ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
Patrice Wendling/Frontline Medical News
Dr. Jesús San Miguel
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.