Jesus San Miguel, MD, PhD, discusses a phase I study examining pembrolizumab added to lenalidomide and low-dose dexamethasone in patients with heavily pretreated relapsed/refractory multiple myeloma, while emphasizing the need for further follow-up.
Jesus San Miguel, MD, PhD
Pembrolizumab (Keytruda) added to lenalidomide and low-dose dexamethasone demonstrated an objective response rate (ORR) of 76% in patients with heavily pretreated relapsed/refractory multiple myeloma, according to results from the KEYNOTE-023 study.
Data from the phase I multicenter, nonrandomized, dose-escalation study, which were presented during the 2015 ASH Annual Meeting, showed that at a median follow-up of 287 days, 13 out 17 patients responded to the triplet therapy. Four patients (24%) achieved a very good partial response and 9 patients achieved a partial response. Moreover, the disease control rate, which measured any response plus stable disease lasting >12 weeks, was 88%.
The maximum tolerated dose/multiple ascending dose was defined as a fixed dose of 200 mg of pembrolizumab in combination with 25 mg of lenalidomide and 40 mg of low-dose dexamethasone.
The regimen was also found to have an impressive safety profile, according to lead study author Jesus San Miguel, MD, PhD. Sixteen patients (94%) experienced at least 1 adverse event (AE) of any grade related to study treatment and 10 patients (58%) experienced grade 3/4 treatment-related AEs. Common treatment-related AEs included thrombocytopenia (47%), neutropenia (41%), fatigue (29%), and anemia hyperglycemia, and muscle spasms (23% each).
The preliminary data show that PD-1 blockade with pembrolizumab in combination with lenalidomide and dexamethasone demonstrates promising activity in this heavily pretreated group, Miguel adds.
In an interview with OncLive, San Miguel, professor of Hematology, medical director of the Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain, discusses the significance of the phase I study while emphasizing the need for further follow-up.San Miguel: This was a phase I trial in which pembrolizumab has been combined with lenalidomide and dexamethasone in heavily pretreated patients with myeloma. Seventy percent of these patients had received 3 or more prior lines of therapy. Over 95% of patients were exposed to lenalidomide and bortezomib, and approximately 25% of patients even received carfilzomib and pomalidomide. Eighty percent of patients received an autologous transplant, and 75% of patients were lenalidomide-refractory, including 50% of patients who were double-, triple-, or quadruple-refractory. Eighty percent of patients were refractory to their last line of therapy.
In this cohort of patients, we tested the possibility of combining this type of therapy to have an immune effect to enhance the immune system’s capacity to control the tumor cells. We observed that the safety profile was pretty good, and we have not found any differences aside from what we normally expect from lenalidomide or pembrolizumab. However, I would like to emphasize that we probably underestimate some of these side effects because, so far, the data on this regimen are limited. This is an ongoing study and the results are preliminary.
Regarding efficacy, in the first 17 patients, we have observed really incredible results. More than 75% of partial responses or better were reported. If we focus on the lenalidomide-refractory population, half of these patients achieved a partial response. Also, we observed that it is possible to have disease-control in 75% of these lenalidomide-refractory patients.
We can summarize that these are really incredible results, but they are preliminary. We need longer follow-up in order to confirm this attractive data.In the expansion phase of this study, which has included 33 patients, the median follow-up was 40 days. These indicate that you need longer follow-up to evaluate the final results. This is hope for the patients—but just wait.The toxicities of these patients were neutropenia, some hematologic toxicity, and fatigue. We have also observed some immune reaction, hyperglycemia, hyperuricemia, and thyroiditis. Thus far, we have not seen colitis. The safety profile is pretty good, but the data is limited.At the 2015 ASH Annual Meeting, data were also presented on pembrolizumab in combination with pomalidomide. In the refractory setting, 56% of patients responded to this combination. This is all speaking in favor of the rationale for using this type of drug.
With lenalidomide, you enhance the immune cells. However, with pembrolizumab, you release the break that is created by the tumor cells in order to invade the immune control. Once you release the break, you allow the activated T cells to control the tumor cells. This is the rationale that is being confirmed in these studies.I am quite conservative when I find something that is very attractive. I’m not conservative if the results are negative, but when the results are positive, I say, “Please, let’s keep attention to that, but we need more follow-up. We need more patients and we need more data.”
San Miguel J, Mateos MV, Shah JJ, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): KEYNOTE-023. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 505.