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Introduction: Amid the current COVID-19 pandemic, the highest mortality rates are among the elderly and immunocompromised. Multiple myeloma (MM) patients are immunocompromised and often are elderly. Not only do MM patients develop more frequent infections, but it is one of the leading causes of death for these patients. This population develops more severe COVID-19 due to various mechanisms that impair their ability to fight infection. This also reduces their ability to generate immunity from vaccination, as has been demonstrated by their diminished responses to vaccines for various respiratory illnesses. It follows that while phase III trial results for mRNA1273 and BNT162b2 COVID-19 vaccines showed an efficacy of 94-95% against even mild infection with this virus, the efficacy has been shown to be lower among MM patients. We recently evaluated patients' antibody responses to vaccination for COVID-19 by measuring anti-spike IgG levels in patient serum from before vaccination (baseline) and two weeks after dose 2 (D2W2) of vaccination with mRNA-1273 or BNT162b2, and found that most MM patients have impaired responses (Stampfer et al., Leukemia 2021). Patients who received mRNA-1273 vaccine had higher antibody levels than those who were vaccinated with BNT162b2, and specific clinical and myeloma-related characteristics predicted vaccine responsiveness. In the current study, we are monitoring anti-spike IgG antibody levels at Dose 2 Week 8 (D2W8) and Dose 2 Week 16 (D2W16) post-mRNA vaccination among these patients and in age-matched healthy controls to investigate antibody decay. Methods: Participants in the trial included MM patients (n=91) at the Berenson Cancer Center, and age-matched healthy controls (n=27). Healthy subjects were not known to be immunocompromised or currently receiving immunosuppressive therapy. Vaccination was done outside of the clinic and subjects provided copies of their CDC-issued COVID-19 vaccination cards to confirm dosing dates. Sera from vaccinated individuals were drawn at baseline (0-60 days prior to first vaccine dose) and at intervals following their second dose (14-21, 56-70, and 112-126 days post-vaccination). Background levels were determined from the clinic's serum bank of healthy subjects drawn pre-April 2019. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined Anti-SARS-CoV-2 spike ectodomain serum antibody levels and quantified them in IU/mL based on the WHO International Standard 20/136. Results: We analyzed the patient and control populations, and specifically for those classified as responders from our original published study (D2W2 >50 IU/mL). All controls but only 70% of patients (64/91) were classified as responders, so this responder-specific analysis was only relevant for patients. There was a significant decline in anti-SARS-CoV-2 spike antibodies from D2W2 to D2W8 for both patients and controls; D2W16 results are pending. Median values dropped from 283.1 IU/mL to 90.9 IU/mL among patients, and 893.6 IU/mL to 354.4 IU/mL among controls. Median antibody levels among patients classified as responders dropped from 482.9 IU/mL to 145.5 IU/mL (p Conclusions: The markedly lower anti-spike antibody levels among MM patients compared to healthy controls at week 8 post-vaccination indicate that they remain at high risk for breakthrough infections. Combined with their rapid decline in anti-spike antibody levels over only a 6-week period, this indicates that even MM patients who responded initially to vaccination are likely to require boosters sooner than healthy individuals. This immunocompromised population remains at high risk even following vaccination and should continue to maintain social distancing precautions during periods of high local SARS-CoV-2 transmission. Disclosures No relevant conflicts of interest to declare.

Background: Anti-CD38 monoclonal antibodies have become a standard treatment option for patients with either relapsed/refractory (RR) or newly diagnosed multiple myeloma (MM). There are two approved drugs in this class, daratumumab and isatuximab. These agents have become a mainstay of myeloma treatment being used in a variety of combination approaches. Although they are widely used, very little has been reported regarding the benefit they provide if they are used again in subsequent lines of therapy among patients that have already been treated with prior anti-CD38 containing regimens. Methods: MM patients that were treated at the Berenson Cancer Center and previously received either daratumumab or isatuximab and were treated with another anti-CD38-containing combination were retrospectively analyzed. Response to each anti-CD38 regimen was evaluated for responses according to the International Myeloma Working Group (IMWG) criteria. We used Kaplan-Meier curves to determine progression free survival (PFS) and overall survival (OS). Results: There were 49 patients identified as having received > 2 anti-CD38 containing regimens. Among these patients, 40, 1, and 8 received only daratumumab, only isatuximab, or a combination of both anti-CD38 regimens. 17, 19, 8, and 41 received an IMiD, PI, a combination of both, or other combinations. Overall, the median PFS was 3.9, 3.2, 2.6, 1.9, and 1.5 months for the first (n=49), second (n=49), third (n=23), fourth (n=15), and fifth (n=8) exposures, respectively. For their first anti-CD38 containing regimen (n=49), the clinical benefit rate (CBR) and overall response rate (ORR) were 44.9% and 38.8%, respectively (7.7% MR, 34.7% PR, and 4.1% CR), and 36.7% showed SD. During their second exposure (n=49), the CBR and ORR were 42.9% and 40.8%, respectively (2.0% MR, 36.7% PR, 12.0% VGPR, and 2.0% CR) and 36.7% showed SD. The PFS among patients who were exposed to a second regimen and discontinued therapy without disease progression to their first anti-CD38 containing regimen was 5.9 months compared with only 3.0 months for those who progressed during their first regimen. OS from the start of anti-CD38 treatment was a median of 36.5 months (range, 1.8-56.5). OS was longer among patients who did not progress on first exposure with a median of 26.2 months (range, 1.8-56.5) compared to patients who progressed during their first regimen (median not yet reached; range, 7.6-54.5). PFS among patients treated with a proteasome inhibitor (PI)-containing combination in their first exposure was 8.7 months versus 4.5 months among patients who were treated with an immunomodulatory agent (IMiD)-containing treatment. Additionally, the PFS among patients treated with a PI versus an IMiD with their second exposure to an anti-CD38 containing regimen was 5.9 and 2.8 months, respectively. Conclusions: Our retrospective study suggests that RRMM patients who are retreated with another anti-CD38 containing regimens can continue to respond after multiple exposures to this drug class. The ORR differs little during the first two exposures to these agents for RRMM patients. To our knowledge, this study provides support for retreatment of RRMM patients with anti-CD38 containing regimens. Additional studies are planned to further investigate this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau.

