New Combination Found Effective for Heavily Pretreated Myeloma


A new combination, including the immunotherapy agent Keytruda, was shown to be highly effective in treating a subset of patients with myeloma.

The triplet of Keytruda (pembrolizumab), Pomalyst (pomalidomide) and dexamethasone showed durable efficacy with a tolerable safety profile for patients with relapsed/refractory multiple myeloma, according to findings from a phase 2 trial that were presented at the 2016 American Society of Hematology (ASH) Annual Meeting.

In the single-center trial, the overall response rate (ORR) was 65 percent with the Keytruda -containing triplet regimen. Overall, 29 percent of patients experienced a very good partial remission (VGPR) or better. The stringent complete remission (sCR) rate was 7 percent and the CR rate was 2 percent. 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, M.D., 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. Keytruda was administered at a flat dose of 200 mg intravenously every two weeks for most patients. The first six patients received a run-in dose of 200 mg every four weeks, to establish tolerability. Pomalyst 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 percent). Thirty-eight percent of patients had standard cytogenetic risk and the remaining 62 percent had high-risk cytogenetics. The median number of prior therapies was three (range, 2-5), and 27 percent of patients had received more than three 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 percent were refractory to Revlimid (lenalidomide). Seventy-three percent of patients were double refractory to an IMiD and PI.

At the data cutoff of Oct. 15, 2016, the median follow-up time was 9.6 months. The median duration of response was 16.3 months and the median progression-free survival (PFS) was 17.4 months. At the time of the analysis, the median overall survival was not yet reached.

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

PD-L1 expression was assessable for 29 patients in the study, with positivity defined as expression on 50 percent or more of cells. In those with PD-L1-positive disease (13 patients), the combination elicited an ORR of 77 percent, with a VGPR or better of 54. Those with PD-L1-negative disease (10 patients) had an ORR of 60 percent and a VGPR rate of 20 percent. There were no CRs. The median PFS in the PD-L1-negative arm was 17.4 months. 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 percent or more and PD-1 on at least 1 percent of cells. In those with CD3+/PD-1+ myeloma (six patients), the VGPR or better rate was 0 percent and patients only experienced partial responses (33 percent). The median PFS was just 6.3 months in this group.

In those with CD3-/PD-1- disease (22 patients), the sCR rate was 14 percent and the VGPR rate was 9 percent. The median PFS in this group was 17.5 months. In those with CD+/PD-1- cells (10 patients), the CR rate was 10 percent and the VGPR rate was 40 percent. 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 or higher adverse events (AEs) were neutropenia (40 percent), hyperglycemia (25 percent), anemia (21 percent), upper respiratory tract infections (21 percent), lymphopenia (15 percent), fatigue (15 percent), rash (10 percent) and thrombocytopenia (8 percent). Immune-related AEs included interstitial pneumonitis (13 percent), hypothyroidism (10 percent), transaminitis (6 percent), adrenal insufficiency (4 percent) and vitiligo (2 percent).

Overall, five patients discontinued therapy due to adverse events (11 percent). These events included pneumonitis (three patients), shortness of breath (one patient), and fatigue (one patient). Forty-nine percent of patients required a Keytruda dose reduction.

"The side effects were manageable but high," Badros noted. "Pneumonitis was seen in six 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. This phase 1 study included nine patients at a median age of 65 years. Patients had received a median of eight prior therapies (range, 5-14), and all had received prior stem cell transplants. Eight of the nine patients had progressed on Pomalyst.

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

A phase III study, labeled KEYNOTE-183, is exploring Pomalyst and low dose dexamethasone with or without Keytruda 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).

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