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B-Cell maturation antigen (BCMA) is a cell membrane receptor expressed on mature B lymphocytes, with elevated serum levels found among patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL). Serum BCMA (sBCMA) levels were measured in 331 untreated, newly diagnosed CLL patients using an enzyme-linked immunosorbent assay with a polyclonal anti-BCMA antibody. Elevated sBCMA levels were found among patients with CLL compared with age- and sex-matched healthy controls and those with more active CLL based on prognostic factors. The relationships between sBCMA, time to first treatment (TTFT), overall survival (OS) and multiple prognostic factors were compared using Mann-Whitney and Kruskal-Wallis tests. The median sBCMA level in the CLL cohort (48.6 ng/mL) was significantly higher (p0.001) compared with those of age- and sex-matched healthy subjects (n = 100; 37.8 ng/mL). Serum BCMA correlated with TTFT (hazard ratio [HR] = 2.9, 95% confidence interval 2.0-4.2, p0.001) and OS (HR = 2.5, 95% confidence interval: 1.5-4.0, p0.001). Multiple models were used to test the predictive effects of sBCMA, sex, CLL International Prognostic Index (CLL-IPI) and International Prognostic Score for early-stage CLL (IPS-E) on TTFT and OS. The addition of sBCMA to CLL-IPI and IPS-E improved their prognostic ability to predict TTFT and OS. Thus, sBCMA is a new promising prognostic biomarker for CLL.

Purpose:Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry.Patients and Methods:A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1–21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR).Results:Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%).Conclusions:This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

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High-risk multiple myeloma (MM) continues to have a poor prognosis and remains a therapeutic challenge. This phase 2 study evaluated the efficacy and safety of elotuzumab in combination with pomalidomide, carfilzomib, and low-dose dexamethasone for patients with high-risk relapsed/refractory (RR)MM (NCT03104270). Of 13 enrolled patients, 11 were evaluable for efficacy. Overall response rate and clinical benefit rate were 45.4% and 54.5%, respectively. Deep responses were observed including two complete responses. The novel quadruplet combination was overall well-tolerated, with clinically manageable adverse events. Common adverse events of ≥ grade 3 included lymphopenia (15%), anemia (15%), sepsis (15%), pneumonia (15%), and hypophosphatemia (15%). The novel combination showed promising efficacy and was well tolerated in this heavily pretreated MM population. Even though the study was terminated early prior to completion of enrollment, the results indicate that this may be a promising therapeutic approach for high-risk RRMM patients, which warrants further study.

Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of MM. Many newer drugs have been evaluated together and in combination with older agents. However, even in combination with other active MM agents, the responses are transient, and; thus, therapeutic approaches to help overcome resistance to these drugs are necessary. Recently, the Janus kinase (JAK) family of tyrosine kinases, including JAK1 and JAK2, has been shown to play a role in the pathogenesis of MM. Preclinical studies have demonstrated that the JAK1/2 inhibitor ruxolitinib, in combination with lenalidomide and dexamethasone, reduces proliferation of the MM cell lines and primary tumor cells derived from MM patients, and this inhibition is greater when these drugs are combined than with single agents. Clinically, early results from the oral treatment regimen of ruxolitinib, corticosteroids (methylprednisolone), and lenalidomide for patients with relapsed/refractory disease are encouraging in terms of safety and efficacy, and additional studies will provide further support for this promising new therapeutic approach for patients with MM.

Chronic lymphocytic leukemia (CLL) is a malignancy of late B cells. In another late B-cell malignancy (multiple myeloma), levels of solubilized B-cell maturation antigen (sBCMA) are elevated and predict outcomes.We sought to evaluate sBCMA as a possible prognostic factor and monitoring tool for patients with CLL.Using an enzyme-linked immunosorbent assay (ELISA), we assessed plasma (p) levels of BCMA in 171 CLL patients and compared them with levels in healthy individuals.pBCMA levels were significantly higher among patients with CLL than those from healthy donors (p 0.0001). Among patients with aggressive disease, pBCMA was elevated compared with patients with indolent disease (p 0.001). Those with an initial pBCMA level in the highest quartile had a shorter time to first treatment compared with CLL patients with pBCMA levels in the lowest three quartiles (p 0.0001). Among those in the highest quartile (pBCMA 110.9 ng/mL), overall survival was shorter than those in the lowest three quartiles (p = 0.0007). Finally, among those patients who underwent serial pBCMA testing, changes in these levels correlated with changes in their clinical status.Together, our findings show that pBCMA is a promising new prognostic and predictive indicator for patients with CLL.