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

Introduction: B-cell maturation antigen (BCMA) is increased in the serum (s) of multiple myeloma (MM) patients (pts). We have previously shown that baseline sBCMA levels predict outcomes for MM pts. The purpose of this study was to determine whether a decrease of sBCMA to normal levels (< 82.69 ng/mL) after initiating treatment predicts both progression free survival (PFS) and overall survival (OS) among MM pts and its relationship to clinical response status in this pt population. Methods: sBCMA levels were determined using an ELISA (R&D Systems; Minneapolis, MN) in 147 consecutive MM pts whose first treatment was in the frontline (n=87 [59%]) or salvage (n=60 [41%]) settings in a single clinic specializing in MM from February 2009 to April 2019 (observation cut-off: May 31, 2019). We determined sBCMA weekly during the first cycle and then monthly thereafter (median follow-up= 28 mo). An age-matched analysis of 206 healthy donors was used to determine a median normal sBCMA level of 37.6 ng/mL (SD 22.5 ng/mL). A reference threshold value of 82.7 ng/mL was determined using 2 SDs above the median. We defined normalization of sBCMA as a decrease in levels to < 82.7 ng/mL on two consecutive measurements. Kaplan-Meier analysis was used to compare PFS and OS among these pts and compared with responses as defined using the IMWG criteria. All pt samples were obtained following informed consent in accordance with the Declaration of Helsinki. Results: One hundred thirteen pts (77%) had a baseline sBCMA ≥ upper threshold of normal (82.7 ng/mL) with a median of 435.3 ng/mL (range, 84.5-9,153.8 ng/mL) whereas the remaining 34 pts (23%) had baseline levels below 82.7 ng/mL and were excluded from analyses in relationship to normalizing sBCMA during their treatment. sBCMA levels normalized (< 82.7 ng/mL) in over half (55%) of evaluable pts (n=62), and these pts showed a markedly longer PFS (median 33.2 mo) than pts that did not (n=51; median 4.0 mo; p We also compared the PFS and OS of pts in CR to normalization of sBCMA. Pts whose sBCMA normalized (n=62) had both similar PFS (p=0.6257) and OS (p=0.7346) to those who achieved CR (n=26). Notably, every pt who achieved CR had normalized sBCMA and all pts who failed to normalize did not achieve CR (n=51). Pts who failed to normalize had shorter PFS (median 4.0 mo; n=51) than those who did not achieve CR (median 12.7 mo; n=87; p=0.0091). Among the pts who normalized sBCMA, pts who achieved CR (n=26) had similar PFS (p=0.4029) and OS (p=0.6354) to those who did not achieve CR (n=36). Conversely, among the 87 pts who did not achieve CR, pts who normalized their sBCMA (n=36) had markedly longer PFS (median 29.4 mo) than those who did not (n=51; median 4.0 mo; p We examined pts whose best clinical response was ≥ MR to determine if normalization of sBCMA improved upon determination of their PFS and OS. We found that among pts who achieved PR, those who normalized sBCMA (n=26) experienced improved PFS (median 33.2 mo) than those who did not (n=18; median 12.8 mo; p=0.0173); OS was also improved in those PR pts who normalized their sBCMA (p=0.0350). Similar findings were found when analyzing those achieving MR or PR, with PFS (p=0.0006) and OS (p=0.0326) for pts who normalized (n=30) being longer than for pts who did not normalize sBCMA (n=28). Of those achieving at least an MR, both PFS (median 33.9 vs 12.8 mo; p Conclusion: We have demonstrated that among MM pts starting new treatment with baseline elevated sBCMA levels, normalization of sBCMA levels (< 82.7 ng/mL) predicts markedly longer PFS and OS. Patients who achieve normalization have similar outcomes to those in CR. Additionally, our findings suggest that normalization of sBCMA predicts longer PFS and OS for pts who achieve ≥ MR. Therefore, normalization of sBCMA may be a novel approach to predict clinical outcomes for MM pts starting new treatment. Disclosures Chen: Oncotraker Inc: Equity Ownership. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Berenson:Sanofi: Consultancy; Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte Corporation.: Consultancy, Research Funding; OncoTracker: Equity Ownership, Other: Officer; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

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.

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.

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.

Introduction:B-cell maturation antigen (BCMA) is a tumor necrosis factor receptor family member that is expressed on normal and malignant B-cells, including those from patients (pts) with multiple myeloma (MM). Our group has recently shown that this protein is present in the serum of MM pts, and preliminary findings from our group suggested that its levels may correlate with their clinical status and overall survival (OS; Sanchez et al. Brit J Haematol 2012). We now have analyzed the relationship between serum BCMA levels and monoclonal (M)-protein levels as well as the relationship of BCMA to response status, progression-free survival (PFS) and OS in a large cohort of MM pts including those with nonsecretory disease (NSD). Methods:Two hundred fifty-two MM pts were evaluated. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum BCMA levels (R&D Systems). The Kruskal-Wallis Test was used to assess the correlation between serum BCMA levels and clinical status, and Dunn’s posttest was used to assess differences between clinical status groups. Kaplan-Meier analysis and multivariate Cox regression models were also used. Kaplan-Meier survival of MM pts was determined from the time of initial serum BCMA measurement to death or the date of last follow-up. PFS of MM pts was evaluated from the time of initial serum BCMA measurement to date of first disease progression. Cox-proportional hazards regression was utilized to determine the predictive influence of serum BCMA and various other factors including age, creatinine, hemoglobin, ISS stage, and bone disease on OS and PFS. P-values less than .05 were considered statistically significant. Changes in serum BCMA levels were correlated with serum M-protein levels for 44 consecutive MM pts during their course of disease. Similarly, BCMA was correlated with bone marrow and PET scan findings for NSD pts. Results: Serum BCMA levels correlated with the patient’s clinical status at the time of its determination (p PR had significantly lower serum BCMA levels (median, 11.69 ng/mL) than those with stable and progressive disease (median, 64.17 ng/mL; p30-140 ng/mL) and Stage 3 (n=55; > 140 ng/mL). Pts in Stage 1 had a longer OS (5-year, 95%) compared to pts in Stage 2 (5-year, 72%; p < 0.0002) while pts in Stage 2 had a longer OS than pts in Stage 3 (5-year, 60%; p < 0.0109). We determined the relationship of OS to serum BCMA level, age, serum creatinine, hemoglobin, ISS stage, and bone disease through Cox proportional-hazards regression. In the multivariate regression analyses, serum BCMA levels significantly correlated with only OS (p Conclusion:The results of this study demonstrate that BCMA is a novel serum marker that can be used to follow the course of disease for MM pts. The level of this serum protein is also correlated with clinical status and predicts their PFS and OS. It also provides MM pts with NSD a new potential way to follow their disease course, which currently requires frequent PET scans and bone marrow exams. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Despite the advances for treating multiple myeloma (MM) patients (pts), it remains an incurable B-cell malignancy. Thus, the objective for treating these pts is to prolong overall survival (OS) and preserve quality of life. New classes of drugs in the past decade have improved OS for MM pts; however, most of the studies conducted to predict outcome and predict factors that determine OS have relied on older data sets derived from large institutions including pts not receiving treatment there and lacking accurate follow up of pts as well as information from centers in which therapeutic choices are limited. These studies have suggested that depth of response, specifically complete response (CR), and lower International Staging System (ISS) staging at diagnosis predict improved OS. We have now analyzed data on all MM pts who have received treatment in a single clinic specializing in MM. Methods: Data was obtained from all MM pts who received treatment in a single clinic specializing in MM that was established 10 years ago. Kaplan-Meier analysis was used to generate all survival curves and the log-rank test was used to measure difference between curves, with P Results: Two hundred sixty-three MM patients (161 male, 102 female) with a median follow-up of 52 months were analyzed in this study. The median age at diagnosis was 63 years (range, 31 to 88). Thirty-seven pts (14%) had smoldering MM (SMM) while the remainder (n=225 [86%]) were diagnosed with active MM. For pts with active disease, ISS staging at diagnosis (n=156) included 68 (44%), 46 (29%) and 42 (27%) pts with ISS Stages I, II and III. The median OS of all patients was 118 months with a 5-year survival of 77%. The 5-year OS of SMM pts was 88% compared to 76% for those with active disease. There were no significant differences in OS between pts with different ISS stages at the time of diagnosis. Specifically, the median 5-year survival of pts with ISS Stage I, II and III disease at diagnosis were 79, 91 and 84 months, respectively. We also analyzed OS of MM pts according to the depth of response from treatment. There were no significant differences in OS between pts who attained a CR during their first treatment regimen compared to those who achieved their first CR during subsequent regimens or those who never attained a CR. During their first treatment, pts with stable disease (SD; n=28) showed no difference in OS compared to those achieving > minimal response (MR; n=135), > partial response (PR; n=107), PR (n=72), or CR (n=35). The OS of pts who had achieved a CR with at least one regimen (n=83 [38% of pts]) was not different than among pts never achieving CR (n=135 [62% of pts]; P=0.1173). In order to further determine whether depth of response predicts OS during the patient’s course of disease, OS was determined based on the best response ever achieved to any anti-myeloma regimen. There was no significant difference in OS between patients who achieved a CR (n=84) with any treatment regimen compared to those who attained an MR or PR (n=108), PR (n=73), MR (n=35) or those who had achieved only an SD (n=11). However, OS among pts who achieved CR, > PR, ≥ MR, or > SD (SD+MR+PR+CR) was better than among those who had only demonstrated PD during their course of disease (P In order to determine whether the initial treatment regimen predicted OS, we also analyzed survival of pts who received bortezomib-based therapy compared to those who received an IMiD or both drugs together as their initial treatment, and showed there was no significant differences in OS between these three upfront treatment approaches. Conclusion: Results from an analysis of a large cohort of MM pts from a single clinic specializing in MM show that the median survival has greatly improved to nearly 10 years due to the availability of many new treatment options. Although previous studies have suggested that ISS staging at diagnosis and depth of response to anti-MM regimens predict OS for MM pts, results from our study involving analysis of a large cohort of MM pts from a single clinic specializing in MM show that these prognostic factors do not predict OS for pts with this B-cell malignancy. Differences in our results compared to other previous studies may reflect the many treatment options available in the clinical setting used to obtain our results. Disclosures No relevant conflicts of interest to declare.

