Kumar, Shaji

Abstract Abstract 1859 Genome wide RNA interference studies identified Aurora Kinase (AURK) A and B as lethal targets in Multiple Myeloma (MM) while suppression of these genes also sensitized MM to bortezomib (BTZ). MLN8237 is an oral inhibitor of AURKA. We therefore conducted a Phase I clinical trial of MLN8237 in combination with BTZ. The study enrolled a total of 19 patients at 5 institutions. 9 patients are still receiving active treatment as of the date of this report. Study Design: The phase I portion of this study uses a standard 3+3 design to determine the maximum tolerated dose (MTD) of MLN8237 and BTZ in patients with relapsed/refractory MM. Eligibility required a minimum of 1 and maximum of 4 lines of prior therapy. Patients who have received prior BTZ therapy were allowed on trial as long as they did not progress during prior BTZ or ≤ 60 days of therapy discontinuation. The following laboratory values were required £7 days prior to registration. ANC3 1000/mL, Hgb ≥9 g/dl, PLT3 100,000/mL, Total bilirubin £1.5 × upper limit of normal (ULN), Creatinine £ 2.5 × ULN, a baseline LVEF ≥45%. Patients were required to be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration. Treatment Overview: The first 3 patients received MLN8237 at 25 mg po days 1–14 and BTZ at 1.3 mg/m2/dose iv. days 1, 4, 8, 11 on a 28 day schedule. Based on data from other concurrent trials an amendment changed dosing of MLN8237 to 20, 30, 40 or 50 mg po twice daily on days 1–7 and BTZ was given at 1.5mg/m2 iv weekly on a 28 day schedule. Results: Median age of patients was 64, 63% were male, 31% had high risk genetics, 84% had prior stem cell transplant, 53% of patients were relapsed and 47% were relapsed and refractory to therapy. No DLTs were observed even at the highest dose level tested. However, one patient at the highest dose level required a platelet transfusion in order to initiate treatment on time in Cycle 2. Thus, a further 3 patients accrued at the highest dose level before declaring the MTD and proceeding to phase II. The highest dose level (Dose Level 3: MLN8237 50 mg po twice daily on days 1–7; BTZ 1.5 mg/m2 iv. given on days 1, 8, 15, 22) was the final dose level tested (the MTD of single agent MLN8237 is 50mg as defined in other Phase I trials). The ORR was 26% (1 CR, 4 PR); when minor responses are included the ORR was 52%. Median follow up was 4.3 months (range 0.9–23.4) and PFS was 5.5 months. At last follow up 12 patients showed no progression and 7 had progressed. Toxicity: 63% of patients experienced a grade 3AE and 5% a grade 4 AE. Grade 3 or 4 toxicity seen in more than one patient was all hematologic with thrombocytopenia and neutropenia being common. Other toxicity of any grade regardless of attribution occurring in more than 20% of patients included neuropathy 63%, fatigue 63%, diarrhea 53%, nausea 47%,vomiting 26%, infection 32%, alopecia 21%, Conclusions: The MTD of the combination is MLN8237 50 mg po twice daily on days 1–7 and BTZ at 1.5mg/m2 iv weekly. Phase II testing is underway and updated results will be presented. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Vij:Millennium: Speakers Bureau. Hofmeister:Celgene: Advisory board Other, Honoraria.