Purpose: Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry. Patients and Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1–21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR). Results: Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%). Conclusions: This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

8048 Background: Preclinical studies from our laboratory have demonstrated that ruxolitinib (RUX) in combination with lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in MM cells. Thus, RUX may restore sensitivity to LEN. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and methylprednisolone (MP) for relapsed/refractory (RR) MM patients (pts) who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 pts. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, pts received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: As of September 1, 2018, 36 pts were enrolled, and 32 were evaluable for efficacy. The median age was 66 years (range, 46-81), and 21 (58%) were male. Pts received a median of 6 prior treatments including LEN and steroids to which they were all refractory and a proteasome inhibitor. No DLTs occurred, and DL+3 was expanded. Among evaluable pts, the CBR and ORR were 47% and 41%, respectively (1 CR, 2 VGPR, 10 PR and 2 MR), and 14 and 3 pts showed SD and PD. All 15 responding pts were refractory to LEN. G3 AEs included anemia (17%), neutropenia (14%), sepsis (14%), lymphocytopenia (11%), thrombocytopenia (11%), and pneumonia (11%). Most common SAEs included sepsis (14%) and pneumonia (11%). Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RR MM pts. These promising results are leading to expansion of the current clinical trial to 78 pts, and represents a novel therapeutic approach for treating MM. Clinical trial information: NCT03110822.

Introduction: B-cell maturation antigen (BCMA) is a protein found on the surface of malignant plasma cells from multiple myeloma (MM) patients (pts). We have previously shown that MM pts show higher serum (s) levels of BCMA than healthy subjects and that these levels predict outcomes and can be used to monitor the disease course of these pts. We have recently shown that the half-life of solubilized BCMA is much shorter (1 day) than the conventional serum marker, monoclonal (M) immunoglobulin (21-28 days; Sanchez et al. Clin Can Res 2016). Given the increasing number of therapeutic options for treating MM pts, it becomes of increasing importance to have more rapid ways to assess the efficacy of therapies. We compared changes in serum BCMA to M-protein levels among MM patients receiving new treatments. Methods: Serum BCMA and M-protein levels were determined from all MM pts showing a measurable serum M-protein beginning any new therapy at a single clinic from March 2015 to July 2016. Samples were obtained during each visit (at least weekly) throughout the first cycle of new therapy (C1 D1) and the first day of their second cycle (C2 D1). Analysis of sBCMA levels was determined using an enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN). All sBCMA samples for each individual pt were measured using a single ELISA plate. All serum M-protein measurements were completed in the same clinical laboratory. Percentage changes in sBCMA and serum M-protein levels during treatment were determined relative to the level from the blood draw obtained just prior to the initiation of a new therapy. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: Twenty MM pts (IgG [n=16] and IgA [n=4]), were studied in frontline (n=5) and salvage (n=15) settings. Eleven (55%) pts responded to treatment (1 complete response [CR], 5 partial response [PR] and 5 minimal response [MR]) whereas 7 and 2 pts showed stable disease (SD) and progressive disease (PD), respectively. Changes from baseline (C1 D1) for samples taken during the remainder of C1 and C2 D1 showed sBCMA levels changed more quickly than serum M-protein among responding and progressing pts (Table 1). A 30 - 43% reduction in relative sBCMA levels by the end of the second week of treatment predicted subsequent achievement of an MR for 3 pts. By C1 D15, serum M-protein levels in these pts only decreased by an average of only 11% (range, 3% - 23%). In all 5 pts who achieved PR, sBCMA decreased >30% (range, 31% - 57%) by C1 D8 whereas serum M-protein only decreased by an average of 5% (range, -15% - +15%). A decrease of >43% (range, 43% - 69%) by C1D15 correlated with an eventual PR (n=5) in all 5 pts who subsequently achieved a PR. During that same time, serum M-protein levels varied by an average of only 26% (range, 16% - 36%). In the patient who achieved a CR, the drop in sBCMA was more marked than serum M-protein and was 20% on C1 D8 and 78% on C1 D15 whereas serum M-protein only decreased by 12% and 61% on C1 D8 and C1 D15, respectively. An increase in sBCMA of >30% by C1 D8 indicated disease progression (n=2) in both pts who developed PD at the end of C1. For pts who only showed SD during C1, sBCMA levels only varied 30% increases relative to the sample obtained one week prior (n=3) correctly predicted disease progression during the following cycle in all of these pts. Conclusions: In this study, we have shown that serum BCMA levels more quickly and markedly change than conventional M-protein levels among MM pts receiving any new treatment. Specifically, relative changes in sBCMA levels >30% during the first week of a new treatment correlate with eventual changes in the clinical status of these pts. Thus, frequent assessment of serum BCMA levels during the first month of any new treatment may be helpful to make more rapid decisions as to whether it will ultimately provide benefit to individual MM pts. Disclosures Etessami: Oncotracker: Employment. Berenson:OncoTracker: Employment, Equity Ownership.

