Search

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.

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.

The purpose of this single-center retrospective study was to determine the incidence of decreased blood phosphorus levels and hypophosphatemia among multiple myeloma (MM) patients treated with elotuzumab. Hypophosphatemia, which is defined as a serum phosphorus concentration

A 52-year-old African-American woman with a prior history of monoclonal gammopathy of undetermined significance (MGUS) developed infiltrating ductal carcinoma of the left breast. Following a mastectomy, she underwent reconstruction with a silicone gel breast implant. Three years later, her MGUS had progressed to active multiple myeloma (MM). She had a minimal response after two different regimens of bortezomib-based treatments and monthly zoledronic acid, and was placed on maintenance therapy with bortezomib, intravenous dexamethasone, and oral methylprednisolone, as well as ongoing monthly zoledronic acid. After 1 year of this maintenance therapy, during which her myeloma markers remained unchanged, she had her silicone implant replaced with saline. Despite no change in her myeloma treatment, her laboratory values began to steadily improve following removal of the silicone implant. Her M-protein decreased from 2.14 to 0.83 g/dL and her IgG levels from 3,330 to 1,210 mg/dL following replacement of her silicone implant with saline. To our knowledge, this is the first report in which removal of silicone implants improved the clinical status of a patient with MM following a year of maintenance therapy during which the patient’s myeloma laboratory values remained unchanged. Further studies are warranted to determine if silicone breast implant removal can, in fact, improve MM patients’ disease status.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (

B-cell maturation antigen (BCMA) is expressed on malignant plasma cells from patients with multiple myeloma (MM). These patients have higher levels of serum (s)BCMA than healthy subjects, and levels correlate with disease status. The half-life of sBCMA is only 24–36 h, and levels are independent of renal function. We determined whether baseline sBCMA values, a ≥ 25% increase, and a ≥ 50% decrease during treatment predicted progression-free survival (PFS) and overall survival (OS) among 81 patients with relapsed/refractory MM (RRMM) starting new treatments. Serum was obtained on day 22 of each patient’s 28-day cycle of new therapy. Kaplan–Meier survival analysis and log-rank comparison tests were used to determine the effect of baseline sBCMA. The effect of percentage change in sBCMA was investigated using time-dependent Cox proportional hazard models. Patients with baseline sBCMA levels above the median had a shorter PFS (p = 0.0077), and those in the highest quartile had a shorter PFS (p = 0.0012) and OS (p = 0.0022). A ≥ 25% increase at week 4, week 8, and anytime through week 12 predicted a shorter PFS (p = 0.0011, p = 0.0005, and p < 0.0001, respectively). A ≥ 50% decrease at week 4, week 8, and anytime through week 12 predicted a longer PFS (p = 0.0045, p = 0.029, p = 0.0055, respectively). A ≥ 25% increase in sBCMA occurred before progression according to International Myeloma Working Group criteria in 67.5% of patients. Our results indicate the potential for the use of sBCMA as a new biomarker for monitoring patients with RRMM.

Background Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. Methods A receiver operating characteristic curve was used to establish a definition for high risk baseline sBCMA. Mantel Byar analysis was used to examine if high risk sBCMA was correlated with shorter time to transformation, and a time dependent cox proportional hazard was used to determine if it is independent of other risk factors. A z-test for proportions was used to compare the percentage of patients that progressed among high risk versus low risk sBCMA patients. Results A baseline sBCMA level ≥ 137.5 ng/mL was found to be the optimal cut off between high and low risk SMM patients. Patients with high risk sBCMA levels had a shorter time to transformation (p = 0.000332). sBCMA was also higher at the time of transformation than baseline levels (p = 0.0116). sBCMA was the only variable found to be significantly predictive of time to transformation, and additionally was found to be independent of other risk factors. Conclusions In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of

New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.

Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients’ quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (

Objective To evaluate the efficacy and safety of elotuzumab and dexamethasone (Ed) for relapsed or refractory multiple myeloma (RRMM) patients. Method This retrospective study evaluated the efficacy and safety of (Ed) treatment for 21 RRMM patients, 11 of whom were considered lenalidomide-refractory, and all of whom had progressed on at least 1 prior steroid-containing regimen. We also evaluated the efficacy of adding lenalidomide to a subset of patients following progression from Ed. Results The overall response rate (ORR) and clinical benefit rate (CBR) of Ed were 10% and 19%, respectively. An additional 52% of patients demonstrated stable disease as their best response. The median PFS was 1.8 months on Ed for all patients. Fifteen patients received ERd following progression on Ed, and 60% of these patients were lenalidomide-refractory. The ORR and CBR were 20% and 33%, respectively, and the median PFS was 3.4 months. Conclusion Our results suggest that some patients can benefit from Ed without an accompanying immunomodulatory agent and that efficacy can be achieved with the addition of lenalidomide at the time of progression. No new safety signals were detected, except for thrombocytopenia in 1 patient on Ed. This article is protected by copyright. All rights reserved.

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).

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance and down-regulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical and overall response rates were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. To further evaluate whether RUX and steroids without LEN demonstrate clinical activity and its tolerability in the same patient population, an ongoing Phase I trial was expanded to also include a cohort of patients treated with this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of July 25, 2020, 16 of the planned 29 patients have been enrolled, and 15 patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The median age was 64 years (range, 46-77), and 9 (60%) were male. Patients received a median of 4 (range, 3-10) prior treatments including LEN and steroids to which they were all refractory. Of the 15 evaluable patients treated with RUX and steroids, the CBR and ORR were 53% (n=8) and 33% (n=5), respectively. With a median follow-up of 4.7 months, the median duration of response was 3.5 months (range, 1-11+). Five and 2 patients showed stable disease and progressive disease, respectively. Notably, all 8 responding patients were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). Of 6 patients who had progressed on the two-drug combination and had LEN added to their regimen, 3 patients responded (2 MR and 1 PR). Four patients experienced SAEs including sepsis (7%), group B strep sepsis with neutropenic fever and nausea (7%), pneumonia and pneumothorax (7%), thrombocytopenia (7%), and hyperglycemia (7%). Two patients died (one each from pneumonia and progressive disease). Conclusions This ongoing phase 1 trial is the first study reporting clinical activity of the JAK inhibitor RUX with steroids for MM. These results demonstrate that RUX with only steroids is also well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Berenson: Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Patents & Royalties: OncoTracker, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Swift:Jassen: Consultancy, Honoraria, Speakers Bureau; bristol myers squibb: Consultancy, Honoraria, Speakers Bureau; Amgent: Consultancy, Honoraria, Speakers Bureau. Boccia:Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Rigel: Consultancy, Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Ruxolitinib and steroids only for treatment patients with Multiple Myeloma

Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma (MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age-, race-, and gender-matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma (SCC) was higher than controls (P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC.

Since the early 1990s, the generation and subsequent use of small molecule inhibitors targeting the ubiquitin proteasome pathway have transformed the treatment and improved the outcomes for patient...

