Introduction: High-risk multiple myeloma (HRMM) patients (pts) will relapse post-autologous stem cell transplant (ASCT) within 1-2 years. Blockade of the PD-1/PD-L1 interaction on activated T-cells may allow the re-establishment of an effective anti-MM immune response. Our hypothesis is that in the post-ASCT setting, where the host immune system is in significant flux, the PD-1/PDL-1 blockade using pembrolizumab (pem), a monoclonal antibody to PD-1, in combination with the immunomodulatory drug (IMiD) lenalidomide (len) and dexamethasone (dex), will prolong post-ASCT remission by eradicating any existing clones and recapturing the smoldering immunophenotype.
Methods: The open-label, Phase II, single center trial of pem + len + dex enrolled pts with HRMM 3-6 months post-ASCT. Pts received pem 200 mg IV day 1; len 25 mg po daily days 1-14; and dex 40 mg daily days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of pem + len without corticosteroids at the same dose and frequency. Pts were eligible if they had HRMM defined by ISS stage 3 and/or del 13q by cytogenetics, and/or 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy by FISH, and/or high-risk gene expression profile score. Exploratory biomarker analysis of the immune phenotype and composition of the intestinal microbiome at pre-treatment, day 1 of each cycle of treatment and end of treatment are currently being done.
Results: Fifteen pts were screened, 12 received at least one dose of therapy and thus were deemed evaluable. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 41.6% received induction bortezomib-len-dex; 33% received induction carfilzomib-len-dex, and the remaining 24.9% received bortezomib-based induction. Overall response rate (ORR) to upfront therapy was 100% with 1 (8.3%) achieving a complete remission (CR), 5 (41.6%) achieving a very good partial remission and 6 (50%) achieving a partial remission to induction. Table 2 shows best response to treatment by cycle. Four pts (33%) have achieved a stringent CR. Of the 4 pts who have completed therapy, 2 were negative for minimal residual disease by multiparametric flow cytometry. Median follow-up is 8.5 months. None of the pts progressed. All patients had AEs of any grade, defined by AEs attributed to pembro/len/dex rather than from ASCT. A total of 90 adverse events (AEs) were reported, with 94% grade 1 or 2 and 5.6% grade 3 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were all grade 1 and 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, and was not thought to be related to pem. After Merck studies using the combination of pem and IMiDS were placed on hold by the FDA, this study was suspended as of 7/5/17.
Conclusions: The combination of pem and len with steroids appears to be well tolerated in the post-ASCT setting in pts with high-risk MM. More mature efficacy follow-up and correlative data will be available at the time of presentation.
Biran: Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Vesole: Celgene: Speakers Bureau; Takeda: Speakers Bureau. Richter: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy.
Asterisk with author names denotes non-ASH members.