ALBERT

Description: Pomalidomide (POM) is a novel IMiD® immunomodulatory agent with clinical activity in several settings including in relapsed / resistant myeloma (RRMM). Several preclinical studies have documented the immunologic effects of IMiD® immunomodulatory drugs. IMiD® now form the backbone of several emerging combination therapies in hematologic malignancies. In prior studies, the clinical activity of POM in relapsed myeloma has been demonstrated using both continuous and intermittent dosing regimens with and without steroids. However the impact of the specific POM dosing regimen and the effect of concurrent steroids (as commonly utilized in most combination regimens) on POM-induced immune activation in vivo is unknown. In order to evaluate these issues more directly, we analyzed samples from patients enrolled in a randomized phase II clinical trial comparing two POM dosing schedules. Comparison of drug-induced immune activation between the two dosing schedules was one of the pre-specified endpoints in this study. Patients (n=39) with RRMM documented to be refractory to lenalidomide were randomized to therapy with POM 2 mg/day for 28/28 days (Arm A, n=19) or POM 4 mg/day for 21/28 days (Arm B, n=20) of a 28 day cycle. All patients (pts) received POM alone for cycle 1, followed by the addition of dexamethasone (DEX) at 40 mg weekly in subsequent cycles in both arms. In recent studies, we have shown that immune effects of lenalidomide are manifest early, within a week of initiation of therapy (Richter et al, Blood 121:423, 2013). Therefore each patient was analyzed 1 week after initiation of POM alone at 2 or 4 mg (cycle 1) or POM + DEX (cycle 2). POM therapy led to an increase in T cells at day 7 after initiation of therapy (mean percent increase compared to baseline 47%, p

Description: Pomalidomide (POM) is a novel IMiD(r) immunomodulatory agent with clinical activity in relapsed / resistant myeloma (RRMM) refractory to both lenalidomide and bortezomib. In prior phase II studies, the clinical activity of POM has been demonstrated using both continuous and intermittent dosing schedules. However the optimal dosing regimen for POM remains to be clarified and prospective data comparing these dosing schedules is limited. Herein we report the results of a randomized phase II clinical trial comparing the two POM dosing schedules. The primary objective was to compare clinical response to therapy (greater than or equal to partial response (PR) according to International Myeloma Working Group (IMWG) criteria). Patients (n=39) with RRMM documented to be refractory to lenalidomide were randomized to therapy with POM 2 mg/day for 28/28 days (Arm A, n=19) or POM 4 mg/day for 21/28 days (Arm B, n=20) of a 28 day cycle. All patients (pts) received POM alone at 2 or 4 mg for cycle 1, followed by the addition of dexamethasone at 40 mg weekly in subsequent cycles in both arms. Aspirin was utilized for thromboprophylaxis in both arms. Toxicity consisted primarily of myelosuppression which was manageable and similar in both cohorts. The incidence of serious adverse events (SAEs) was 36% in arm A and 55% in arm B. Grade 3 or 4 neutropenia (common toxicity criteria v4.0) was the most common toxicity and was observed in 42% and 45% of patients in arm A and arm B respectively. There was no treatment-emergent grade 3 or 4 neuropathy observed in either arm. Only one patient (in arm B) experienced grade 3 / 4 thromboembolic complication. Overall, objective response to therapy (greater than or equal to PR by IMWG criteria) was observed in 21% (4/19 patients) in arm A and 45% (9/20 patients) in arm B (p=0.18). There were no complete remissions in either cohort. Patients in arm B did have greater maximal reduction in measurable disease compared to arm A (percent maximal reduction mean (+ SD) 54% (+ 34%) in arm B versus 28% (+ 35%) in arm A, p=0.02). However both cohorts had comparable event-free survival (EFS) and overall survival (OS). The mean EFS in arm A and arm B was 4.4 months (95% confidence intervals (CI) 2.21 months, 7.67 months) and 5.1 months (95% CI 3.4 months, 9.2 months) respectively (p=0.56). Similarly the median OS in the arm A (17.7 months, 95% CI 10.02, not reached) was similar to that in arm B (17.7 months, 95% CI 9.98, not reached)(p=0.73). These data demonstrate in the context of a prospective randomized controlled clinical trial that both continuous (28/28) and intermittent (21/28) dosing regimens of POM with dexamethasone have remarkable clinical activity in this heavily pretreated MM population. These data provide further support towards the choice of POM at 4 mg/day for 21/28 days for phase III testing. The finding that intermittent dosing at 4 mg/day led to greater maximal cytoreduction of measurable disease compared to continuous dosing at 2 mg/day, without any differences in survival suggests that understanding the biology of residual disease will be essential to further improving outcome in these patients. Disclosures: No relevant conflicts of interest to declare.