Introduction: B-cell maturation antigen (BCMA) is a protein that is expressed on malignant plasma cells from patients (pts) with multiple myeloma (MM). Our group has previously shown that MM pts have higher levels of serum (s) BCMA than healthy subjects and that sBCMA levels can be used to monitor the disease course of MM pts. Notably, we have shown that the half-life of soluble BCMA is only 24-36 hours which is much shorter than sM-protein, and its levels are independent of renal function. With the expanding therapeutic options for the treatment (Tx) of MM, there is a need for more rapid and accurate ways to assess the efficacy of new therapies. In this study, we analyzed the relationship between progression free survival (PFS) and changes in weekly levels of sBCMA, sM-protein and serum free light chain (sFLC) during the first cycle of a new treatment among relapsed/refractory (RR)MM patients. Methods: Serum was obtained weekly during each pt's first cycle of a new therapy (C1) and the first day of their second cycle (C2D1) from all RRMM pts (n = 122) at a single clinic from August 2016 to December 2018. sM-protein and sFLC levels were measured, and sBCMA levels were determined using an enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Percentage changes in sBCMA, sM-protein and sFLC (difference between involved and uninvolved FLCs) throughout Tx were determined relative to levels measured at the start of treatment (C1D1). Kaplan-Meier analysis was used to assess differences in PFS based on the percentage changes from baseline in these levels at cycle 1 day 8 (C1D8), day 15 (C1D15), day 22 (C1D22), and day 29 (C2D1). All pt samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: The analysis involved 122 Tx in 75 RRMM pts undergoing new treatment (IgG [n = 33], IgA [n= 15], IgM [n = 1], and light chain only [n = 26]). All pts were evaluable by sBCMA (above the lower limit of detection of the assay [16 ng/mL]). Pts whose baseline sBCMA was higher than the median (217.6 ng/mL) had a significantly shorter PFS (n = 61, median PFS = 2.5 mo) than those below the median (n = 61, median = 7.3 mo, p = 0.0003). When baseline sBCMA levels were quartiled, there was an inverse relationship between sBCMA and PFS (Q1: n = 30, median = 8.0 mo; Q2: n = 31, median = 7.2 mo; Q3: n = 31, median = 3.2 mo; Q4: n = 30, median = 1.9 mo; p = 0.0002). Pts whose sBCMA increased ≥ 25% on C1D8 (n = 8) had a shorter PFS (median = 1.6 mo) than those that did not (n = 114, median = 3.9 mo, p = 0.0042). Those whose sBCMA increased ≥ 25% at any time during C1 (n = 31) also had a shorter PFS (median = 1.6 mo) than those that did not (n = 91, median = 5.2 mo, p < 0.0001). sM-protein was only evaluable by IMWG criteria (> 1.0 g/dL) in 45 (37%) of the pts and only 2 and 5 pts showed an increase of > 25% on C1D8 and anytime during cycle 1, respectively. In the remaining 77 pts who were not evaluable by sM-protein, 51 (68%) were evaluable by sFLC using IMWG criteria (> 100 mg/L difference between the involved and uninvolved FLC) and only 13 showed a > 25% increase during the first cycle. Next, we determined if changes in sBCMA could be used for pts who were not evaluable by either sM-protein or sFLC. Among pts that could not be followed by sM-protein, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 18, median = 2.2 mo) had a significantly shorter PFS than those who did not (n = 59; median = 4.4 mo; p = 0.0218). Among pts that could not be followed by sFLC, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 12) had a significantly shorter PFS (median = 1.6 mo) than those who did not (n = 30; median PFS = 8.7 mo; p = 0.0072). Among pts that could not be followed by either sFLC or sM-protein, a > 25% in sBCMA at any point in C1 (n = 8) showed a shorter PFS (median = 1.6 mo) than those who did not (n = 17; median = 19.3 mo; p = 0.0154). Notably, among pts whose sFLC or sM-protein were below evaluable levels, ≥ 25% increases in sFLC or sM-protein did not predict PFS. Conclusions: We have shown that serum BCMA was evaluable in all RRMM pts at the start of new therapy in contrast to the standard sM-protein and sFLC biomarkers. Baseline levels of sBCMA predict PFS in RRMM pts undergoing new therapy. Additionally, increases of sBCMA > 25% during the first cycle occur in more pts than sM-protein or sFLC, and predict for a shorter PFS. These results suggest that baseline sBCMA and monitoring its levels weekly during the first cycle of a new treatment can help improve predicting outcomes for RRMM pts. Disclosures Chen: Oncotraker Inc: Equity Ownership. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Berenson:Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; OncoTracker: Equity Ownership, Other: Officer; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding.

Summary Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3–29·0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.