Background Thalidomide and its immunomodulatory drug (IMiD) derivatives such as lenalidomide (LEN) have shown great promise as treatment options for multiple myeloma (MM) patients (pts). Pomalidomide (POM) is a newer IMiD with high in vitro anti-MM potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM pts. Recent data has shown POM to be effective in combination with dexamethasone (DEX), even for patients who are refractory to bortezomib and lenalidomide (Richardson et al, 2012). It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM pts (Offidani et al, 2006; 2007). Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). These results imply that the combination of POM, DEX and PLD may be an effective regimen for treating R/R MM pts. We conducted a phase 1/2 trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using our modified dose, schedule, and longer 28-day cycle for pts with R/R MM. Methods For enrollment into the phase 1 portion of the study, eligible pts had to show progressive MM at the time of enrollment. For participation in the phase 2 portion, pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving this IMiD or relapsed within 8 weeks of their last dose. Pts who received previous POM treatment were ineligible. During the phase 1 part of the trial, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX (40 mg intravenously over 30 min) and PLD (5 mg/m2infused over 30-90 min) both were given on days 1, 4, 8, and 11 of each cycle. POM doses were escalated per cohort until maximum tolerated dose (MTD) was reached. Phase 2 patients were all enrolled at what was established as the MTD. Results As of July 9, 2013, 33 pts were registered: 11 and 22 enrolled in the phase 1 and 2 portions, respectively. Fifteen patients have discontinued treatment thus far and 18 remain active. Pts had received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimen (range, 0-2) and 1 prior IMiD regimen (range, 0-4). Pts have completed a median of 4 cycles (range: 0-8) with a median of 3.2 months of follow up (range: 0-9.7). During the phase 1 portion, no dose-limiting toxicities were identified, so the highest administered dose of 4 mg was initially established as the MTD. However, neutropenia ≥ G3 was observed in 10/17 phase 2 pts (58.8%) at this dose; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all phase 2 pts beyond the 29thpt (n = 4). Thirty-two pts have received study drug. Twenty-nine pts were evaluable for response at data cutoff as 3 were active but had not yet had any post-baseline disease assessments. Of the 29 considered evaluable, overall response rate and clinical benefit rates were 34.5% and 48.3%, respectively, Six pts (20.7%) showed stable disease while 8 (27.6%) pts exhibited progressive disease. There was ≥ grade 3 (G3) neutropenia in 12 (37.5%) pts. Two pts experienced this toxicity during the phase 1 portion (3 mg and 4 mg doses- 1 each) whereas the other 10 pts experienced this side effect at the 4 mg dose during phase 2 enrollment. Following the lowering of the MTD to 3 mg due to this issue, neutropenia (≥ G3) has not been observed to date. Other treatment-emergent AEs ≥ G3 occurring in more than 1 pt were leukopenia in 12 (37.5%), lymphopenia in 8 (25%), anemia in 3 (9.4%), hyponatremia in 3 (9.4%), thrombocytopenia in 2 (6.3%), and duodenal ulcers in 1 (3.4%) pts. One pt died during treatment due to sepsis. Conclusions Results from this phase 1/2 trial demonstrate that the combination of pomalidomide with dexamethasone and PLD using a 28-day cycle shows efficacy for MM pts with progressive disease who are refractory to lenalidomide. Notably, less neutropenia has been observed at the 3 mg dose of pomalidomide, with 4 mg POM dosing associated with a high incidence of ≥ G3 neutropenia when used in this three-drug combination. Disclosures: Berenson: Celgene: Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vescio:Celgene: Speakers Bureau.