Description: Background: P is used in combination with G-CSF to improve the mobilization of peripheral blood hematopoietic stem cells in poor mobilizers. Limited data are available in regard to effects of P on post-transplant outcomes in comparison with non-P chemomobilized patients. Methods: In this retrospective study, we compare the engraftment and the outcomes of 34 patients mobilized with P + G-CSF or just-in-time rescue P in combination with chemotherapy and G-CSF to 143 patients (control group) mobilized with G-CSF with or without chemotherapy in lymphoma and myeloma patients who underwent ASCT between February 2012 and April 2014 at the University of Maryland Greenebaum Cancer Center. Post-transplantation outcomes including infections, hematologic recovery, relapse, progression and survival were recorded. Results: The median number of collected of CD34+ cells/Kg was 5.9 x 10(6) in the P group and 12.3 x 10(6) in the control group (p=0.0002). Median time to neutrophil engraftment (〉0.5 × 10(9) /L) was comparable between the 2 groups: 12 days for the P group and 11 for the control group (p=0.28). There was a trend toward a shorter time to platelet engraftment (〉20 × 10(9) /L) in the control (12 days) compared to the P group (14 days) (p=0.056). Progression-free survival at 1 year after (ASCT) was 88.2% in the P group and 81.8% in the control group. There was no difference in the overall survival of both groups (p=0.62) Conclusions: Short and long-term engraftment and outcomes after ASCT seem to be comparable in lymphoma and myeloma patients receiving plerixafor compared to chemomobilized patients without plerixafor. This observation support the use of plerixafor + G-CSF or just-in-time rescue P in patients who mobilize poorly without P. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: The incidence of MM is 2 to 3 fold higher in blacks than in whites; they present at a younger age and have better overall survival. The biological bases for these disparities remain unclear. Outcome of MM is linked to cytogenetic and molecular changes, both primary (hyperdiploidy and heavy chain (IgH) translocations) and secondary (rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, and deletions of 17p). Methods: Cytogenomic alterations in consecutive MM patients were assessed using integration of metaphase chromosome analysis by GTG-banding and interphase fluorescence in situ hybridization (iFISH) in CD138-positive cells isolated from fresh BM samples using a protocol of magnetic-activated cell sorting. Changes evaluated included monosomy 13/del(13q), monosomy 17/del(17p), gain of 1q21, and rearrangements of the IGH gene including t(4;14), t(11;14) and t(14;16). Results: Samples from 218 consecutive MM patients were analyzed (Table 1). 108 were from black and 110 were from white patients. Median age for blacks was 59 years (range: 36 - 82) and for whites, 63 years (range: 39 - 83) (p=0.008). Fewer black men than whites were observed (46.3% versus 64.6%, p=0.007). Overall, blacks had fewer abnormal karyotypes compared to whites (18.1% versus 31.8%; p=0.02). Black patients had a lower frequency of non-hyperdiploid karyotypes (8.5% versus 20.6%; p=0.01) and had a trend toward lower frequencies of rearrangements of IGH (30.8% versus 43.5%; p=0.055) than white patients. Most notably, they had significantly lower frequencies of monosomy 17/del(17p) (5.6% versus 18.5%; p=0.003) and monosomy 13/del(13q) (28.9% versus 46.3%; p=0.008). After stratification by age (Figure 1), younger patients showed significantly higher frequencies of the monosomy 17/del(17p) abnormality (p=0.001) and the t(4;14) (p=0.04) than older patients, with the difference more significant in white patients. The associations among molecular cytogenetic abnormalities (Figure 2) showed a different association pattern for black and white patients. White patients with t(11;14) were more likely to have monosomy 13/del(13q) (p=0.003) and gain of 1q21 (p=0.02), while this association was not observed in black patients. Conclusion: Black MM patients had significantly different cytogenetic profiles detected by iFISH on CD-138 selected malignant cells, compared to whites. Black MM patients had a more favorable profile, including lower frequencies of non-hyperdiploid karyotype and of IGH rearrangements. This study supports a biological basis for previously described outcome disparities between black and white patients with MM. Further studies will focus on identifying specific molecular targets and their impact on therapy and on overall outcome. Table 1. Demographics and cytogenetic abnormalities of the MM patients Demographics Black White P-value# Total, n 108 110 Gender, n (%) =0.007* Male 50 (46.30%) 71 (64.55%) Female 58 (53.70%) 39 (35.45%) Age (median) 59 63 =0.008* Chromosome (karyotype) =0.022* Normal 86 (81.90%) 73 (68.22%) Abnormal 19 (18.10%) 