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 Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent 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 multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients 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 expansion once a MTD was determined. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients 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 Thirty-four patients have been enrolled, and 31 were evaluable for response as of July 13, 2018. The median age was 68 years (range, 49-81), and 20 (59%) were male. Patients received a median of 6 prior treatments including lenalidomide and a PI. No DLTs occurred, and DL+3 was expanded (n=25). Among all 31 evaluable patients, the CBR and ORR were 48% and 39%, respectively (1 CR, 9 PR, 2 VGPR, and 3 MR), and 11 and 5 showed SD and PD, respectively. Notably, all 15 patients achieving ≥ MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 7.4 months. Grade 3/4 adverse events included transient thrombocytopenia (11.1%), anemia (8.8%), neutropenia (6.7%), hypoxia (4.4%) and gastrointestinal bleeding (4.4%). Common serious adverse events included abdominal pain (6.7%), gastrointestinal bleeding (6.7%) and hypoxia (6.7 %). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to other clinical trials using immunomodulatory agents, steroids and RUX, for treating RRMM patients, and this may represent a new therapeutic approach for these patients. Disclosures Berenson: BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Daiichi: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Background: B-cell maturation antigen (BCMA) is highly expressed on malignant plasma cells from patients with multiple myeloma (MM). We have previously shown that serum (s) BCMA levels are elevated among MM patients, and baseline levels predict both progression free and overall survival in an unselected MM population. The half-life of soluble BCMA is much shorter (approximately 24-hours) than sM-protein (3-4 weeks). As a result, we have monitored sBCMA and sM-protein levels weekly among unselected MM patients starting any new therapy in our clinic. We have previously reported that this biomarker much more quickly determines changes in their clinical status than conventional biomarkers. In this study, we determined whether both baseline and changes in sBCMA levels during cycle 1 can predict progression-free survival (PFS) and best response among patients enrolled on the IRUX 1504 phase 1 trial evaluating ruxolitinib, lenalidomide and methylprednisolone for relapsed or refractory (RR) MM patients. Methods: Serum (s) was obtained weekly during the first cycle (C1) and first day of the second cycle (C2D1) and monthly thereafter from patients enrolled on the IRux 1504 trial from February 2017 to July 2018. sM-protein levels were assessed using standard protein electropheresis, and sBCMA levels were determined using an ELISA (R&D Systems; Minneapolis, MN). Kaplan-Meier analysis was used to assess differences in PFS based on baseline sBCMA levels and the percentage (%) change in sBCMA from baseline to C1D8. We also determined the relationship between changes in sBCMA on C1D8 and best response as determined using International Myeloma Working Group criteria. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: Twenty-eight MM patients (IgG [n=13], IgA [n=5], free light chain only [n=10]), were evaluated. However, one patient progressed before reaching C1D8; and, thus, could not be included in analysis evaluating the relationship between changes at C1D8 and best response. Patients with a baseline sBCMA value in the highest quartile (range, 414.7 - 1655.1 ng/mL) had a significantly shorter PFS than those in the lowest three quartiles (range, 10.3 - 318.2 ng/mL; median PFS: 1.12 vs. 6.64 months; P=0.006). Moreover, the percentage change in sBCMA during the first week of study treatment accurately predicted their best response. Specifically, all patients that experienced ≥ 50% decrease in sBCMA on C1D8 achieved ≥ partial response; and, furthermore, all of those that experienced a ≥25% decrease in sBCMA on C1D8 achieved at least a minimal response. In contrast, all patients that experienced ≥ 25% increase during the first week showed either only disease that was stable or progressed within two study treatment cycles. Additionally, no patient that experienced any increase in sBCMA on C1D8 achieved any response better than stable disease. These results were not seen with sM-protein, as no patient with evaluable sM-protein levels at baseline showed a ≥ 25% change on C1D8. Patients that showed any increase in sBCMA on C1D8 (n=6) had a significantly shorter PFS than those whose sBCMA decreased on C1D8 (n=21, PFS = 1.4 vs 5.1 months, P = 0.0212). Conclusion: This study represents the first prospective clinical trial in which sBCMA has been studied as a biomarker to predict clinical outcomes. In this phase 1 trial evaluating ruxolitinib, lenalidomide and steroids for RRMM patients, we have shown that baseline sBCMA levels predict PFS. Moreover, percentage changes in the levels of sBCMA unlike sM-protein during the first week of study treatment were highly predictive of these patient's best responses achieved and their PFS. Thus, baseline sBCMA levels and changes in its levels during the first week of treatment may predict outcomes for MM patients faster than conventional biomarkers. Disclosures Soof: OncoTracker: Employment. Li:OncoTracker: Equity Ownership. Wang:OncoTracker: Equity Ownership. Sanchez:OncoTracker: Equity Ownership. Chen:OncoTracker: Equity Ownership. Berenson:OncoTracker: Employment, Equity Ownership.

Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment. Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug. Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n = 52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN. The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.

We sought to evaluate baseline mRNA values and changes in gene expression of myostatin-related factors in postmenopausal women taking hormone therapy (HT) and not taking HT after eccentric exercise. Fourteen postmenopausal women participated including 6 controls not using HT (59 ± 4 years, 63 ± 17 kg) and 8 women using HT (59 ± 4 years, 89 ± 24 kg). The participants performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a dynamometer. Muscle biopsies from the vastus lateralis were obtained from the exercised leg at baseline and 4 hours after the exercise bout. Gene expression was determined using reverse transcriptase polymerase chain reaction for myostatin, activin receptor IIb (ActRIIb), follistatin, follistatin-related gene (FLRG), follistatin-like-3 (FSTL3), and GDF serum�associated protein-1 (GASP-1). In response to the exercise bout, myostatin and ActRIIb significantly decreased (p < 0.05), and follistatin, FLRG, FSTL3, and GASP-1 significantly increased in both groups (p < 0.05). Significantly greater changes in gene expression of all genes occurred in the HT group than in the control group after the acute eccentric exercise bout (p < 0.05). These data suggest that postmenopausal women using HT express greater myostatin-related gene expression, which may reflect a mechanism by which estrogen influences the preservation of muscle mass. Further, postmenopausal women using HT experienced a profoundly greater myostatin-related response to maximal eccentric exercise.

Previous studies have shown that low serum vitamin D levels have been associated with many skeletal and non-skeletal disorders. We studied the relationship between 25-hydroxyvitamin D (25D) levels and motor and sensory peripheral neuropathy (PN) among multiple myeloma (MM) patients who have been treated with bortezomib and/or thalidomide.We performed a study of 111 MM patients who had received at least one of these two agents for at least 12 weeks by correlating physical exam/neurologic assessment findings with patient self-assessment responses.The median age of study patients was 66 years (range 42-89 years) and 54 % were males. 25D levels were determined, and complete history and physical and neurologic examinations were performed at the same study visit. In addition, study subjects completed questionnaires regarding symptoms related to motor and sensory PN. Overall, patients had a median serum 25D level of only 32 ng/ml; 42 % of patients were considered either 25D-deficient (20.0 ng/mL; 16 % of patients) or 25D-insufficient (20.0-29.9 ng/mL; 26 %). Notably, we found that 25D-deficient MM patients were more likely to have severe PN (grade 2) of both motor (p = 0.0415) and sensory (p = 0.0086) types although the overall incidence of PN was not higher in this patient population.These results show that the severity of peripheral neuropathy is associated with lower vitamin D levels and provides the rationale for monitoring vitamin D for myeloma patients especially those receiving drugs associated with the development of peripheral neuropathy.

8005Background: 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 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 28 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...

e20012Background: Pomalidomide (POM) is a third–generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) previ...

The use of hormone replacement therapy (HRT) is a potential treatment to relieve symptoms of menopause in postmenopausal women; however, the effects on skeletal muscle are unclear. Specifically, it is unknown if HRT enhances estrogen receptor (ER) transcriptional activation in skeletal muscle at rest and after resistance exercise. Purpose: To evaluate changes in the messenger RNA (mRNA) expression of ER coregulators (steroid receptor coactivator-1 (SRC-1) and silencing mediator of retinoid and thyroid receptors (SMRT)) in postmenopausal women after a maximal eccentric exercise bout. Methods: Fourteen postmenopausal women were divided into two groups: Control, women not using HRT (n = 6, 59.2 +/- 4.2 yr, 63.1 +/- 17.4 kg); or HRT, women using traditional HRT (n = 8, 58.5 +/- 3.7 yr, 89.5 +/- 23.7 kg). Participants performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60[degrees][middle dot]s-1 with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. mRNA expression was determined using real-time polymerase chain reaction for SRC-1 and SMRT. Results: mRNA expression of SRC-1 significantly increased (P