Introduction: CD147 is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. CD147 gene expression levels are elevated in several types of human cancer. Recent studies show that expression of CD147 is increased in multiple myeloma (MM) patients (pts)' tumor cells and higher levels are associated with progressive disease (PD) and resistance to immunomodulatory agents through its binding to cereblon. CD147 forms a complex with MCT1, a proton monocarboxylate and lactate transporter, and this complex is a regulator of glycolysis and cellular metabolic pathways promoting the survival and proliferation of MM cells. However, no data exists on levels of serum CD147 among pts with MM or other hematological malignancies. Plasma levels of CD147 are elevated in pts with acute kidney injury (AKI). We analyzed the relationship between serum (s) CD147 levels and renal function and response to treatment among MM pts and its relationship to their progression free survival (PFS). Methods: We collected serum samples from 152 MM pts who were treated at a single clinic. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. To determine levels of sCD147, we used an enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN). Mann-Whitney analysis was used to analyze the relationship between sCD147 and clinical status. A subset of pts (n=62) had their sCD147 levels measured immediately prior to starting a new treatment regimen. Using Kaplan-Meier analysis, PFS was compared between pts with sCD147 levels above or below 5.00 ng/mL. Levels of sCD147 were measured from pts at the start of treatment who achieved a complete response (CR) and among those with PD without achieving any response (refractory disease [RD]). In addition, sCD147 levels were also assessed among pts in CR and those with PD at the time of their sample blood draw. The Spearman correlation coefficient was used to correlate levels of serum creatinine with sCD147. Results: Previous studies show median sCD147 levels in healthy donors is 2.5 ng/mL and invariably below 4.5 ng/mL consistent with our healthy donors (all < 4.50 ng/mL). At the time of sampling, the median level of sCD147 among pts with MM who were in CR (n=49, median=3.69 ng/mL) was not different compared with the median level of among pts with PD (n=74, median=3.86 ng/mL; P=0.3525). Overall, pts' sCD147 levels assessed prior to the initiation of treatment were not different among those achieving CR (n=16, median=3.79 ng/mL) compared with those showing RD (n=46, median=4.06 ng/mL; P=0.3895). Consistent with data obtained on pts with AKI from other causes, levels of sCD147 were directly correlated with serum creatinine levels in MM pts (n=136, Spearman correlation coefficient < 0.0001). Among pts without renal failure, only 1/52 (2%) of pts in CR at the time of blood draw showed a sCD147 level > 6.00 ng/mL (6.39 ng/mL) whereas 21/97 (22%) of pts with RD showed a level above this threshold (range, 6.01-17.20 ng/mL). Notably, pts with sCD147 levels drawn prior to the start of treatment that were above the maximum value for all normal donors (sCD147 levels > 5.00 ng/mL; n=34) showed a much shorter PFS (median=2.11 months) compared with those with levels below this level (n=81; median=4.64 months; P=.0204). When PFS was determined among MM pts without renal failure, there remained a difference among those with levels > 5.00 ng/mL compared with those with levels below this threshold (2.11 vs 5.27 months; P=0.04). Conclusions: This is the first study to evaluate serum CD147 levels in hematologic malignancies. Our results in MM pts show these levels correlate with renal function as previously shown among pts with AKI. Notably, sCD147 levels > 6.00 ng/mL predict for RD, and baseline levels elevated above the threshold of healthy donors (> 5.00 ng/mL) also predict for a markedly shorter PFS among all MM pts or those without renal failure. This demonstrates that sCD147 levels > 5.00 ng/mL at baseline may predict poor outcome for MM pts and may be a new prognostic factor for MM pts and those with other hematologic malignancies. Current work is focusing on the relationship of sCD147 levels to outcomes among MM pts receiving specific drug treatments especially immunomodulatory agents given recent studies suggesting that increased intratumoral expression of CD147 is associated with poor outcome for MM pts receiving these drugs. Disclosures Etessami: Oncotracker: Employment. Berenson:OncoTracker: Employment, Equity Ownership.