34 (31.78%) Hyperdiploidy 8 (7.6%) 8 (7.4%) Non-hyperdiploidy 9 (8.5%) 22 (20.6%) =0.013* 11;14 translocation 2 (1.9%) 4 (3.7%) FISH abnormality -13/del(13q) 31 (28.97%) 50 (46.30%) =0.008* Gain of 1q21 35 (32.71%) 47 (43.52%) =0.103 -17/del(17p) 6 (5.61%) 20 (18.52%) =0.003* IGH rearrangements 33 (30.84%) 47 (43.52%) =0.055^ t(4;14) 7 (6.54%) 13 (12.38%) =0.146 t(11;14) 15 (20.55%) 15 (19.48%) =0.870 t(14;16) 2 (3.85%) 6 (10.71%) =0.175 others 16 (14.95%) 15 (13.89%) =0.824 *means statistical significant (p-value 〈 0.05), where ^ means marginal significant (0.05 〈 p-value 〈 0.10). #p-values come from the Cochran-Mantel-Haenszel tests for categorical variables, and t tests for continuous variables. Associations among eight molecular cytogenetic abnormalities. Each solid black line indicates one abnormality is statistically significantly associated with another abnormality. Figure 1. Distributions of cytogenetic abnormalities by age and race Figure 1. Distributions of cytogenetic abnormalities by age and race Figure 2. Relationship of various cytogenetic abnormalities in the MM patients Figure 2. Relationship of various cytogenetic abnormalities in the MM patients Disclosures No relevant conflicts of interest to declare.

Description: Next generation sequencing of purified plasma cells from myeloma patients has revealed the genomic complexity of tumors and is being utilized for developing personalized approaches to therapy. Evaluation of functional properties of these genetic changes and the growth potential of human tumors / their subclones has been limited by difficulties in reliable engraftment of primary human tumor cells in mice. The growth of human cells in mice is limited in part due to the presence of species non-cross-reactive cytokines/growth factors and innate immune rejection mechanisms. In order to overcome these barriers, we designed MISKI TRG6 mice, wherein human IL6 was additionally knocked in on the backbone of MISKI TRG mice. Both MISTRG and MISKI TRG support enhanced engraftment of human hematoipoietic cells (Rongvaux et al. Nat Biotechnol. 2014) and the addition of IL6 provides an essential MM growth factor. Injection of primary tumor cells from MM patients led to reliable engraftment of primary tumor cells in these mice. In this study, we utilized whole exome sequencing (WES) to compare the genomic changes in paired tumors isolated from (n=3) patients versus those growing in xenografts. In some patients, tumor cells from more than one xenografted mouse were analyzed separately to allow for evaluation of tumors growing in each individual mouse. Tumor cells were sorted by flow cytometry and subjected to DNA isolation followed by whole exome capture and sequencing. Germline and tumor DNA were captured on a Roche NimbleGen Sequence Capture V2.0 human exome array following the manufacturer's protocol, with protocol modifications at the Yale Center for Genome Analysis. Captured libraries were sequenced on the HiSeq 2500 sequencing system. Analysis of sequencing data was performed with the Yale exome-sequencing pipeline, as described (Choi et al. Nat. Genet. 2015). Mean depth of coverage for primary and xenografted samples was comparable. Comparison of loss of heterozygosity (LOH) patterns revealed that the majority of LOH changes in baseline tumors were also observed in xenografts, but the latter also contained additional changes. Profile of somatic copy number alterations (CNA) also revealed that while the xenografts captured the majority of CNA detected in freshly isolated tumor cells, they also exhibited additional genomic changes not detected in the initial tumor. Importantly, this included genomic changes in chromosome 1 typically associated with high-risk MM. Interestingly, the pattern of LOH and CNA were identical in individual mice transplanted with the same tumor cells, indicating that the new patterns of genomic changes observed in xenografts were likely already present at baseline, but clinically occult as in a minor subclone. Analysis of somatic non-synonymous variants (SNVs) revealed that the great majority of SNVs detected in the parent tumor were also identified in the xenografts, which also contained additional SNVs not detected at baseline. This included some targetable SNVs with known oncogenic potential. Together, these data demonstrate the capacity of MISKI TRG6 mice to recapitulate the genomic complexity of primary MM tumor cells and reveal their growth potential. These data provide a novel approach to investigate the genetics of human plasma cell neoplasia in vivo and reveal subclinical genetic lesions that may contribute to future relapse. Humanized models may be essential to fully understand genomic complexity of human tumors at a functional level and to optimize personalized approaches to therapy of human MM. Disclosures No relevant conflicts of interest to declare.

