Pembrolizumab, Lenalidomide and Dexamethasone Post Autologous Transplant in Patients with High‐Risk Multiple Myeloma
Authors: Noa Biran, Elli Gourna Paleoudis, Rena Feinman, David H. Vesole, Joshua Zenreich, Shuqi Wang, Jaeil Ahn, Meena Bansal, Scott Rowley, Michele Donato, Andrew L. Pecora, Joshua Richter, Palka Anand, Laura McBride, Kristin Ivanovski, Robert Korngold, David S. Siegel
Journal: American Journal of Hematology (2021)

Multiple myeloma (MM) is a heterogeneous disease, with an estimated 34 920 newly diagnosed cases in the United States in 2021 according to the American Cancer Society. Long-term survival has improved with the development of proteasome inhibitors (PI), immunomodulatory drugs (IMiDs), and monoclonal antibodies with overall survival (OS) exceeding 10 years for patients with standard-risk MM. However, outcomes for the 25%-45% of patients characterized as high-risk are poor, with a median OS of 18–24 months.1, 2 Relapse after autologous stem cell transplantation (ASCT) is inevitable with or without lenalidomide (len) maintenance.2 Immune dysfunction in MM is, in part, due to functionally defective dendritic cells, increased TH17 cells, myeloid devoid suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the BM and peripheral blood. Since T-cell clonal expansion after ASCT has been associated with improved clinical outcomes,3 we hypothesized that by incorporating a checkpoint inhibitor into post-ASCT consolidation, it will reinvigorate a T-cell inflamed phenotype to target residual MM. We used len which has shown to enhance T cell and NK cell effector anti-MM responses, reducing PD-L1 expression on MM cells4 and combine it with pembrolizumab, a PD-1 inhibitor. We used the combination of pembrolizumab (pembro) plus len and dexamethasone (dex) which has previously shown an acceptable safety profile and improved efficacy in previous studies5 and intended to enroll 58 patients to our an open-label, phase II single-arm trial (NCT02906332). However, all studies evaluating the combination of PD-1 or PDL-1 inhibitors with IMiDs were halted by the FDA on July 3, 2017 due to a higher incidence of immune-related toxicities and deaths in the pembro arm. At the time of the FDA hold, 12 subjects were enrolled. Follow-up was permitted. Study procedures were as follows: Patients were enrolled between days +60 and + 180 following ASCT and received treatment with pembro-len-dex (pembro-rd) for a total of four cycles. The combination included pembro 200 mg IV on day 1; len 25 mg p.o. daily on days 1–14; and dex 40 mg daily at days 1, 8, 15 of a 21-day cycle for a total of two cycles and then an additional two cycles of pembro-rd at the same dose and frequency. After the completion of cycle four, each subject was followed for 30 days. Serious adverse events were collected for 90 days after the end of treatment. Subjects who discontinued treatment for reasons other than disease progression continued post-treatment follow-up. Participants included adult patients with measurable disease and hrMM defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t (4;14), t (14;16), t (14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Minimal Residual Disease (MRD) assessments were performed 30 days after the fourth cycle for those achieving VGPR or better. Peripheral blood samples were analyzed at screening, at cycle two, day 1 of treatment and at long-term follow-up. Cells were processed by Ficoll-Paque Plus (Fisher Scientific) separation. A portion of the cells underwent immune phenotyping by fluorescent-labeled monoclonal antibody (mAb) staining for T-cell subsets. This included mAb purchased from BD Biosciences for: CD3-Alexa Fluor 647 (#557706), CD4-APC-Cy7 (#557871), CD45RO-FITC (#555492), CD25-PerCP-Cy5.5 (#560503), CD127-FITC (#560549), CD8-PE (#555635), CCR7-PC7 (#557648), and matched fluorescent labeled isotype control mAb. The intent-to-treat population consisted of all the enrolled patients who received at least one dose of study drug and was the basis for the analysis of efficacy endpoints. Demographic and clinical variables were summarized using median (IQR) for continuous variables and counts (percentages) for categorical variables. The Kaplan–Meier method was used to determine median PFS and OS, respectively. Responses to treatment by each cycle were descriptively summarized. Both AE and SAEs were tabulated descriptively. For T-cell subset phenotypic analysis, paired continuous data were compared using Mood's median test. A two-sided p < 0.05 was considered statistically significant. Data analysis was performed using R (ver. 4.0.2). Results were as follows: Of the 12 patients, five (41.7%) were ISS 3, six (50%) had a p53 deletion by FISH, three (25%) had 1q21 gain, and two (17%) were considered ultra-high risk with combination of 1q21 gain and 13q deletion by FISH (Table S1). All patients received triplet or quadruplet induction. Five patients (42%) received induction bortezomib-lenalidomide-dex; four (33%) carfilzomib-lenalidomide-dex, two (24.9%) bortezomib-cyclophosphamide-dex and one bortezomib-cyclophosphamide-len-dex. Median follow-up was 50 months. The median PFS from the date of ASCT for all patients with a median follow-up of 50.7 months (range: 6–55.5 months) was 27.7 months (95% CI: 22.6 months - not reached, Figure S1). The PFS rates at 1 and 2-year follow-up was 90.9% and 63.6%, respectively. Overall response rate was 100% at time of best response (Figure S2). The rate of stringent complete remission was 33% at the end of induction and 83.3% at the end of consolidation and 83.3% at the pre-specified 7th follow-up point (a median of 19 months after completion of treatment) (Figure 1). For all patients, over the 2-year follow-up period, 11/12 (91.7%) achieved a complete remission or better, and 10/12 (83.3%) achieved stringent complete remission (Table S2). Of the 11 patients who completed therapy, eight had MRD status assessed and among them, seven (87.5%) were MRD negative by multiparametric flow cytometry with a cut-off value of 10−5. Adverse events (AEs) were monitored at every visit and graded according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All patients had one or more AEs attributed to pem, len or dex. Of the 97 AEs reported, 6.2% were grade 3 and 93.8% were grade 1 or 2. The most common non-hematologic AEs were respiratory (cough) and gastrointestinal (diarrhea and constipation), all grade 1 or 2, while the most common hematologic AE was neutropenia with six occurrences observed among two patients, grade 1–3. Immune-mediated AEs included diarrhea in four patients, fever in one patient, maculopapular rash in one patient, and dyspnea in two patients. All were grade 1 or 2. There was one serious AE, H. influenza pneumonia requiring inpatient admission, which was unrelated to pembrolizumab (Table S3). In comparison to the C1D1 start of the first treatment cycle, the median percent effector memory CD4+ T cells within the CD3 compartment decreased steadily through C4D1 (p = 0.037). The effector memory CD8 compartment in the CD3 population exhibited a small decrease at the time of the second cycle (C2D1) (p = 0.032) and returned to insignificantly increased levels by the third cycle (p = 0.199). The median percentage Memory regulator T cells was not significantly decreasing through the second cycle (C2D1) and third cycle (C3D1) (p = 1.0, p = 0.199, respectively) (Table S4). Our results suggest that PD-1 blockade in combination with len, given as post-ASCT consolidation, was well tolerated and efficacious in 12 hrMM patients with a median PFS of 2.3 years, exceeding So, PFS in hrMM patients without len maintenance from historical controls.6 Immune mediated AEs were only grade 1 or 2 while the one SAE observed was unrelated to pembro. Lymphocyte composition and function after ASCT guided optimal timing of immunotherapy and helped identifying potential markers of relapse. Regulatory T cells (Treg) decline as CD8(+) T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8(+) effector T-cell ratio. These CD8(+) T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. A subpopulation of exhausted/senescent CD8(+) T cells, however, downregulates CD28 and upregulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. Thus, PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8(+) T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT (Table S4). The pembro-rd combination may have an important role as consolidation therapy after ASCT, aiming to achieve a change from an "anergic" to a more "active" immune milieu. This trial provides long-term follow-up of patients with hrMM who have received the combination of checkpoint inhibitors and IMiDS regarding safety and efficacy. While enrollment was limited after the FDA hold, the outcomes were significantly better than historical controls for unmaintained patients would have suggested. The combination of PD1 blockade and IMiDs as a short consolidative regimen offers the possibility of long-term disease control in a population of patients that do not typically achieve this, even with standard maintenance therapies. N.B. has received consultancy fees, honoraria and speakers' bureau fees from Janssen, B.M.S., Takeda, Amgen, Karyopharm, Celgene, and Sanofi. D.S.S. has received consultancy fees, honoraria and speakers' bureau fees from Janssen, BMS, Takeda, Amgen, Karyopharm, Celgene, and Sanofi. D.H.V. has received consultancy fees, honoraria and speakers' bureau fees from Janssen, G.S.K., Karyopharm, Amgen, Takeda. He is also in the Advisory board for Pfizer and owns stock from Abbvie, Amgen, Biogen, Gilead, Johnson & Johnson, Lilly. J.R. has received consultancy fees honoraria and speakers' bureau fees from Janssen, Celgene, B.M.S., Karyopharm, Sanofi, X4 pharmaceuticals, Oncopeptides, adaptive biotechnologies, Secura bio, Astra Zeneca. J.A. is a statistical consultant of the company "KeifeRx". E.G.P., J.Z., A.L.P., P.A., K.I., M.B., R.K., M.D., L.M., R.F., S.W., S.R. have nothing relevant to disclose. Study conception and design: David S. Siegel and Noa Biran. Provision, collection, and assembly of data: All authors contributed to data collection. Data analysis and interpretation: All authors had access to the data and participated in data collection and interpretation. Manuscript writing, editing and approval: All authors. Supported in part by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Table S1 Baseline characteristics (N = 12) . Table S2: Best overall response to treatment. Table S3: Weighted reported adverse events (All AEs presented below are grade 1 or 2 apart the ones marked with "̂" that are grade 3). Table S4: T cell subset phenotypic analysis. Figure S1 Progression-free survival Kaplan–Meier curve Figure S2: Overall survival Kaplan–Meier curve. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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