Hormone replacement therapy (HRT) is used in postmenopausal women to relieve symptoms of menopause and prevent osteoporosis. We sought to evaluate changes in mRNA expression of key myogenic factors in postmenopausal women taking and not taking HRT following a high-intensity eccentric resistance exercise. Fourteen postmenopausal women were studied and included 6 control women not using HRT (59 ± 4 years, 63 ± 17 kg) and 8 women using traditional HRT (59 ± 4 yr, 89 ± 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a Cybex dynamometer at 60°/s. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined using RT-PCR for follistatin, forkhead box 3A (FOXO3A), muscle atrophy F-box (MAFbx), muscle ring finger-1 (MuRF-1), myogenic differentiation factor (MyoD), myogenin, myostatin, myogenic factor 5 (Myf5), and muscle regulatory factor 4 (MRF4). At rest, the HRT group expressed higher levels of MyoD, myogenin, Myf5, MRF4, and follistatin ( P < 0.05). In response to eccentric exercise, follistatin, MyoD, myogenin, Myf5, and MRF4 were significantly increased ( P ≤ 0.05) and FOXO3A, MAFbx, MuRF-1, and myostatin were significantly decreased in the control and HRT groups ( P ≤ 0.05). Significantly greater changes in mRNA expression of follistatin, FOXO3A, MAFbx, MuRF-1, MyoD, myogenin, myostatin, Myf5, and MRF4 (p≤0.05) occurred in the HRT group than in the control group after exercise. These data suggest that postmenopausal women using HRT express higher myogenic regulatory factor gene expression, which may reflect an attempt to preserve muscle mass. Furthermore, postmenopausal women using HRT experienced a greater myogenic response to maximal eccentric exercise.

Hormone therapy (HT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation [serum creatine kinase (CK), serum lactate dehydrogenase (LDH), and skeletal muscle mRNA expression of IL-6, IL-8, IL-15, and TNF-alpha] in postmenopausal women after a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: women not using HT (control; n = 6, 59 +/- 4 yr, 63 +/- 17 kg) and women using traditional HT (HT; n = 8, 59 +/- 4 yr, 89 +/- 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60 degrees /s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined by RT-PCR for IL-6, IL-8, IL-15, and TNF-alpha. Blood draws were performed at baseline and 3 days after exercise to measure CK and LDH. Independent t-tests were performed to test group differences (control vs. HT). A probability level of Por= 0.05 was used to determine statistical significance. We observed significantly greater changes in mRNA expression of IL-6, IL-8, IL-15, and TNF-alpha (Por= 0.01) in the control group compared with the HT group after the exercise bout. CK and LDH levels were significantly greater after exercise (Por= 0.01) in the control group. Postmenopausal women not using HT experienced greater muscle damage after maximal eccentric exercise, indicating a possible protective effect of HT against exercise-induced skeletal muscle damage.

8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.

e19528 Background: Pomalidomide (POM) is a third –generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) for patients (pts) previously treated with bortezomib and lenalidomide (LEN) and in combination with dexamethasone it has been shown to overcome resistance in RRMM. In this phase 2 trial, we are evaluating the efficacy, safety and tolerability of POM as a replacement therapy for LEN for pts who have progressed receiving a LEN combination regimen. Methods: This is a phase 2, multicenter, open-label and non-randomized study. Pts who have failed a combination regimen containing LEN were treated with POM along with all of the other drugs previously used in the regimen. POM administered orally (dose is determined based on the previous regimen) on days 1-21 of a 28-day cycle, whereas other drugs are administered using the same schedule(s), dose(s) and drug combination as the last LEN-containing regimen that the patient received and failed. The planned enrollment on the study will be 45 pts. Results: To date, a total of 29 pts have been enrolled, 25 pts are evaluable and 12 pts have discontinued treatment. Of the evaluable pts, 9 (36%) and 16 (64%) received 3mg and 4mg of POM, respectively. The median age of all pts was 72 years (range, 52-81), and 17 (68%) were males. Pts have received a median of 3 prior treatments (range, 1-7). The median follow-up time for all pts is 3.1 months (range, 0.2-8.1). Amongst evaluable pts, 5 (23.8%) pts achieved at least a minimal response, 10 (47.6%) pts showed stable disease while 6 (28.6%) pts exhibited disease progression. At the time of data cutoff, only 17 pts have completed more than 1 full cycle of treatment; and, thus, the overall response and clinical benefit rates are fairly low (14.3% and 23.8%, respectively) but expected to improve with further follow up. The median PFS for the cohort was 7.6 months. Common ≥ Gr3 adverse events were neutropenia (8%), hypomania (4%) and leukopenia (4%). Conclusions: We show thatPOM appears to be promising replacement therapy for LEN in RRMM pts who have progressed within receiving a LEN combination regimen.