Description: Multiple myeloma (MM) is characterized by progressive growth of transformed plasma cells (PC) in the bone marrow. In nearly all cases, MM is preceded by clinically asymptomatic precursor states termed as monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic MM (AMM). Almost all prior attempts to study the growth of transformed PCs in vivo have been restricted to patients with clinical MM, and there is an unmet need for in vivo models to understand the biology of precursor states. Major obstacles to xenotransplantation of human cells in immune-deficient mice include murine innate immune rejection, as well as presence of species-restricted non-cross reactive growth factors/cytokines. In order to help overcome these obstacles, we utilized humanized mice in which human versions of 5 genes important for innate immune cell development and hematopoiesis were knocked into their respective murine loci. These mice termed MIS(KI)TRG for human M-CSF, IL-3, GM-CSF, Thrombopoietin and SIRPα knock-in on a Rag2-/-IL-2Rγ-/- background, exhibited superior multi-lineage engraftment of human hematopoietic stem cells including innate immune cells. Interleukin-6 (IL-6) is well established as a critical growth factor for human MM cells and lacks species cross-reactivity. Therefore, we knocked-in human IL-6 to MIS(KI)TRG mice to generate MIS(KI)TRG6 mice that were utilized for these studies. MIS(KI)TRG6 mice were transplanted intra-femoral with bone marrow mononuclear cells isolated from patients with plasma cell disorders (n=27). Growth of tumor cells was monitored by flow cytometry and by ELISA detection of tumor-derived clonal human Ig. We observed successful engraftment of tumor cells following transplantation of purified CD138+ cells as well as CD3-depleted CD138- mononuclear cells or simply CD3-depleted bulk bone marrow mononuclear cells in 〉80% of experiments. Importantly, the engrafted myeloma cells were primarily restricted to the transplanted bone confirming the niche requirement of these cells. Growth of tumor cells in the contralateral bone was typically observed when samples from patients with more aggressive disease were transplanted. Growth of tumor cells in the spleen was only observed in the setting of patients with circulating phase tumors, such as those with plasma cell leukemia. In contrast to tumor cells, non-malignant cells such as human T, NK or myeloid cells readily migrated to the periphery and were detected in the spleen by flow cytometry. Together these data indicate that the capacity to grow independent of the marrow niche is a late event in the pathogenesis of MM. Importantly, in addition to clinical MM, this model also allowed for the first time, efficient growth of asymptomatic precursor states (MGUS/AMM) in 5 of 5 patients engrafted. Interestingly, tumor cells from MGUS/AMM mediate progressive growth in vivo, indicating that the clonal stability observed in these patients is likely mediated by features extrinsic to the plasma cell clone. Detailed analysis of phenotypic features of engrafted plasma cells by single cell mass cytometry revealed phenotypic similarities between freshly isolated tumor cells and those growing in mice. In summary, our studies demonstrate that humanized MIS(KI)TRG6 mice are an excellent host for in vivo growth of the entire spectrum of human plasma cell tumors, including for the first time, pre-neoplastic states. Our studies provide evidence that clonal stability in MGUS/AMM is likely in part due to growth controls extrinsic to the tumor cells. The capacity to metastasize from bone to bone and eventually to extra-medullary sites is acquired later during evolution of tumors. The ability to faithfully reproduce homing and growth patterns of primary tumor cells will allow detailed evaluation of plasma cell tumors in their natural microenvironment. Disclosures No relevant conflicts of interest to declare.