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Myeloma remains incurable due to a stem cell/proliferative component that responds poorly to standard treatments. We have shown that aberrant IL-1beta stimulates the generation of paracrine IL-6, a central myeloma growth factor. A Phase II trial was completed using IL-1 receptor antagonist (IL-1Ra/Anakinra), which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with SMM/IMM. SMM/IMM patients are most likely to benefit from anti-cytokine therapy in order to delay/prevent the development of active myeloma. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of IL-1Ra SQ qd for 6 months unless clinical progression occurred. Non-progressors were allowed to continue on therapy with IL-1Ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1Ra or for evidence of clinical progression; the dose was adjusted based on response/toxicity. Results: To investigate the effects of IL-1Ra and Dex alone and in combination in vitro, we co-cultured IL-1beta transduced +/− myeloma cells with stromal cells +/− dexamethasone, IL-1Ra, or both for 48 hours and quantitated the percent apoptotic cells by flow cytometry and IL-6 production by ELISA. The results showed that: 1) IL-1Ra was superior to Dex at inhibition of IL-6 but caused no myeloma apoptosis; 2) Dex induced apoptosis was inhibited by IL-6 3) Dex and IL-1Ra combined induced maximal IL-6 inhibition and apoptosis of myeloma cells. In the clinical trial, data were available on 47 patients; smoldering (79%) / indolent (21%). All patients received IL-1Ra initially and 20/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI), a marker of cell proliferation, on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP). Interestingly, in one patient treated with Dex alone for 6 months, Dex induced a decrease in the M-protein and IL-1 levels, however, the PCLI and CRP values increased. The IL-1Ra/Dex combination has resulted in stability of disease in the majority of the 47 patients; 28 continue on therapy with a median overall progression-free survival (PFS) of 37.5 months. Four of the 47 pts achieved a minor response (MR) with IL-1Ra alone, and an additional 6 pts achieved a MR/PR after addition of dex. The continuous measure of % reduction in CRP was significantly associated with time to progression (p=0.02). Similarly, those patients who had a >5% decrease in serum M protein also had a longer PFS (p<0.001). Of note, 2 patients with high PCLI values of 6.4 and 3.0, characteristic of poor prognosis, responded with a reduction in the PCLI values and continue on combination therapy for 3 and 1.5 years, respectively with stable disease. Conclusion: Agents such as IL-1Ra that specifically inhibit paracrine IL-6 production are more effective at targeting the proliferative component than apoptosis inducing agents such as Dex; the combination may be especially useful in patients that have an elevated PCLI at presentation.

Abstract Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

Abstract Abstract 3138 Background: Several recent reports have suggested that doxycycline can inhibit amyloid fibril formation in different in vitro and in vivo model systems. Doxycycline is the antibiotic of choice for infectious disease prophylaxis in patients with penicillin allergy, following autologous peripheral blood stem cell transplantation for various hematological malignancies. We examined the outcome of patients with light chain amyloidosis (AL) undergoing autologous stem cell transplantation to study the impact of doxycycline used as antibacterial prophylaxis. Patients and methods: We studied 455 patients who underwent autologous stem cell transplant (ASCT) for AL between March 1996 and December 2011. We excluded 44 patients who died of transplant related complications or did not survive beyond 100 days after transplant. Patient records were reviewed to ascertain the prophylactic antibiotic used. Survival was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. Cox proportional hazard model was used to estimate the prognostic impact of different variables. Results: The median age of the patients was 58 years (range, 26–74); 290 (67%) were male. The median estimated follow up for the entire cohort was 73 months (95% CI; 66, 79) and 314 (69%) were alive at last follow up. Doxycycline was used a prophylaxis in 106 (23%) of the patients, with most of the remaining receiving penicillin. The usual reason for using doxycycline was a history of penicillin allergy. Hematological response to transplant occurred in 377 (87%) patients, and there was no significant difference between patients receiving doxycycline prophylaxis compared with the rest. The median OS for the entire cohort was 161 months (95% CI; 101, NR). The median OS for those receiving doxycycline prophylaxis was not reached compared with 113 months for the rest (P=0.09). Looking specifically at those patients with a hematological response, the median OS was not reached for the doxycycline group compared with 161 months for the rest (P=0.04, figure). There was no difference in the OS between the groups among those with no hematological response. The impact of the prophylaxis was independent of the number of organs involved as well as organ response to SCT. Conclusions: The results of the current study appear to demonstrate a survival advantage for patients with AL who receives doxycycline prophylaxis, in the setting of hematological response from SCT. The results are consistent with the data regarding the effect of doxycycline on amyloid fibril formation. These initial findings should form the basis of clinical exploration of doxycycline as an adjunctive therapy in patients receiving other standard therapies for AL. Such a study can further clarify if use of doxycycline for longer duration can be of additional benefit. Disclosures: Kumar: Cephalon: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Merck: Consultancy, Honoraria; Genzyme: Research Funding.

