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Pembrolizumab in Combination with Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM)

Ashraf Z Badros, Elizabeth Hyjek, Ning Ma, Alexander M. Lesokhin, Aaron P. Rapoport, Mehmet H. Kocoglu, Emily Lederer, Sunita Philip, Patricia Lesho, Ashlee Johnson, Cameron Dell, Olga Goloubeva and Zeba Singh

Abstract

BACKGROUND: Immunotherapy in MM is emerging as an effective modality in therapy of MM with the approval of several monoclonal antibodies and encouraging results for vaccines and T cell therapy. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) is one mechanism of immune evasion by MM to suppress T cell function. In this trial, we hypothesized that pembrolizumab, a PD-1-blocking antibody, would enhance immune modulatory properties of pomalidomide in RRMM pts.

METHODS: In this single center, phase II study, 48 patients with RRMM received 28-day cycles of pembrolizumab (at a dose of 200 mg IV) every 2 weeks (in a run in phase, first 6 patients received 200 mg IV every 4 weeks) plus pomalidomide (4 mg daily x 21 days) and dexamethasone 40 mg weekly. Study objectives were measurements of safety & efficacy and correlation of the CD3/PD-1 on T cells and PD-L1 on plasma cells with response.

RESULTS: The median age was 64 years (range: 35-82); 38% were black and 65% were men, Patients had a median of 3 lines of prior therapy (range: 2-6); All patients had received both IMids and Proteosome inhibitors; 70% had prior auto-SCT. 80% were double refractory to both IMids (lenalidomide) and Proteosome inhibitors [bortezomib (n=18) or carfilzomib (n=20)] and an additional 20% were refractory to lenalidomide. The median time from MM diagnosis to study entry was 4 years (range: 1-25). Most common cytogenetic abnormalities were 1q+ (60%), hyperdiploidy (15%) and high-risk FISH [del 17p, t(4:14) and/or t(14:16)] in 38%. Six patients had soft tissue extramedullary plasmacytomas. There were no infusion-related reactions. Hematologic toxicities (≥ grade 3) were anemia (21%), neutropenia (40%), lymphopenia (15%) and thrombocytopenia (8%). Non-hematologic events Grade ≥3 were fatigue (15%), hyperglycemia (25%), upper respiratory tract infections (21%), rash (10%); and most frequent grade ≥2 were dyspnea (54%), dizziness (44%), increased creatinine 38%, edema (35%), rash (30%), constipation 30%) and arrhythmias (19%). Events of clinical significance, autoimmune mediated, included interstitial pneumonitis (13%), hypothyroidism (10%), transaminitis(6%), adrenal insufficiency (4%) and vitiligo (2%). Nine pts had pomalidomide dose reductions due to rash, neutropenia, palpitations and fatigue; one pt reduced pembrolizumab for pneumonitis. At a median follow up of 10 months (range: 2-18): 25 pts continue on the study and 23 pts discontinued therapy due to disease progression (n= 15), side effects (n=7) and protocol violation (n=1). Five pts died while on study due to progressive disease (n=3), sepsis (n=1, sAE), and one from a cardiac event. Three additional pts died off therapy. On intent to treat analysis; the overall response rate (ORR) with ≥ Partial response were observed in of 27 of 48 pts (56%) including: sCR (n=4, 8%), nCR (n=3, 6%), VGPR (n=6, 13%), PR (n=14, 29%). Additionally, 7 pts (15%) had minimal response, 9 (19%) had stable disease, 2 progressed and 3 were not evaluable for response. Of 38 double refractory pts ORR was 55% including, sCR (n=2, 5%), nCR (n=2, 5%), VGPR (n=4, 10%) and PR (n=13, 27%). Of 18 high-risk pts ORR was 33% including VGPR (n=2, 11%) and PR (n=4, 22%). Median duration of response for responding pts was 8.8 months and for pts ≥ VGPR, DOR was 10.7 months. Correlation of PD-1 and PD-L1 expression and response will be presented.

CONCLUSION: Pembrolizumab, pomalidomide and dexamethasone shows promising durable therapeutic activity and an acceptable safety profile in RRMM pts.

ClinicalTrials.gov number, NCT02289222

Disclosures No relevant conflicts of interest to declare.

  • * Asterisk with author names denotes non-ASH members.