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.

Background: B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that promote survival of B-cells, including neoplastic B cells from chronic lymphocytic leukemia (CLL) patients (pts). We have found that BCMA is increased in plasma or serum from patients with multiple myeloma (MM). The level of serum BCMA found among MM pts associates with clinical status and predicts overall survival (OS). However, it is not known whether plasma (p) BCMA levels are elevated in pts with other B-cell malignancies, such as CLL. We examined plasma from healthy adults and pts with CLL for pBCMA and associated the observed levels in CLL pts with disease characteristics and/or known prognostic markers, such as white blood cell counts (WBC), serum β2-M, CLL-cell expression of mutated (M) or unmutated (U) immunoglobulin heavy-chain variable region (IGHV) or ZAP-70, or CLL-cytogenetic markers. We also examined the relationship between pBCMA and time from diagnosis (DX) or sample collection (SC) to initial treatment (treatment-free survival (TFS)) or OS. Methods: We examined the archived, plasma samples of 171 pts with CLL that were collected upon initial presentation to UCSD for studies on factors that could associate with disease outcome. Pts received therapy if they satisfied International Workshop on CLL (IWCLL) criteria for treatment. We examined serial plasma samples from a subset of these pts (n = 21) collected soon after DX, prior to first treatment, after treatment, and at relapse after therapy. We also assessed plasma samples of 76 healthy adults. We determined the pBCMA levels using a polyclonal anti-BCMA antibody in an ELISA available from R&D Systems (Minneapolis, MN). We used Mann-Whitney analysis to assess for associations between the relative pBCMA levels and disease characteristics assessed at the time of SC and Kaplan-Meier analysis to assess the relationship between measured pBCMA and TFS (median 4.1 years) and OS (median follow-up 7.8 years). Results: The median level of pBCMA in pts with CLL obtained from pts that were untreated at the time of first determination of pBCMA levels, regardless of whether they subsequently received therapy (n = 166; 58.54 ng/mL), was higher than that of healthy adults (n = 76; 6.32 ng/mL, P < 0.0001). The median pBCMA levels of samples from pts with CLL-cells that used M-IGHV (n = 87; median 42.13 ng/mL), or that lacked expression of ZAP-70 (n = 88; median 42.59 ng/mL), was lower than that of pts with CLL-cells that used U-IGHV (n = 84; 87.46 ng/mL, P < 0.0001), or that expressed ZAP-70 (n = 83; median 87.38 ng/mL, P < 0.0001). The median pBCMA level of pts with CLL cells that had del(13q) (n = 83; 46.57 ng/mL) was lower than that of pts with CLL cells that did not have detectable del(13q) (n = 77; 73.8 ng/mL; P = 0.0002). The median pBCMA of pts with CLL cells with del(17p) (n = 16; 77.23 ng/mL) appeared lower than that of pts without detectable del(17p) (n = 144; 51.77 ng/mL), but did not reach significance (P = 0.09). The TFS was longer (overall median time from SC to treatment: 2.36 years) among pts with pBCMA levels in the lowest three quartiles (median 3.72 years; range of pBCMA 13.21 - 104.69 ng/mL) when compared to patients with pBCMA in the highest quartile (median 0.67 years; range of pBCMA 110.1 - 782.97 ng/mL; P < 0.0001). Serial pBCMA levels consistently correlated with changes in clinical status among pts (n = 21) who had a pBCMA sample taken within three months of the determination of their clinical status. CLL pts with a pBCMA in the highest quartile had a significantly shorter OS when compared to pts with pBCMA levels in the lower three quartiles (P = 0.023). Conclusions: This is the first study to show that BCMA levels are increased in the plasma of CLL pts. We also demonstrate that the pBCMA levels correlate with other known prognostic indicators of CLL, such as IGHV mutational status, ZAP-70 expression and chromosomal abnormalities. CLL pts with higher pBCMA levels have a shorter TFS and OS. Furthermore, changes in pBCMA levels show consistent correlation with changes in the pts' clinical