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Pembrolizumab Plus Lenalidomide Gets Response in MM

— Combo shows signs of benefit in relapsed/refractory myeloma

MedpageToday

CHICAGO -- Combining pembrolizumab (Keytruda) and lenalidomide (Revlimid) appears to give heavily pretreated multiple myeloma patients who respond to therapy an extended duration of response, researchers suggested here.

In the study, patients who had progressive disease despite having taken at least two lines of other therapies achieved a median duration of response of 11.3 months, reported consultant physician in hematology at University Hospital Salamanca, Spain.

Action Points

  • Combining pembrolizumab (Keytruda, a monoclonal antibody against PD-1) and lenalidomide (Revlimid) appears to give heavily pretreated multiple myeloma patients who respond to therapy an extended duration of response.
  • Of particular note was that 28 of the subgroup of 29 patients refractory to lenalidomide alone had disease stabilization or better, and one achieved a very good partial response.
  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

In her oral presentation at the annual meeting of the American Society of Clinical Oncology, Mateos presented the updated results of the phase I KEYNOTE-023 trial, designed to determine the maximum tolerated dose of the combination which turned out to be 200 mg of pembrolizumab, 25 mg of lenalidomide, and 40 mg of dexamethasone. Patients treated with that formula did not experience any dose limiting toxicities, Mateos said.

"Initial efficacy results show promising activity in heavily pretreated patients with relapsed/recurrent multiple myeloma, and support the continued development of pembrolizumab in patients with multiple myeloma," she said.

Of the 51 patients who comprised the safety analysis, 48 experienced at least one adverse event; 33 of those events were grade 3-5 adverse events. The two fatalities included one person who died of hepatic failure due to veno-oclusive disease related to the combination treatment, and another person who died after suffering an ischemic stroke linked to lenalidomide. Three patients discontinued therapy due to treatment-related adverse events.

In the 40 patients who were enrolled in the efficacy portion of the studies, 20 achieved an objective response – including one patients who achieved a stringent complete response, five patients who achieved a very good partial response, and 14 patients who were observed to have received a partial response. Mateos said 19 other patients were able to achieve disease stabilization. Just one of these 40 patients had progressive disease on the drug combination.

She and her colleagues also looked at outcomes in the patients within that group who were refractory to lenalidomide. Those 29 patients included one who achieved a very good partial response. Overall 28 of this subgroup had disease stabilization or better. She said 35 of 40 patients exhibited a decrease in M-protein or free light chains.

The patients in the study experienced five immune system-mediated adverse events: grade 1 hyperthyroidism; grade 1 hypothyroidism; grade 1 thyroiditis; grade 3 increased liver enzymes and grade 3 renal failure. "No dose modification or treatment discontinuation was required for management of the reported immune related adverse events," Mateos said. "No cases of pneumonitis or colitis were reported. Infusion reactions were reported."

The median follow-up for the patients is 9 months; the median time to first objective response was 1.5 months; 75% of the patients in the study remained alive at the time of the final report of the study, Mateos said.

"These data suggest that this treatment combination has an acceptable safety and tolerability profile and is consistent with adverse events reported for pembrolizumab in solid tumors," she said. She noted that a phase III trial with pembrolizumab in multiple myeloma patients has been initiated.

Discussant assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, said, "There is very good rationale to investigate checkpoint inhibitor therapy in multiple myeloma. PD-L1 is expressed on myeloma cells. There is also good rational to investigate checkpoint inhibitors in combination with immunomodulatory agents."

But despite laboratory studies that indicated that these drugs would be beneficial, the single agent trials were disappointing and showed limited activity in multiple myeloma. But Cho noted studies with the agents and in combination continued.

"I think the most interesting part of this report is the activity among patients who were lenalidomide refractory," he said. "These results support continued investigation into the application of checkpoint modulators in multiple myeloma. The full benefit of checkpoint modulation in combination with other therapies will ultimately be judged on whether they provide a progression-free survival or overall survival benefit."

Disclosures

The trial was supported by Merck.

Mateos disclosed relevant relationships with Janssen, Celgene, Amgen, Takeda and Bristol-Myers Squibb.

Cho disclosed relevant relationships with Genentech, Janssen Research and Development, Agenus, and Bristol-Myers Squibb.

Primary Source

American Society of Clinical Oncology

Mateos M-V, et al "Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma: Final efficacy and safety analysis" ASCO 2016; Abstract 8010.