Abstract 2979 Background: Thalidomide and its immunomodulatory (IMiD) derivatives such as lenalidomide have shown great promise as a treatment option for multiple myeloma (MM) patients. Pomalidomide is a newer IMiD with high in vitro potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM patients. Recent data has shown pomalidomide to be effective in combination with dexamethasone, even for patients who are refractory to bortezomib and lenalidomide. It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM patients. Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the dose and schedule of these drugs. These data imply that the combination of pomalidomide, dexamethasone, and PLD for R/R MM patients may be an effective regimen. We conducted a phase 1/2 trial investigating the safety and efficacy of pomalidomide in combination with IV dexamethasone and (PLD) using a modified dose and longer 28-day schedule for patients with R/R MM. The combination of PLD, dexamethasone and lenalidomide without bortezomib has not been previously evaluated. Methods: For enrollment into the phase 1 dose-escalation portion of the study, eligible pts had to have progressive MM at the time of enrollment that has relapsed following stabilization to at least one anti-myeloma regimen or is refractory defined as progressed while receiving anti-myeloma treatment. For enrollment into the planned phase 2 portion of the study, eligible pts have to be refractory to lenalidomide (singe-agent or in combination) demonstrated by progressive disease while receiving lenalidomide or relapse within 8 weeks of the last dose of lenalidomide. Patients who have received previous pomalidomide treatment were not eligible. Patients must not have received chemotherapy, corticosteroids, immunotherapy, antibody therapy, or treatment with thalidomide, lenalidomide, or bortezomib within 3 weeks of receiving study drug, nor extensive radiation therapy within 4 weeks of receiving study drug. During the phase 1 part of the trial, pomalidomide was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 patients each on days 1–21 of each 28-day cycle. Dexamethasone was administered intravenously at 40 mg over 30 min on days 1, 4, 8, and 11 of each cycle. PLD was administered at 5 mg/m2 as an IV infusion over 30–90 min on days 1, 4, 8, and 11 of each cycle. Pomalidomide doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent patients will be enrolled at that dose. Results: Ten of 40 planned patients have been enrolled to date, all during the phase 1 portion of the trial. Pts received a median of 4 prior treatments (range, 1–8) with a median of 1 prior PLD regimens (range, 0–1). Pts have completed a median of 1 cycle (range: 0–12) with a median of 1.2 months of follow up (range: 0.2–3.6). To date, the trial has enrolled all three cohorts in phase 1 (1 patient in cohort 1 chose to withdraw during Cycle 1 and was replaced). MTD has not yet been reached with no dose limiting toxicities (DLTs) in the first 2 cohorts. The 3 patients in cohort 3 are currently in Cycle 1. Seven patients are currently evaluable for efficacy and the 3 patients in cohort 3 have not yet had response assessment. Best response for evaluable patients is as follows: 3 patients have shown partial response, 2 patients have shown minor response, 1 is exhibiting stable disease (SD) but shows a decreasing monoclonal protein, and 1 has progressed. The incidence of reported adverse events (AEs) so far is low. Only 1 grade 3 or 4 (G3, G4) AE has been observed. The most common AEs were lymphopenia, which occurred in 6 pts (G1: 3; G2: 2; G3: 1), elevated urea nitrogen occurred in 4 pts (all G1), neutropenia occurred in 4 pts (all G1), and leukopenia occurred in 4 pts (all G1). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle may be an effective treatment option with acceptable tolerability for relapsed/refractory MM patients. Disclosures: Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Abstract 4063 Background: Carfilzomib has shown promise in treating both newly diagnosed and relapsed/refractory MM patients. Recent data has suggested that single agent carfilzomib can produce a response for MM pts refractory to previous treatment regimens, including prior bortezomib-containing regimens. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of carfilzomib as a replacement for bortezomib in bortezomib-containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent bortezomib-containing regimen after at least 4 doses of bortezomib at ≥ 1.0 mg/m2 in ≤ 4 weeks per cycle. Patients treated with bortezomib-containing combination regimens, including alkylating agents, anthracyclines, glucocorticosteroids, and/or immunomodulatory agents were eligible. Carfilzomib replaced bortezomib in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. For each pt, carfilzomib doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m2 or until maximum tolerated dose (MTD) was reached for that regimen. Aside from carfilzomib replacing bortezomib, regimens utilized the same dose(s) and schedule(s) of each drug administered in the most recent bortezomib-containing regimen to which the patient was refractory. Results: The trial has currently enrolled 32 of 45 planned patients. Pts received a median of 6 prior treatments (range, 1–18) and 2 different bortezomib-containing regimens (range, 1–13). Pts were treated with carfilzomib and 13 different combination regimens at varying doses and schedules. Agents in these combination regimens varied per patient, potentially including any of the following: ascorbic acid, bendamustine, clarithromycin, cyclophosphamide, dexamethasone, lenalidomide, melphalan, methylprednisolone, pegylated liposomal doxorubicin, and/or thalidomide. Six patients received a regimen containing IMiDs (thalidomide or lenalidomide). Pts have completed a median of 3 cycles (range: 0–12) with a median of 5.9 months of follow up (range: 0.4–14.1). To date, 1 regimen, carfilzomib + ascorbic acid + cyclophosphamide, has reached MTD with the maximum dose of carfilzomib (45 mg/m2) without any DLTs. Efficacy data stems from 24 of 32 enrolled pts who have completed at least 1 cycle of treatment. Clinical benefit was seen in 18 (75%) pts (complete response = 8.3%; very good partial response = 16.7%; partial response = 29.2%; minor response = 20.8%) with another 16.7% showing stable disease. Notably, response was achieved for each type of agent included in the trial across a variety of specific treatment combinations. Only 3 pts have progressed while on study, one with progressive disease after an initial response. Kaplan-Meier analysis reveals the median progression-free survival (PFS) at this point in the study to be 10 months (95% confidence interval: 8.6–11.2). The median time to progression (TTP) and duration of response (DOR) have not yet been reached. Safety data stems from all 32 enrolled pts. The most common grade 3/4 hematologic adverse events include: thrombocytopenia, occurring in 16 pts (G3: 5; G4: 2); lymphopenia occurring in 12 pts (G3: 6; G4: 1) and fever occurring in 2 pts (G3). The most common grade 3/4 non-hematologic adverse events include: fever, occurring in 8 pts (G3: 2); urinary tract infection, occurring in 3 pts (G3: 1); sepsis occurring in 1 pt (G4); pneumonia occurring in 2 pts (G3: 1); tumor lysis syndrome occurring in 1 pt (G3). Ten pts experienced a serious adverse event on study. Conclusions: These early results suggest that carfilzomib is an effective and tolerable replacement for bortezomib among pts who are refractory to bortezomib-containing combination regimens. These results appear to be applicable to a variety of combination regimens consisting of a wide array of therapeutic agents. Disclosures: Berenson: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Abstract 1857 Background: Multiple myeloma (MM), the second most common hematologic cancer in the United States, has a 5-year survival rate of 38%. Bendamustine is a unique alkylating agent with multiple actions leading to cancer cell death in several tumor types. In patients with MM, bendamustine, alone and in combination with prednisone, has been shown to be efficacious, with durable responses. Bortezomib is a proteasome inhibitor approved as monotherapy for MM. It has been found to sensitize highly chemoresistant MM cell lines to alkylating agents such as melphalan. Subsequent clinical trials have reported anti-MM activity and acceptable safety for bortezomib plus melphalan for relapsed or refractory MM and for bortezomib, ascorbic acid, and melphalan (BAM) for patients with newly diagnosed MM. The present phase 1/2 study assessed the safety, tolerability, and efficacy of bortezomib plus bendamustine for patients with relapsed or refractory MM. Methods: All patients were ≥18 years old and had biopsy-confirmed MM, measurable by a serum monoclonal immunoglobulin spike ≥1 gm/dL and/or a urine monoclonal spike ≥200 mg/24 hours. Also, all patients received ≥1 prior MM treatment, not including bendamustine, and showed signs or symptoms of progressive disease, either relapsed (progression following stabilization or response) or refractory (progression during or within 6 months after an antimyeloma regimen). Patients were enrolled in successive groups of 3 to 5. The groups received open-label bendamustine administered as a 1-hour intravenous (IV) infusion of 50, 70, or 90 mg/m2 on days 1 and 4 of each 28-day treatment cycle. Each infusion was preceded by bortezomib administered as a 3- to 5-second IV push of 1.0 mg/m2. Bortezomib was also given on days 8 and 11. Enrollment at each dose level was permitted only if the first 3 patients at the previous level received 1 cycle without unacceptable dose-limiting toxicity (DLT). If not, an additional 3 patients would be treated at the previous level (for a maximum 6 at each level). The maximum tolerated dose was defined as the highest dose at which Results: Because no DLT was observed in phase 1, the bendamustine dosage selected for phase 2 was 90 mg/m2 (plus bortezomib at 1.0 mg/m2). A total of 40 patients (median age, 67.0 years; range, 43–89) were enrolled and had received a median of 6 (range, 2–20) prior therapies, including bortezomib (75%) and alkylators (70%). Following enrollment, 5 patients received a mean (SD) of 3.0 (1.7) cycles of 50 mg/m2 of bendamustine, 4 received 4.0 (2.9) cycles of 70 mg/m2, and 31 received 4.7 (2.8) cycles of 90 mg/m2. Among the 39 patients with efficacy data, the overall response rate was 48.7% (n=19); 53.3% in the subgroup of patients receiving 90 mg/m2 (n=16). Of the 19 responses, 1 was complete (in the 90 mg/m2 group), 2 were very good partial (both in the 90 mg/m2 group), 8 were partial, and 8 were minimal. Another 16 patients (41.0% of 39) had stable disease, and the remaining 4 (10.3%) individuals showed progressive disease. Among all 40 patients, 28 (70.0%) had grade 3 or 4 AEs: 3 of 5 patients (60.0%) receiving 50 mg/m2, 3 of 4 (75.0%) receiving 70 mg/m2, and 22 of 31 (71.0%) receiving 90 mg/m2. There were 3 deaths (unknown/old age, disease progression, and septic shock). Grade 3 or 4 AEs in ≥10% of patients were neutropenia (37.5%), thrombocytopenia (25.0%), anemia (12.5%), and leukopenia (10.0%). Conclusions: In pretreated patients with relapsed or refractory MM, 28-day cycles of bendamustine 90 mg/m2 on days 1 and 4 plus bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 were well tolerated and showed promising efficacy. This research was sponsored by and conducted by Cephalon, Inc., Frazer, PA. Disclosures: Berenson: Millennium: Consultancy, Honoraria, Research Funding; Cephalon, Inc.: Research Funding. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Boccia:Millennium: Speakers Bureau. Noga:Cephalon, Inc.: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene Corporation: Honoraria; Millennium: Honoraria; Takeda: Honoraria. Gravenor:Cephalon, Inc.: Research Funding. Siegel:CVS/Caremark: Consultancy; Cephalon, Inc.: Research Funding. Kewalramani:Cephalon, Inc.: Research Funding. Swift:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayo:Cephalon, Inc.: Employment.