status during treatment. In summary, pBCMA appears to be a new plasma biomarker to monitor the disease course of CLL patients and determine their outcome. Disclosures Kipps: Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Background: Waldenström's macroglobulinemia (WM) is an incurable B-cell lymphoplasmacytic lymphoma. B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that can induce activation of NF-κB and promote survival of B cells, including neoplastic B cells. We previously showed that serum BCMA levels are elevated in multiple myeloma (MM) patients, and correlated with disease status and overall survival (OS). In this study, we sought to determine whether BCMA levels are elevated in the serum of WM patients, track with conventional WM tumor markers, and correlate with disease status and OS. Methods: Data was obtained on a total of 67 WM patients who received treatment in one of two clinics that specialize in the treatment of WM. Serum BCMA levels were determined with a polyclonal anti-BCMA antibody using an ELISA (R&D Systems, Minneapolis, MN). Mann-Whitney analysis was used to measure differences in serum BCMA levels between WM patients and healthy subjects as well as the clinical status of WM patients. Using Kaplan-Meier analysis, OS (median follow up 5.1 years) in WM patients was measured from the time of the first assessment of serum BCMA levels in each patient. In addition, serum BCMA levels were compared to serum M-protein and IgM levels in 12 patients, serially, during their individual courses of treatment. Results: We compared serum BCMA levels for all 67 patients, including 27 untreated WM patients to healthy subjects (n = 76). Serum BCMA levels were markedly elevated in all WM patients (median 79.53 ng/mL), including those who were untreated (median 82.72 ng/mL) versus healthy subjects (median 6.32 ng/mL, p < 0.0001 for both comparisons). Serum BCMA values were compared to both serum M-protein and IgM levels in 12 WM patients during their disease course. Serum BCMA levels consistently correlated with changes in both of these established WM serum markers during their course of disease. Serum BCMA levels of WM patients also correlated with patient disease status at the time of sample collection. Specifically, serum from patients achieving > partial response (PR, n = 12) showed significantly lower levels of BCMA than samples from patients with either stable disease (SD, n = 8, p = 0.030) or progressive disease (PD, n = 21, p = 0.0004). OS (median 12.5 years) was determined among patients in the highest serum BCMA quartile (n=16; quartile range 128.91-812.48 ng/mL) and compared to levels in the lower three quartiles (n = 48; range 20.13-128.85 ng/mL). Notably, OS was shorter among patients in the top quartile compared to those in the other three quartiles (p = 0.02). Conclusions: This is the first study to demonstrate that serum BCMA levels are elevated in Waldenström's macroglobulinemia patients. Importantly, serum BCMA levels correlated with both serum IgM and M-protein levels, as well as tracked with these established WM biomarkers for individual patients during their course of disease. Additionally, patients with levels of BCMA in the highest quartile exhibited shorter OS. Thus, serum BCMA represents a new serum biomarker to predict outcome and monitor patients with Waldenström's macroglobulinemia. Disclosures No relevant conflicts of interest to declare.

Aim: Oestrogen receptors (ER) are present in human skeletal muscle (hSkM) cells; however, the function of the receptor is currently unknown. We investigated the influence of oestradiol and selective ER modulators [tamoxifen (TAM), raloxifene (RAL)] on ER coregulator mRNA expression in hSkM. Methods: Human skeletal muscle cells were treated with 10 nm oestradiol, 5 μm TAM and 10 μm RAL over a 24-h period. Following the treatment period, mRNA expression was quantified using real-time PCR to detect changes in ER-α, ER-β, steroid receptor coactivator (SRC), silencing mediator for retinoid and thyroid hormone receptors (SMRT), MyoD, GLUT4 and c-fos. Results: ER-α mRNA expression increased with all three drug treatments (P