Description: Current therapy of myeloma including combination with IMID(R) immunomodulatory agent such as pomalidomide (POM) leads to high rates of clinical responses in patients with advanced multiple myeloma without translating to cures. Therefore, there is a need to better characterize the nature of residual disease after anti-myeloma therapy. POM has shown clinically promising efficacy in relapsed myeloma but nearly all patients eventually progress. In order to better understand the nature of residual disease, we compared baseline CD138+ myeloma tumor cells from 3 patients with those remaining after completing 2 cycles of therapy with POM (2-4 mg/day) and dexamethasone (40 mg/week). CD138+ plasma cells were isolated from the bone marrow before and after POM therapy and analyzed with gene expression profiling (GEP), and whole exome sequencing (WES). Principal component analysis (PCA) on the GEP data (pre vs. post POM treatment) revealed that in contrast to baseline samples, the ones with residual disease were clustered together, and this was further confirmed with unsupervised hierarchical clustering. Analysis of differentially expressed genes revealed nearly 600 differentially modulated genes, including some involved in the immune system regulation, inflammatory pathways and stem cells. Gene set enrichment analysis (GSEA) identified enrichment of distinct gene-sets/pathways including- transcriptional targets regulated by core embryonal stem (ES) cell factors SOX2 and NANOG. Analysis of genes in the core ES signature (Nat Genet. 2008; 40: 499) revealed that nearly 80% of these ES genes were enriched in the residual disease after treatment with POM. Whole exome sequencing has emerged as a powerful tool to dissect the genomic complexity in cancer. Genomic DNA from bone marrow derived CD138+ tumor cells before and after POM therapy was captured on the NimbleGen 2.1M human exome array and subjected to 74 base paired-end reads on the Illumina HiSeq instrument as described previously (Proc Natl Acad Sci U S A. 2009; 106:19096). Sequence reads were mapped to the reference genome (hg19) using the ELAND program. Reads outside the targeted sequences were discarded and statistics on coverage were collected from the remaining reads using perl scripts. ELAND was also used for indel detection. For matched normal/germline and CD138+ tumor pairs, somatic mutations were called by comparing reference and non-reference reads from the matched pair by Fisher’s exact test with tumor-specific thresholds determined from approximation of the null distribution. WES analysis of baseline (pre therapy) samples identified a median of 36 protein altering coding mutations per sample. Importantly, the degree of mutational load was very comparable between baseline and residual disease (post therapy), and nearly 80% of the mutations detected in the residual disease were also observed at baseline. These data suggest that residual disease following therapy in myeloma is characterized by high level of genomic complexity similar to that observed at baseline. However in spite of the genetic heterogeneity and complexity at baseline, the residual CD138+ plasma cells converge to a distinct signature enriched in a transcriptional program associated with embryonal stem cell genes known to be targets of SOX2 and NANOG. Drug resistant/residual CD138+ tumor cells in myeloma therefore show transcriptional profiles previously implicated in cancer stem cells. Targeting stemness-associated genes may be essential to effectively treat residual disease in myeloma. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 325 Multiple Myeloma (MM) is a human hematopoietic malignancy of the B cell lineage with 5 year survival of only 40%. Most MM patients succumb to progressive disease and therefore novel therapies are urgently needed. MM is characterized by growth of malignant plasma cells in the bone marrow microenvironment (ME) leading to bone erosion and fracture. Interactions between tumor and host ME play a critical role in the biology of MM and are a target of most new therapies against this tumor. The dependence of human MM on ME is further illustrated by the preferential requirement for growth of primary MM cells in implanted human fetal bone, but not the murine bone in immune-deficient mice in the scid-hu model. This model is however suboptimal for preclinical testing of novel therapies and there is a major unmet need for development of newer models to study MM and the interactions between human MM and its microenvironment. Some of the barriers to growth and xenotransplantation of human cells in immune-deficient Rag2−/−Il2rg−/− mice include macrophage-mediated innate immune rejection, as well as non-cross reactive growth factors. In order to overcome these limitations, Rag2−/−Il2rg−/− mice were genetically engineered to express human versions of the macrophage receptor signal regulatory protein-alpha (SIRPa), as well as several non-cross-reactive growth factors. The combination of these growth factors leads to synergistic enhancement of growth of transplanted human cells in these mice. In order to facilitate the potential ability of these mice to serve as hosts for human MM, these mice were further modified to express a human growth factor that is a critical MM-related cytokine and that is also non-cross reactive between humans and mice. INA-6 is a human IL6 dependent MM cell line that is unable to grow in standard immunodeficient mice such as NOD/scid/Il2rg−/−, but instead grows only in the implanted fetal bone in the scid-hu model. Injection of genetically humanized mice with INA6 cells led to facile growth of MM cells in the bone, leading to lytic bone disease. Next we tested whether primary tumor cells from MM patients could grow in these genetically engineered mice. Bone marrow mononuclear cells were separated into CD138+ and T cell depleted-CD138- fractions. Injection of either fraction led to growth of MM cells in these mice. These data therefore indicate that the prior inability to reliably grow primary MM cells in mice outside of the scid-hu model was primarily related to the non-cross-reactive cytokines and innate immune barriers mediated by the CD47-SIRPa axis. These data demonstrate that the genetic humanization of immune-deficient mice to modify the bone marrow niche to express non-cross reactive growth factors leads to facile growth of primary human MM cells in vivo. These mice can therefore serve as a valuable tool to test new patient-specific therapies depending on the genetic makeup of the tumor. Further advancement of this model to include growth of autologous immune cells would lead to humanized immune-competent models much needed for patient-specific preclinical testing of novel targets. Similar approaches can also be extended to develop in vivo models for other hematologic malignancies as well. Disclosures: Dhodapkar: Celgene: Research Funding; KHK: Research Funding.