Abstract Abstract 2973 Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat B-cell cancers, consists of two active components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. The required number of 3 patients completed the dosing schedule in Cohort 1 from a total of 6 patients enrolled. Two of three patients had not progressed on treatment, based on standard response criteria including the monoclonal protein, and were considered stable at week 3 and week 6 the end of the dosing regimen. Three patients were withdrawn from the study by their physicians due to disease progression before completing treatment. One of the responding patients has continued to have stable disease at week 10, a month after the end of treatment with SNS01-T. The first group of patients received 0.0125 mg/kg, approximately 1 mg per patient by intravenous infusion. The planned dose levels for the second, third and fourth groups are 0.05, 0.2 and 0.375 mg/kg, respectively. The results to date of this first in man clinical trial indicate that SNS01-T was safely administered without dose-limiting toxicities in the first group of multiple myeloma patients. The MTD has not yet been reached. (Clinical Trials.gov Identifier: NCT01435720.) Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09–061–01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Barranco:Senesco Technologies: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Taylor:Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment.

Abstract We and others previously demonstrated an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of multiple myeloma (MM) and MGUS patients, underscoring a familial component to this disease. However, MM is known to be a collection of cytogenetically distinct diseases, with 40-50% of MM cases having a reciprocal translocation involving the IgH locus on chromosome 14q32 and in many of the remaining patients, trisomies. In a small proportion of cases, both IgH abnormalities and trisomies are found in the same clone. These MM cytogenetic subtypes are associated with differential prognosis. Whether there are differences in familial risk by cytogenetic subtypes is not known. Patients with MM were recruited from the Mayo Clinic Hematology practice in Rochester, Minnesota (MN) between 2005 and 2015. Serum samples were collected from first-degree relatives and subjected to electrophoresis and immunofixation for MGUS determination. Age- and sex-specific rates of MGUS from the population-based Olmsted County, MN, prevalence study were used as expected rates for the calculation of risk ratios (RRs) for comparisons of first-degree relatives. Cytogenetic subtypes were classified by FISH testing performed in the clinic and categorized into groups defined by IgH translocation , trisomy, intermediate/ high-risk disease (t(4;14), t(14;16), t(14;20), and del17p). Further, the distribution of cytogenetic subtypes was compared between MM cases with and without evidence of MGUS in first degree relatives using Chi square tests. Analyses were also subset to MM probands diagnosed in MN. There were a total of 442 MM probands, with 1235 first-degree relatives recruited and eligible for the study. MGUS was detected in 78 relatives, for an age- and sex-adjusted prevalence of 6.1% (4.7%-7.5%). Analyses comparing prevalence of MGUS in first degree relatives to population-based rates from Olmsted County showed a 2.5-fold (95% CI=1.9-3.0) increased prevalence. When performing analyses among MN probands only (RR=2.9; 95% CI=2.1-3.8), results were similar. Of the 442 probands, 310 had FISH performed on plasma cells (identified by cIG staining; cIg-FISH) at diagnosis. Of these cases, 49% had a trisomy, 23% had an IgH translocation, and 9% had both. Although the proportion of trisomies and IgH translocations were 4-6% higher among MM probands with a relative with MGUS compared to those without, these differences were not statistically significant (Table 1). MM probands with a first degree relative with MGUS also had a similar proportion of cytogenetic subtypes that are considered of intermediate or high risk compared to those MM without a family history (26.9% vs 25.2%) (p=0.79) (Table 1). When restricted to MM probands from MN, results remained non-statistically significant (Table 1). We showed an increased risk of MGUS in first-degree relatives of MM cases, implying shared environment and/or genetics underlying this malignancy. However, we did not find an association between family history of MGUS in MM probands and the cytogenetic subtypes examined. Larger cohorts are needed to examine if a relationship exists between cytogenetic subtypes of MM and familial risk. Disclosures Kumar: Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; BMS: Consultancy.

