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

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.

Immune checkpoint blockade for hematologic malignancies: a review

“…among patients double-refractory to both proteasome inhibitors and IMiDs, and ORR 33% among patients with high-risk cytogenetics (98). Pembrolizumab, pomalidomide, and dexamethasone evaluated in a phase II study enrolling 48 patients with R/R MM, among which the overall response rate was ≥PR in 27 of 48 patients (55%), including sCR (n=4, 8%), nCR (n=3, 6%), VGPR (n=6, 13%), PR (n=14, 29%), and 7 minimal responses (15%), stable disease (n=9, 19%), 2 with progressive disease and 3 patients were not evaluable for response (83). Interestingly, responses correlated with presence of bone marrow infiltrating CD8 + effector T cells [ASH 2016 oral presentation (83)].…”

“…Pembrolizumab, pomalidomide, and dexamethasone evaluated in a phase II study enrolling 48 patients with R/R MM, among which the overall response rate was ≥PR in 27 of 48 patients (55%), including sCR (n=4, 8%), nCR (n=3, 6%), VGPR (n=6, 13%), PR (n=14, 29%), and 7 minimal responses (15%), stable disease (n=9, 19%), 2 with progressive disease and 3 patients were not evaluable for response (83). Interestingly, responses correlated with presence of bone marrow infiltrating CD8 + effector T cells [ASH 2016 oral presentation (83)]. A retrospective series also supports the activity of this combination in a heavily pretreated and pomalidomideexposed population, with an ORR of 33%, with 89% of patients achieving clinical benefit (3 PR, 2 MR, 3 SD) (84).…”

Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors

“…A phase II trial in 48 lenalidomide-refractory RRMM patients evaluated pembrolizumab in combination with pomalidomide and dexamethasone. 54 Besides lenalidomide, 80% of enrolled patients were also refractory to a proteasome inhibitor. The overall response rate (ORR) was 56% and responding patients had a median duration of response of more than 6 months.…”

Monoclonal Antibodies and Multiple Myeloma: All in All It's Just Another Brick in the Wall?

“…Monotherapy with nivolumab had no relevant activity in RRMM . Conversely, combination of pembrulizumab with lenalidomide or pomalidomide plus dexamethasone induced ORRs up to 77%, including a significant proportion of at least VGPR, with durable benefit even in the double‐refractory (IMIDs and PIs) population . Notably, the rate of autoimmune disorders was significant in one study .…”

“…Conversely, combination of pembrulizumab with lenalidomide or pomalidomide plus dexamethasone induced ORRs up to 77%, including a significant proportion of at least VGPR, with durable benefit even in the double‐refractory (IMIDs and PIs) population . Notably, the rate of autoimmune disorders was significant in one study . Thus, several trials were initiated to evaluate various combinations of check‐point inhibitors with other agents (in particular IMIDs and MoAbs) .…”