Abstract 3044 Background: Despite the availability of many new therapeutic options showing efficacy for R/R MM patients, many of these treatments produce significant side effects and the disease remains incurable. The combination of PLD and bortezomib has shown significant anti-MM efficacy leading to FDA approval of that combination for patients who have received one prior therapy and are naïve to bortezomib. Moreover, the combination of lenalidomide and dexamethasone has also been approved for patients who have received one prior regimen. However, both regimens are associated with significant toxicity and produce response rates in only 40–60% of patients. Previous studies in our laboratory show the increased efficacy and improved tolerability of PLD given daily compared to weekly administration in severe combined immunodeficient mice bearing human MM. Based on these results and the frequent occurrence of peripheral neuropathy with bortezomib when given at 1.3 mg/m2 dose on days 1, 4, 8, and 11 of a 3-week schedule, we modified the doses and schedules of both drugs and added intravenous (i.v) dexamethasone for MM patients. Using a modified lower dose (1.0 mg/m2) and longer cycle (4 weeks) of bortezomib administered on days 1, 4, 8, and 11 with lower dose PLD and intravenous (i.v.) dexamethasone administered on the same days for MM patients in both the frontline and R/R setting, we have shown the efficacy and marked reduction in AEs including neuropathy, hematologic, and hand-foot syndrome. A recent phase I/II trial investigating the combination of higher doses of lenalidomide, bortezomib, oral dexamethasone, and PLD on a 3-week schedule for newly diagnosed MM patients showed a high response rate but was associated with frequent AEs. Methods: Thus, we conducted a single-arm multi-center phase II study for R/R MM patients to evaluate the combination of i.v. dexamethasone, bortezomib, PLD, and lenalidomide. The treatment consisted of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and then 4.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Lenalidomide was administered orally at a dose of 10 mg daily on days 1–14 of each cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Eighteen (of 40 planned) patients have been enrolled to date with a median age of 72 years (range, 34–82 years). Patients were heavily pretreated with a median of 4 (1-17) prior regimens. Sixteen (89%) patients received prior bortezomib and 11 (61%) were previously treated with either doxorubicin or PLD. Seven (39%) of these patients were exposed to both drugs. Fifteen (83%) had received prior glucocorticoids. Nine (50%) individuals had received immunomodulatory agents with 6 (33%) having been exposed to lenalidomide and all 9 to thalidomide. The majority of patients (72 %) showed International Staging System II or III disease. To date, 16 patients (89%) have shown objective responses to the DVD-R regimen, including 1 complete response (6%), 5 very good partial responses (28%), 4 partial responses (22%) and 6 minimal responses (33%). One of the nonresponding patients showed stable disease and the other progressed after one cycle of therapy. Thus, disease control was achieved in all but one patient (94%). To date, 6 patients have shown progressive disease after a median follow-up time of 6 months (1+ - 9+ months). The DVD-R regimen was well tolerated and only one patient discontinued treatment because of toxicity (peripheral neuropathy). Ten patients experienced grade 3 or 4 adverse events. The most common grade 3 adverse events were reversible neutropenia (n=3), pneumonia (n=3), reversible anemia (n=2), and thrombocytopenia (n=2). There were two patients with grade 4 thrombocytopenia that was reversible. To date, 5 patients (28%) have developed treatment-emergent peripheral neuropathy (four grade 1 and one grade 3). Notably, there have been no cases of stomatitis or hand-foot syndrome. Conclusions: Thus, these results suggest that the DVD-R regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib, PLD and lenalidomide is a well tolerated treatment that produces high response rates for heavily previously treated MM patients with R/R disease. Disclosures: Berenson: Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Centocor OrthoBiotech: Consultancy. Vescio:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Swift:Millennium: Consultancy.

Abstract 3057 Background: Multiple myeloma (MM) is an aggressive and incurable disorder with an eventual fatal outcome bringing urgency to the identification of effective treatments for patients who have exhausted standard chemotherapy. New agents, such as lenalidomide and bortezomib have led to a rapid increase in therapeutic options as single agents and in combination with other agents. However, despite this progress nearly all patients will relapse and require additional therapeutic options. Bendamustine is a unique chemotherapeutic agent that combines an alkylating group with a purine-like benzimidazole ring that is approved in the US for the treatment of CLL and refractory indolent B-cell NHL. Bendamustine is approved in Europe for the treatment of MM. Bortezomib is a proteasome inhibitor (PI) that is approved for the treatment of MM and the combination of this PI with alkylating agents including melphalan and cyclophosphamide has proven highly effective in the treatment of MM. Thus, the combination of bortezomib with bendamustine which also possesses alkylating agent properties may enable patients that were previously treated with bortezomib to have additional therapeutic options. In addition, this combination may allow use of lower doses of bortezomib to be used potentially reducing the incidence of peripheral neuropathy as has been observed in other combinations involving bortezomib with other alkylating agents. This study is being conducted to assess the safety and efficacy of bendamustine in combination with bortezomib for the treatment of relapsed/refractory MM. Methods: This open-label, Phase 1/2 study, will enroll up to 40 patients (pts), age ≥18 years, with measurable MM that has relapsed following or is refractory to at least 1 previous treatment. Patients received bendamustine infused intravenously over 1 hour on days 1 & 4 in 3-dose cohorts of 50, 70, or 90 mg/m2 and bortezomib on days 1, 4, 8, & 11 at a fixed dose of 1.0 mg/m2 for up to eight 28-day cycles. Three pts were initially enrolled at each dose cohort. Up to 5 pts were allowed to enroll in each initial cohort if they were all in screening prior to the 3rd pt being enrolled. After the first 3 pts completed cycle 1 of each dose, the cohort was assessed for dose-limiting toxicities (DLT). In this study, a DLT was defined as any study drug related grade 3 or grade 4 non-hematologic toxicity, grade 4 hematologic toxicity, grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 febrile neutropenia, grade 3 or grade 4 nausea and vomiting refractory to anti-emetic therapy, or any drug-related deaths. A standard 3+3 approach was used for determining the MTD. The MTD cohort will be expanded so that up to 40 total pts are enrolled. Results: Twenty-five pts with a median age of 62 (44-91) have been enrolled on the study and received at least 1 dose of study drug, and 52% of the pts are male. Patients had received a median of 4 (1-17) prior therapies. Notably, 80% (20/25) of pts had received at least one prior bortezomib-containing regimen. For the Phase 1 portion, 5 pts were enrolled into the 50 mg/m2 cohort, 4 pts were enrolled into the 70 mg/m2 cohort and 5 pts were enrolled into the 90 mg/m2 cohort. No DLTs were observed in the phase 1 portion of the study. The maximum dose (90 mg/m2) was well tolerated. Patients are currently enrolling into the Phase 2 portion of the study and receiving this dose of bendamustine in the combination treatment. To date, the most common grade 3 or 4 adverse events, occurring in more than 10% of pts, were neutropenia (36%), anemia, (24%), thrombocytopenia (24%), and renal failure (12%). A worsening of baseline peripheral neuropathy was reported in 20% of pts. Two (8%) pts were reported to have grade 1, treatment emergent peripheral neuropathy. To date, nearly one-third (8/25) of pts have achieved an MR or PR. To date, 16 pts have been enrolled at the 90 mg/m2 dose of bendamustine and 5 (31%) have achieved an MR or PR. Conclusions: The combination of bendamustine 90 mg/m2 on days 1 and 4 and bortezomib 1.0 mg/m2 on days 1, 4, 8, & 11 appears to be safe and effective in this heavily pre-treated patient population. The phase 2 portion of this study is ongoing. Disclosures: Berenson: Cephalon: Consultancy, Research Funding; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Bendamustine is approved for CLL and refractory NHL. It is being studied in combiantion with bortezomib for multiple myeloma. Siegel:Cephalon: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Marmatech: Research Funding; Medivation: Research Funding; Caremark/CVS: Consultancy. Swift:Millennium: Speakers Bureau. Ehrman:Cephalon Inc.: Employment. Bensen-Kennedy:Cephalon Inc.: Employment.

Abstract 1855 Poster Board I-881 We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized. Disclosures: Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.

Abstract 4936 Despite recent advances in the treatment of MM, the disease remains incurable and many of the most effective, newer combination therapies are accompanied by significant side effects that have a major negative impact on the patient's quality of life. Pegylated liposomal doxorubicin (PLD) and bortezomib have shown anti-MM efficacy in the laboratory and for the treatment of previously treated MM patients, leading to FDA approval for patients who have failed one prior therapy. Using our severe combined immunodeficiency-hu murine models of human MM, we have previously demonstrated that lower doses of PLD administered daily are more effective and better tolerated than higher amounts given weekly. Moreover, the combination of bortezomib and dexamethasone has been shown to be effective for previously untreated MM patients. Prior studies by our group have shown that combining chemotherapy including PLD with bortezomib administered at 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle rather than the standard 1.3 mg/m2 on the same days of a 21-day schedule is effective for MM patients with relapsed or refractory disease and associated with a reduction in the incidence and severity of peripheral neuropathy. Thus, we conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the combination of intravenously administered dexamethasone, bortezomib and PLD (DVD). The treatment consisted of intravenous administration of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and finally 5.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. To date, 22 (of 35 planned) patients have been enrolled with a median age of 64 years (range, 42-79 years). The majority of those on study (68 %) were diagnosed with International Staging System II or III MM. Four patients are too early to assess for response. To date, among the 18 evaluable patients, 16 (89%) have shown objective responses to the DVD regimen, including 2 complete responses (11%), 8 partial responses (44%) and 6 minimal responses (33%). The other 2 patients (11%) had stable disease, with one of these subjects showing a continuing reduction in M-protein after 2 cycles of therapy to date. Thus, disease control was achieved in all patients. To date, no patient has shown progressive disease after 2+ - 12+ months of follow-up. Six patients experienced grade 3 adverse events and one patient with a prior history of pulmonary interstitial fibrosis developed a grade 4 toxicity (shortness of breath). Grade 3 adverse events in three of the six patients were judged not to be related to the study treatment. The most common grade 3 adverse event was reversible neutropenia (n=2). To date, only 2 patients (9%) have developed peripheral neuropathy (grade 1). Notably, there have been no cases of stomatitis or hand-foot syndrome. Thus, these results suggest that the DVD regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib and PLD is a well tolerated treatment that produces high response rates for previously untreated patients with multiple myeloma. Disclosures Berenson: Millennium Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Speakers Bureau. Hilger:Millennium Pharmaceutcals: Employment.

