory Multiple Myeloma

Introduction: Modern therapy for multiple myeloma including generations of thalidomide analogues, proteasome inhibitors and alkylating agents has substantially improved the survival for this disease. Patients who have progressed through these agents have limited options and a very poor prognosis. Programmed death ligand 1 (PD-L1) is expressed by myeloma cells and associated cells in the microenvironment. Blockade of the PD1-PDL1 axis enhances anti-myeloma activity in pre-clinical models. Pembrolizumab, a monoclonal antibody that blocks PD1-PD-L1 signaling, has shown clinical activity when combined with pomalidomide and dexamethasone in pomalidomide naïve patients with relapsed or refractory multiple myeloma (Badros et al, ASH 2015). Here we report the clinical experience of a previously pomalidomide exposed patient population receiving PEMBRO/POM/DEX.

Methods: We retrospectively analyzed the efficacy of PEMBRO/POM/DEX in 9 heavily, pre-treated pomalidomide exposed patients with relapsed or refractory multiple myeloma between February 2016 and July 2016. All patients had been treated with ≥ 5 prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and alkylating agents including high dose melphalan and autologous stem cell transplantation. The PEMBRO/POM/DEX regimen included pembrolizumab 2 mg/kg administered intravenously over 30 minutes every 2 or 3 weeks with pomalidomide 4 mg (range 2-4 mg) orally daily 21/28 days and dexamethasone 40 mg (range 4-40 mg) weekly until evidence of progression (PD) or unacceptable toxicity. Adverse events were captured via chart review. Responses were assessed as per IMWG criteria.

Results: The median age of the patients was 65 years (range 51-77) with 66% females. The patients had a median of 8 prior lines of therapy (range 5-14). The majority of subjects (78%) had cytogenetic abnormalities: 33% were gain of 1q21, 44% monosomy 17, and 11% t(11;14). Prior to therapy, 89% had significant anemia, 78% lytic bone lesions and 2 with significant renal insufficiency (creatinine 2.32 and 3.32 mg/dl respectively) though no one was on dialysis. Isotype included 5 IgA, 2 IgG, 2 lambda light chain. All patients progressed after prior lenalidomide and 8 of 9 patients progressed on previous pomalidomide the other one having stable disease. Patients received a median 3 cycles (range 2-7) of PEMBRO/POM/DEX, with modifications of pomalidomide and dexamethasone dosage dependent on toxicity. Seven patients received aspirin DVT prophylaxis. The overall response rate of PEMBRO/POM/DEX was 33%. Eighty-nine percent of patients achieved clinical benefit (3 PR, 2 MR, 3 SD). Median PFS was 57 days (0-85 days). There were no observed discontinuations of treatment or deaths attributed to drug toxicity and no pneumonitis was seen. However, adverse events consistent with previous reports from pembrolizumab as well as pomalidomide and dexamethasone were observed across all 9 patients. These AEs included: fatigue (n=9), anemia (n=9), thrombocytopenia (n=7), neutropenia (n=5), diarrhea (n=5), fevers (n= 4), shortness of breath (n=4), lower extremity edema (n=4), nausea/ vomiting (n=3), and renal insufficiency (n=3). Two patients experienced non-infectious colitis that responded to prednisone. Overall survival at 6 months for the 9 patients was 56%. 4 patients have died from progressive disease.

Conclusion: PEMBRO/POM/DEX is an active regimen for relapsed and refractory multiple myeloma with acceptable toxicity even in a heavily treated pomalidomide exposed patient population. Further investigation of this combination earlier in the course of the disease is warranted.