Description: BACKGROUND: Immunotherapy in MM is emerging as an effective modality in therapy of MM with the approval of several monoclonal antibodies and encouraging results for vaccines and T cell therapy. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) is one mechanism of immune evasion by MM to suppress T cell function. In this trial, we hypothesized that pembrolizumab, a PD-1-blocking antibody, would enhance immune modulatory properties of pomalidomide in RRMM pts. METHODS: In this single center, phase II study, 48 patients with RRMM received 28-day cycles of pembrolizumab (at a dose of 200 mg IV) every 2 weeks (in a run in phase, first 6 patients received 200 mg IV every 4 weeks) plus pomalidomide (4 mg daily x 21 days) and dexamethasone 40 mg weekly. Study objectives were measurements of safety & efficacy and correlation of the CD3/PD-1 on T cells and PD-L1 on plasma cells with response. RESULTS: The median age was 64 years (range: 35-82); 38% were black and 65% were men, Patients had a median of 3 lines of prior therapy (range: 2-6); All patients had received both IMids and Proteosome inhibitors; 70% had prior auto-SCT. 80% were double refractory to both IMids (lenalidomide) and Proteosome inhibitors [bortezomib (n=18) or carfilzomib (n=20)] and an additional 20% were refractory to lenalidomide. The median time from MM diagnosis to study entry was 4 years (range: 1-25). Most common cytogenetic abnormalities were 1q+ (60%), hyperdiploidy (15%) and high-risk FISH [del 17p, t(4:14) and/or t(14:16)] in 38%. Six patients had soft tissue extramedullary plasmacytomas. There were no infusion-related reactions. Hematologic toxicities (≥ grade 3) were anemia (21%), neutropenia (40%), lymphopenia (15%) and thrombocytopenia (8%). Non-hematologic events Grade ≥3 were fatigue (15%), hyperglycemia (25%), upper respiratory tract infections (21%), rash (10%); and most frequent grade ≥2 were dyspnea (54%), dizziness (44%), increased creatinine 38%, edema (35%), rash (30%), constipation 30%) and arrhythmias (19%). Events of clinical significance, autoimmune mediated, included interstitial pneumonitis (13%), hypothyroidism (10%), transaminitis(6%), adrenal insufficiency (4%) and vitiligo (2%). Nine pts had pomalidomide dose reductions due to rash, neutropenia, palpitations and fatigue; one pt reduced pembrolizumab for pneumonitis. At a median follow up of 10 months (range: 2-18): 25 pts continue on the study and 23 pts discontinued therapy due to disease progression (n= 15), side effects (n=7) and protocol violation (n=1). Five pts died while on study due to progressive disease (n=3), sepsis (n=1, sAE), and one from a cardiac event. Three additional pts died off therapy. On intent to treat analysis; the overall response rate (ORR) with ≥ Partial response were observed in of 27 of 48 pts (56%) including: sCR (n=4, 8%), nCR (n=3, 6%), VGPR (n=6, 13%), PR (n=14, 29%). Additionally, 7 pts (15%) had minimal response, 9 (19%) had stable disease, 2 progressed and 3 were not evaluable for response. Of 38 double refractory pts ORR was 55% including, sCR (n=2, 5%), nCR (n=2, 5%), VGPR (n=4, 10%) and PR (n=13, 27%). Of 18 high-risk pts ORR was 33% including VGPR (n=2, 11%) and PR (n=4, 22%). Median duration of response for responding pts was 8.8 months and for pts ≥ VGPR, DOR was 10.7 months. Correlation of PD-1 and PD-L1 expression and response will be presented. CONCLUSION: Pembrolizumab, pomalidomide and dexamethasone shows promising durable therapeutic activity and an acceptable safety profile in RRMM pts. ClinicalTrials.gov number, NCT02289222 Disclosures No relevant conflicts of interest to declare.