Abstract 4234 Traditional bone marrow procedures using a manual device hand-inserted by the clinician may be associated with pain, bleeding and inability to obtain adequate specimens leading to multiple attempts and a prolonged time to complete the procedure. These procedures take from approximately 7 minutes to more than 30 minutes to collect adequate aspirate and core biopsy samples. Notably, it has been shown that the duration of needle insertion is the sole predictor of patient pain during the procedure. In an attempt to overcome these shortcomings of the traditional technique, the OnControl bone marrow aspiration and biopsy system has recently been developed. It is an FDA-cleared device, comprised of the driver, a metal needle set and a connector. The driver is a small battery-powered device for insertion of a single lumen needle into the intraosseous space of the adult iliac crest. This device allows for a minimally-invasive procedure that in a 2007 study showed a substantially faster time for needle insertion into the medullary space of the iliac crest with a mean insertion time of 5 seconds. In an interim analysis of a single-arm validation study for the OnControl system, 36 patient procedures were completed with a mean user satisfaction score of 4.6 (on a scale of 0-5, with 5 indicating high satisfaction), a biopsy core acquisition success rate of 92%, a mean length of biopsy core of 1.22 cm, and a mean time from needle insertion to core extraction of 2 minutes and 9 seconds. Thus, we are currently enrolling patients on a multicenter, prospective, randomized controlled trial in order to directly compare results of using this new powered core biopsy needle to traditional manually inserted needles in terms of patient level of pain, time from needle insertion to removal, insertion success rate, core biopsy capture rate, quality of yield of this device, rate of complications, and operator satisfaction with the device. Patients requiring conscious sedation/narcotics for pain relief or extra bone marrow for research purposes/additional tests beyond that required for routine clinical evaluation will be excluded. Block randomization with blocks of size 4 will be used to prevent unequal treatment-group sizes. Each patient is being randomized to undergo a bone marrow procedure with the standard manual device or the powered device. Patient pain is being assessed using the Visual Analog Scale of 0 to 10; with 0 = no pain and 10 = extreme pain. The pain level will be assessed immediately following needle removal and at days 2 and 8 following the procedure. We plan to enroll 102 patients in this study and expect to have all patients enrolled in the next 3 months. Updated data as part of an interim analysis of this randomized trial will be presented at the time of the ASH meeting. Disclosures: Berenson: Vidacare, Inc.: Research Funding.

ATN-224 (bis-choline tetrathiomolybdate) is an orally-available small molecule that is currently being studied in several phase II oncology clinical trials. ATN-224 inhibits copper-zinc superoxide dismutase (Cu/Zn-SOD; SOD1) in endothelial and tumor cells. SOD1 is an enzyme that mediates signaling by a number of mitogens including VEGF, FGF-2, EGF, IGF-1 and PDGF. The inhibition of SOD1 by ATN-224 leads to the inhibition of proliferation in endothelial cells and the induction of apoptosis in tumor cells. In a preclinical mouse model using multiple myeloma (MM) cells obtained from a patient that was refractory to bortezomib, the combination of ATN-224 and bortezomib was more effective than either agent alone and led to tumor regression. Based on this data, a phase I/II clinical study evaluating the combination of ATN-224 and bortezomib for MM patients that had previously failed bortezomib was initiated. The phase I portion of this study evaluated the safety of several doses of both ATN-224 and bortezomib and established a recommended dose and schedule of this combination for the phase II portion of the study. The phase I study has completed enrollment and results are presented here. Patients with recurrent or refractory MM that had previously failed bortezomib and currently showing evidence of disease progression were enrolled. Patients had adequate ECOG performance status (PS 0–2) and hematologic and organ function. Patients were monitored for safety and preliminary evidence of efficacy. Blood samples were collected at specific intervals for pharmacokinetic and pharmacodynamic analyses. Twenty-one patients (62% male), aged 46–80 (mean 66) with PS 0–1 were enrolled into 6 cohorts. Dose Limiting Toxicity (DLT) was defined as grade 3 or 4 neutropenia with neutropenic fever, grade 4 neutropenia, grade 3 or 4 thrombocytopenia, grade 2 peripheral neuropathy with pain, grade 3 or 4 neuropathic pain and/or peripheral sensory neuropathy, grade 4 anemia or a fall in hemoglobin by >3 g/dL when day 1 hemoglobin is ≥11 g/dL or >2 g/dL when day 1 hemoglobin is 2g/dL from baseline (n=3) and grade 3 fatigue (n=1)] were observed within the first three cohorts. After review of this data, it was determined that the more appropriate dosing schedule included a 7 day drug holiday. In cohorts 4 through 6 (n=11), ATN-224 was administered at doses of either 180 or 210 mg daily for 21 days in combination with bortezomib at a dose of either 1.0 or 1.3 mg/m2/dose on days 8,11, 15 and 18 of a 28 day cycle. One DLT (grade 4 thrombocytopenia) was observed and occurred in the 180 mg ATN-224 plus 1.3mg/m2/dose bortezomib cohort. By incrementally increasing each dose of ATN-224 and bortezomib individually and modifying the treatment schedule, treatment-related toxicities have been minimized while maximizing the treatment doses. One patient experienced a complete response that was durable for over 10 months. The other 20 patients experienced disease progression within 90 days. A daily dose of 210 mg of ATN-224 for 21 days and a dose of bortezomib at 1.0 mg/m2 on days 8, 11, 15, and 18 of a 28 day cycle was well tolerated and recommended for the phase II portion of this trial, which is now enrolling patients. The phase I portion of the study demonstrates that the combination of ATN-224 and bortezomib can be safely administered and may be an effective treatment for MM patients that are relapsed from or refractory to bortezomib.

MGUS occurs in 5% of individuals over 70 yrs of age and these pts have been found to have increased rates of bone resorption. Osteoporosis associated with MGUS have higher bone resorption compared to sex and aged-matched pts with osteoporosis but without evidence of MGUS. Not only do pts with MGUS have a higher prevalence of osteopenia/osteoporosis than the normal population but they also have an increased risk of fractures (fx). ZOL has been shown to increase BMD in the treatment of gonadotropin agonist-induced osteoporosis in men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies coupled with the knowledge that pts with this disorder have a higher prevalence of bone loss and fx risk. To date, no agents have been formally studied in the treatment of osteopenia/osteoporosis associated with MGUS. A schedule of 4 mg every 6 mos has been shown to be safe and effective in increasing BMD for other cancer pts without metastatic bone disease but with significant bone loss. This open-label study was designed to evaluate the efficacy and safety of this dose and schedule of ZOL for MGUS pts with significant loss of bone. Pts had to have osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and a diagnosis of MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than three mos within the last two yrs or prior use of intravenous (IV) BIS within the last two yrs were excluded. ZOL at 4 mg was administered IV at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and one mo after the final ZOL infusion (13 mos). Fifty-four pts were enrolled on this trial with an average age of 68 (range, 50 to 91 yrs). The starting L-spine T-scores ranged from −3.97 to −1.10 (mean = −2.16). After one year of ZOL therapy, T-scores improved by a mean of +0.55 (range, −0.40 to +3.90; P = 0.0042). This corresponded to a mean increase in BMD of +25.5% (range, −19.0% to +134%). Similar evaluation in the hip showed baseline T-scores of −3.50 to −1.00 (mean = −1.88). The mean change in T-score was +0.27 (range, −0.60 to +2.00; P = 0.0046) corresponding to a mean increase of +14.4% (range, −54.5% to +163%). One pt developed chronic lymphocytic leukemia while on study whereas no other pt showed progression to myeloma or a related B-cell disorder. No pt developed osteonecrosis of the jaw or a significant adverse renal event. During the study, no pt developed a new fx. This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves BMD in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fxs in this high risk population.

