Pembrolizumab Combo Highly Effective for Heavily Pretreated Myeloma

Silas Inman @silasinman
Published: Monday, Dec 05, 2016

Dr Ashraf Z. Badros

Ashraf Z. Badros, MD

Treatment with the combination of pembrolizumab (Keytruda), pomalidomide (Pomalyst), and dexamethasone demonstrated promising durable efficacy and a tolerable safety profile for patients with relapsed/refractory multiple myeloma, according to phase II findings presented at the 2016 ASH Annual Meeting.1

In the single-center trial, the overall response rate (ORR) was 65% with the pembrolizumab-containing triplet regimen. Overall, 29% of patients experienced a very good partial remission (VGPR) or better. The stringent complete remission (sCR) rate was 7% and the CR rate was 2%. Responses remained consistent in those with double-refractory disease and for those with high-risk cytogenetics.

"In this heavily pretreated patient population, I think these responses are quite impressive. I do not believe that any other agents have resulted in this type of responses," said Ashraf Z. Badros, MD, Greenebaum Cancer Center, University of Maryland School of Medicine. "The durability of the responses are also impressive."

The study enrolled 48 patients with relapsed/refractory multiple myeloma at the University of Maryland. Pembrolizumab was administered at a flat dose of 200 mg intravenously every 2 weeks for most patients. The first 6 patients received a run-in dose of 200 mg every 4 weeks, to establish tolerability. Pomalidomide was given at 4 mg daily for 21 days and dexamethasone was administered at 40 mg weekly.

The median age of patients was 64 years, and the ECOG performance status was primarily 0 to 1 (92%). Thirty-eight percent of patients had standard cytogenetic risk and the remaining 62% had high-risk cytogenetics. The median number of prior therapies was 3 (range, 2-5), and 27% of patients had received >3 prior regimens. All patients had received a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). Seventy-nine percent of patients were refractory to a PI and 90% were refractory to lenalidomide. Seventy-three percent of patients were double refractory to an IMiD and PI.

At the data cutoff of October 15, 2016, the median follow-up time was 9.6 months. The median duration of response was 16.3 months (95% CI, 9.8-19.1) and the median progression-free survival (PFS) was 17.4 months (95% CI, 11.7-18.8). At the time of the analysis, the median overall survival was not yet reached (95% CI, 18.8-not reached).

In those with double-refractory disease (n = 32), the ORR was 68% and the VGPR rate or better was 24%. In those with high-risk cytogenetics (n = 27), the ORR was 56% and the VGPR or better rate was 15%.

PD-L1 expression was assessable for 29 patients in the study, with positivity defined as expression on ≥50% of cells. In those with PD-L1-positive disease (n = 13), the combination elicited an ORR of 77%, with a VGPR or better of 54% (P = .05; versus PD-L1-negative). Those with PD-L1-negative disease (n = 10) had an ORR of 60% and a VGPR rate of 20%. There were no CRs. The median PFS in the PD-L1-negative arm was 17.4 months (95% CI, 10.6-18.4). In those with PD-L1-positive disease, the median PFS was not yet reached.

"High expression of PD-L1 was associated with deeper responses. There was also a trend toward longer progression-free survival in the positive arm," Badros said. "This is identical to what is reported for solid tumors."

A further assessment looked at CD3 and PD-1 expression, with positivity defined as CD3 expression on ≥5% and PD-1 on ≥1% of cells. In those with CD3+/PD-1+ myeloma (n = 6), the VGPR or better rate was 0% and patients only experienced partial responses (33%). The median PFS was just 6.3 months in this group.

In those with CD3-/PD-1- disease (n = 22), the sCR rate was 14% and the VGPR rate was 9%. The median PFS in this group was 17.5 months. In those with CD+/PD-1- cells (n = 10), the CR rate was 10% and the VGPR rate was 40%. The median PFS was 16.5 months.

"Progression-free survival was significantly longer in patients with T-cell infiltrate that was not activate or exhausted by PD-1 expression," said Badros. "This is similar to solid tumors."

The most common grade ≥3 adverse events (AEs) were neutropenia (40%), hyperglycemia (25%), anemia (21%), upper respiratory tract infections (21%), lymphopenia (15%), fatigue (15%), rash (10%), and thrombocytopenia (8%). Immune-related AEs included interstitial pneumonitis (13%), hypothyroidism (10%), transaminitis (6%), adrenal insufficiency (4%), and vitiligo (2%).

Overall, 5 patients discontinued therapy due to adverse events (11%). These events included pneumonitis (n = 3), shortness of breath (n = 1), and fatigue (n = 1). Forty-nine percent of patients required a pembrolizumab dose reduction.

"The side effects were manageable but high," Badros noted. "Pneumonitis was seen in 6 patients. These patients responded quite well to treatment and restarted on the same doses of pembrolizumab. Two patients had dose reductions but had recurrent episodes and were taken off study."

Continued efficacy for the triplet was demonstrated in a second study for patients with pomalidomide-refractory multiple myeloma.2 This phase I study included 9 patients at a median age of 65 years. Patients had received a median of 8 prior therapies (range, 5-14), and all had received prior stem cell transplants. Eight of the 9 patients had progressed on pomalidomide.

The partial response rate was 33% and the minor response rate was 22%. The stable disease rate was 33%, for an overall clinical benefit rate of 89%. The median progression-free survival was 57 days (range, 0-85). After 6 months, approximately 55% of patients remained alive.

A phase III study, labeled KEYNOTE-183, is exploring pomalidomide and low dose dexamethasone with or without pembrolizumab for patients with refractory or relapsed and refractory multiple myeloma. The primary endpoints for the study, which is still enrolling, are PFS and overall survival (NCT02576977).
References
  1. Badros AZ, Hyjek E, Ma N, et al. Pembrolizumab in Combination with Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 490.
  2. Wilson L, Cohen AD, Weiss BM, et al. Pembrolizumab in Combination with Pomalidomide and Dexamethasone (PEMBRO/POM/DEX) for Pomalidomide Exposed Relapsed or Refractory Multiple Myeloma. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 2119.


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