Previously, we and others have shown that bortezomib overcomes chemotherapy resistance in multiple myeloma cells. We recently published a Phase I trial that established the maximum tolerated dose (1.0 mg/m2 of bortezomib on days 1, 4, 8, and 11 with melphalan 0.1. mg/kg PO daily on days 1–4 of a 28-day cycle) for this combination and suggested its clinical activity in relapsed or refractory MM. The anti-MM activity of melphalan is dependent upon reactive oxygen species (ROS) and free glutathione (GSH) reduces intracellular ROS. Ascorbic acid (AA) reduces free GSH levels; and thus, should enhance the anti-MM activity of melphalan as our laboratory has recently demonstrated both in vitro and in vivo (Campbell et al. Brit J Haematol 2007). Therefore, we conducted a single-arm multi-center phase II study that evaluated the combination of bortezomib, ascorbic acid and melphalan (BAM) regimen in newly diagnosed pts with symptomatic myeloma. Treatment consisted of a 28-day cycle of bortezomib administered at a dose of 1.0 mg/m2 on days 1, 4, 8, and 11, and on days 1, 2, 3, and 4 oral AA at a dose of 1 g and oral melphalan 0.1 mg/kg were given. Based on preclinical studies suggesting potential inhibitory effects of AA on bortezomib’s anti-MM activity, bortezomib was administered in the morning and AA with melphalan in the evening. Pts were treated to maximum response plus two additional cycles or completed eight cycles of therapy without disease progression. These pts were eligible to be subsequently treated with bortezomib at a dose of 1.3 mg/m2 every other week until progressive disease occurred. Thirty-five pts, at a median age of 70 years (range, 50–90 years); have been enrolled in this study. To date, 27 pts are evaluable with a median survival of 12 months (range, 2 to 19+ months). Responses occurred in 17 of 27 pts (63%), including four complete responses (15%), two very good responses (7%), four partial responses (15%), and seven minimal responses (26%). Eight pts (30%) had stable disease. Thus, disease control was achieved in 25 (93%) pts. Six of the 27 pts have shown progressive disease after 2–13 months of treatment. Eleven pts experienced ≥ grade III adverse events with only one patient demonstrating a grade IV toxicity (shortness of breath). Six of these adverse events were judged not to be related to the study medications including the only grade IV event. The most common grade III adverse events included reversible neutropenia (4 events), neuropathy (2 events) and reversible thrombocytopenia (2 events). Only 11 pts had some form of increased neuropathy from baseline (Grade I (n=7), Grade II (n=2), and Grade III (n=2) with one of those pts starting with a Grade I). The peripheral neuropathy was reversible. BAM represents a steroid and IMID-free regimen with a high response rate (63%) as frontline therapy for MM pts. Importantly, this regimen was well tolerated with few significant adverse events. Treatment-related neuropathy was reported but reversible in all but one case. Thus, BAM has proven to be a promising new regimen for the first-line treatment of pts with MM.

Background: Multiple myeloma (MM) is a highly radiosensitive B-cell malignancy and radiation therapy is an effective treatment for these patients. Recent preclinical studies have demonstrated that the bone-seeking radionuclide, Samarium Sm153 lexidronam (Sam) in combination with the proteasome inhibitor, bortezomib (Velcade [Vel]), can synergistically inhibit proliferation of myeloma cell lines in vitro and reduce MM growth in mice bearing murine MM without significant myelotoxicity. These results provide the basis for a new targeted therapeutic approach for refractory and relapsed MM patients involving combining Vel with Sam to improve the anti-MM effects of these agents without increasing their toxicity. Aims: The primary objective of this dose escalation Phase I study is to determine safety and tolerability as well as the response rate as determined by Blade criteria of Vel + Sam treatment for patients with relapsed or refractory MM. Methods: MM patients who had failed ≥2 prior treatments will be enrolled on this Phase I dose-escalation trial which involves six cohorts with three patients each. Previous treatment with Vel is allowed. Dose escalations in parallel arms are as follows: A complete treatment cycle is 8 weeks, and patients are to receive a maximum of 4 cycles. Vel is given on days 1, 4, 8 and 11 followed by a 45-day rest period. Sam is administered only on day 3. The cycle is repeated on Day 57 if disease is stable or improved and platelets and neutrophils recover to at least Grade 1 toxicity (may be delayed for up to four weeks). Dose limiting toxicity (DLT) is defined as cycle 1 Grade 4 hematologic or Grade ≥3 non-hematologic toxicity. Results: Eighteen patients have been enrolled to date in cohorts 1 through 5. Three patients have been treated in cohorts 1, 2, 4, and 5, and 6 patients have been entered in cohort 3. Fifteen patients are evaluable for response and the other 3 patients have not yet completed a treatment cycle. Of 15 evaluable patients, 3 patients including one Velcade-refractory patient have shown responses [immunofixation+ complete response {IF+ CR} (n=2) and minor response (n=1)], 3 have stable disease, and 9 patients showed progressive disease. One Velcade-refractory patient with progressive disease initially showed a transient IF+ CR. Two patients developed transient Grade 4 thrombocytopenia. One of these episodes occurred during Cycle 1 in a patient in cohort 3; and, as a result, cohort 3 has been expanded to a total of 6 patients. Four patients showed transient Grade 3 neutropenia. Only two patients showed treatment emergent neuropathy one of which resolved while on study. To date, seven patients remain on study and one patient has completed 4 cycles of therapy. Conclusions: Early results from this dose escalation Phase I trial evaluating the combination of Vel and Sam are encouraging and demonstrate responses in relapsed and refractory MM patients. The trial continues to enroll subjects. Updated results from this study will be presented at the meeting. Arm 1 Arm 2 Sam Vel Sam Vel Cohort 1 0.25 mCi/kg 1.0 mg/m2 Cohort 4 0.25 mCi/kg 1.3 mg/m2 Cohort 2 0.5 mCi/kg 1.0 mg/m2 Cohort 5 0.5 mCi/kg 1.3 mg/m2 Cohort 3 1.0 mCi/kg 1.0 mg/m2 Cohort 6 1.0 mCi/kg 1.3 mg/m2

Pleiotrophin (PTN), an 18 kD heparin-binding protein, has been found to be expressed in some solid tumors whereas it has not been previously evaluated in hematologic malignancies. Constitutive expression of PTN promotes tumor expansion and may increase metastatic potential. This protein binds to syndecan-1 (CD138) and stimulates angiogenesis. Its role in multiple myeloma (MM), thus far, has not been evaluated. Recently, we showed that PTN was strongly expressed in MM cell lines and malignant plasma cells from fresh bone marrow samples but not in normal control bone marrow specimens. Since PTN has been shown to be elevated in the serum of some solid tumor patients, we determined whether PTN may be elevated in the serum of MM patients, and correlated these levels with the patients’ disease status. By using a highly sensitive and specific enzyme-liked immunosorbent assay (ELISA) for PTN, we tested 270 different serum samples [MM (n=194), MGUS (n=18) and age-matched healthy control subjects (n=58)]. Serum samples from MM patients were obtained at the time of diagnosis as well as during the course of their disease. Serum PTN levels were higher in MM patients than in the control subjects (median=1.44 ng/ml vs 0.42 ng/ml, p

BACKGROUND: Zoledronic acid has demonstrated efficacy and safety in the treatment of bone lesions in patients with multiple myeloma. However, bisphosphonates are known to have dose-dependent and infusion rate-dependent effects on renal function and patients with multiple myeloma may have disease-associated compromise of renal function. The pharmacokinetics (PK), pharmacodynamics (PD), and safety of monthly intravenous (IV) infusions of zoledronic acid (4, 8, and 12 mg) were investigated in a subset of patients with multiple myeloma as part of an open-label, phase I, multiple-dose study. Doses higher than the approved 4-mg dose were infused over 1 or 2 hours based on an infusion-rate model that predicted a Cmax similar to that of the approved regimen (4 mg via 15-minute IV infusion). Moreover, levels of tumor markers were measured to assess potential clinical antitumor activity at various dose regimens. METHODS: Patients received a total of 6 infusions of zoledronic acid in 28-day cycles: 4 mg via 15-minute infusion on day 1; 8 mg via 60-minute infusion on days 29 and 57; 12 mg via 120-minute infusion on days 85 and 113; and 4 mg via 15-minute infusion on day 141. RESULTS: Ten patients with multiple myeloma were enrolled, and 7 completed all 6 infusions. Median age was 58 years, ECOG performance status was ≤ 1 in 9 patients and 2 in 1 patient; 80% had received prior antineoplastic therapy, and 100% had received prior radiation and/or surgery. Three patients discontinued because of abnormal laboratory values (n = 2) or withdrawal of consent (n = 1). The most common AEs were fatigue (60%), myalgia (50%), arthralgia (40%), and nausea (40%). Increased serum creatinine > 0.3 mg/dL over baseline prompted a dose delay/reduction in 1 patient and discontinuation of treatment in 2 patients. In multiple myeloma patients, mean Cmax (± SD) was 329 (± 89) ng/mL after the first 4-mg dose infused over 15 minutes (1st infusion), 407 (± 105) ng/mL after the 2nd 8-mg dose infused over 60 minutes (3rd infusion), and 385 (± 114) ng/mL after the 2nd 12-mg dose infused over 120 minutes (5th infusion). Increasing doses produced proportional increases in drug exposure (AUC). Decreases from baseline were observed in serum markers of bone resorption; however, there were no consistent or meaningful changes in tumor marker levels (eg, serum IL-6). CONCLUSIONS: This study indicates that by prolonging infusion times to 1 hour and 2 hours using 8-mg and 12-mg doses of zoledronic acid, respectively, Cmax can be maintained and is similar to that obtained with the approved 4-mg dose infused over 15 minutes.

Background: Both arsenic trioxide and bortezomib as single agents have shown efficacy for patients with relapsed/refractory multiple myeloma (MM). Recently, we have demonstrated synergistic anti-MM effects when these two agents are combined to treat human MM in SCID mice and evaluated in in vitro studies. In addition, we and others have also shown that the addition of ascorbic acid (AA) sensitizes MM cells to the cytotoxic effects of arsenic trioxide both through in vitro and in vivo studies. Thus, the objective of the current Phase I clinical trial was to assess the safety and tolerability of bortezomib + arsenic trioxide + AA treatment for patients with refractory/relapsed MM. Methods: A treatment cycle comprised of intravenous injections of arsenic trioxide, bortezomib and AA on days 1, 4, 8, and 11 followed by a 10-day rest period every three weeks. Bortezomib was given at one of three dose levels (0.7, 1.0, or 1.3 mg/m2), followed by arsenic trioxide at one of two doses (0.125 or 0.25 mg/kg) intravenously followed by AA (1000 mg). Patients were treated for a maximum of eight cycles and were eligible for maintenance therapy with the same treatments given once every other week. Results: Eighteen patients have been enrolled to date, with three patients enrolled in each of the six cohorts. Patients had received a median of three prior therapies (range, 1–6), and five patients had received prior bortezomib therapy. Fifteen patients are evaluable for efficacy to date, and response data are summarized in Table 1. Overall, among the 15 evaluable patients, seven patients responded (2 PR, 5 MR), three patients showed stable disease, and five patients progressed. Among the six patients (in cohorts 1 and 4) enrolled at the lowest (0.7 mg/m2) bortezomib dose level, only one achieved a MR whereas among the nine evaluable patients enrolled at the higher (1.0 and 1.3 mg/m2) bortezomib dose levels six patients responded (2 PR, 4 MR). In general, the regimen was well tolerated. One patient in cohort 3 was removed from study during the first cycle because of the development of an asymptomatic arrhythmia which resolved spontaneously. Other serious adverse events included pneumonia in two patients, chest pain, and abdominal pain (one patient each). Conclusion: These early results from this Phase I/II study indicate that the combination of bortezomib, arsenic trioxide and ascorbic acid has efficacy and is well tolerated in a heavily pretreated population of patients with relapsed or refractory MM. Because of these encouraging clinical results, we plan to further evaluate this combination in a larger group of patients with relapsed/refractory myeloma. Table 1. Dose escalation scheme Cohorts Arsenic trioxide Bortezomib No. of evaluable pts Response *one patient in cohort 3 went off study during cycle 1 (see above), and the other two patients (one each in cohorts 3 and 6) are too early for response evaluation Cohort 1 0.125 mg/kg 0.7 mg/m2 3 1 MR, 2 PD Cohort 2 0.125 mg/kg 1.0 mg/m2 3 1 PR, 1 SD, 1 PD Cohort 3 0.125 mg/kg 1.3 mg/m2 1* 1 PR Cohort 4 0.25 mg/kg 0.7 mg/m2 3 1 SD, 2 PD Cohort 5 0.25 mg/kg 1.0 mg/m2 3 3 MR Cohort 6 0.25 mg/kg 1.3 mg/m2 2* 1 SD, 1 MR

Introduction: Bortezomib (VELCADE®) is a proteasome inhibitor that has demonstrated durable responses as monotherapy for the treatment of pts with relapsed and refractory multiple myeloma. In vitro, bortezomib has been shown to restore melphalan sensitivity to melphalan-resistant cell lines (U266-LR7) and to synergize with melphalan in killing myeloma cells, thereby allowing the use of lower concentrations of melphalan (Ma et al, Clin Cancer Res.2003;9:1136). The objective of this dose-escalation phase I/II study was to determine an optimal dose of combination bortezomib + melphalan, starting with doses below those usually recommended for each agent for pts with refractory or relapsed multiple myeloma. Dose limiting toxicities, safety, tolerability, and activity were assesed in a dose-escalation study. Methods : Bortezomib 0.7 mg/m2 was administered by IV push on days 1, 4, 8, and 11 in combination with oral melphalan (0.025, 0.05, 0.1, 0.15, 0.25 mg/kg) on days 1–4 every 4 weeks for up to 8 cycles to 3-pt cohorts with active progressive disease. In the absence of dose-limiting toxicity (DLT), bortezomib was increased to 1.0 mg/m2 and melphalan co-administered using the original 5 escalating doses to subsequent cohorts. Results : Twenty six pts (50% male, median age 55 years, range 33–90 years) have been accrued to the study. The myeloma subtypes include IgG (16/26), IgA (4/26), IgM (2/26) and light chain only (4/26). The median ß2 microglobulin level was 5.0 mg/L (range 2.2–14 mg/L). In this heavily pretreated population (range 2–7 prior therapies), 12 patients received prior melphalan, 12 prior thalidomide, 7 prior CC-5013, 13 prior VAD, 2 prior bortezomib, and 8 prior autologous stem cell transplantation. Dose escalation has proceeded into the bortezomib 1.0 mg/m2 + melphalan 0.10 mg/kg cohort. Toxicities have been manageable. One DLT, grade 4 anemia, was observed at bortezomib 1.0 mg/m2 + melphalan 0.025 mg/kg, requiring expansion of that specific cohort. Grade 3 events were predominantly associated with myelosuppression (anemia, neutropenia, and thrombocytopenia) and were observed only among pts with baseline cytopenia. Among the 12 pts with baseline peripheral neuropathy (PN), symptoms worsened transiently in 1 pt, resolved in 1 pt, and remained stable in the other pts. Treatment-related PN (grade 1) developed de novo in 2 pts. Responses were observed in 67% (16/24 evaluable) of pts: 1 CR, 1 near CR, 6 PR, and 8 MR. The CR and near CR occurred in pts receiving bortezomib 1.0 mg/m2 in combination with melphalan .025 mg/kg. PR or better was independent of prior type of therapy and was also observed among pts who had previously received melphalan or bortezomib. Median time to progression was 1-18 mo. Six active pts out of 26 total pts remain progression-free for 2-8+ mo. Conclusion : Combination bortezomib plus oral melphalan is a promising regimen for the treatment of relapsed, refractory myeloma. The responses that were observed in pts who had previously received either drug serve as preliminary confirmation of preclinical evidence that the combination of low-dose bortezomib and melphalan has the capacity for chemosensitization and suggest possible synergy. Dose escalation with melphalan plus a fixed dose of bortezomib 1.0 mg/m2 is continuing in order to explore the full potential of this combination.