Abstract Background: Patients with monoclonal gammopathies typically have a single clone making a unique type of monoclonal protein, one heavy chain and one light chain. In a small proportion of patients, more than one (typically two) types of monoclonal protein can be seen and differ with respect to the heavy chain or light chain or both. There is limited information on the clinical course of patients with more than one monoclonal protein identified in their serum or urine. Objectives: We report outcomes of patients with more than one monoclonal protein at our institution over the past thirty years. Patients and Methods: We queried the existing clinical database to identify all patients with at least two different monoclonal protein types identified on serum or urine studies during the course of their disease. Retrospective chart review was performed on 551 patients, who had more than one type of monoclonal protein on electrophoresis and/or immunofixation. Results: Among the entire study cohort (N=551), 461 pts (84%) had a biclonal pattern, 7 (1%) had a triclonal pattern and the remaining 83 (15%) had a monoclonal pattern at the time of initial positive study. The median age at the time of initial diagnosis was 69.7 years (range; 32-93); 359 (65%) were male. Among these, 390 were diagnosed as MGUS/BGUS, 18 with SMM, 36 with MM, 20 with WM, and rest with another lymphoproliferative disorders. The median duration between the initial detection of monoclonal protein and the emergence of the biclonal protein was 40 months for the 83 patients, who were monoclonal initially. The distributions of the dominant monoclonal proteins were GK (30%), GL (21%), MK (22%), ML (9%), AK (9%), and AL (8%). The distributions of the second monoclonal proteins were GK (27%), GL (24%), MK (16%), ML (15%), AK (10%), and AL (7%). Overall, 20 patients with a MGUS/BGUS progressed to smoldering or symptomatic myeloma, while 12 patients with an initial diagnosis of SMM progressed to MM. The median estimated follow up for the MGUS/BGUS group and those with SMM were 6.5 years (95% CI; 5, 7) and 9.8 (95% CI; 4, 13), respectively. This translates to 20 progressions over 3822 person years of follow up for the MGUS/BGUS patient group and 12 progressions over 131 person years of follow up for the SMM group. The rate of progression was ~1% per year for patients with MGUS/BGUS and the median estimated time to progression was 2.6 years for the SMM group. (Figure). In majority of patients, the dominant M spike increased with the disease progression. Conclusion: Patients with biclonal gammopathies appear to have a similar rate of progression compared to what has been historically described for MGUS/ SMM population. For the patients who progressed and received treatment, both M proteins typically responded to therapy, and during relapse, the original dominant M protein typically reemerged as the dominant M protein. Figure 1 Figure 1. Disclosures Kumar: Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

Abstract Objective: To fully contextualize the benefit of novel agents such as daratumumab (DARA) monotherapy for the treatment of patients with heavily pre-treated and highly refractory multiple myeloma (MM), it is critical to understand the real-world outcomes of this patient population on current standard of care (SOC) therapies. The objective of this study was to perform adjusted comparisons to determine the comparative effectiveness of DARA monotherapy versus real-world SOC therapies. Methods: Data for patients treated with DARA 16 mg/kg monotherapy were available from clinical trials MMY2002 (n=106) and GEN501 (n=42), while patients treated with SOC therapies were derived from the International Myeloma Foundation (IMF) chart review of patients with MM who had ≥3 prior lines of therapy and were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (n=543) (Kumar et al., ASH 2016; submitted). The pooled DARA studies demonstrated a median overall survival (OS) of 20.1 months versus 13.0 months for SOC based on the IMF cohort (Usmani et al., Blood 2016; Kumar et al., ASH 2016; submitted). The relative treatment effect of DARA versus SOC was estimated using two adjusted comparison methodologies, propensity score matching (PSM) and multivariate Cox regression analyses. Both methodologies utilized individual patient data to compare OS. Modeled covariates for the PSM were age, gender, prior lines of therapy, albumin, and refractory status to bortezomib (BOR), carfilzomib (CAR), lenalidomide (LEN), and pomalidomide (POM). PSM was performed using caliper matching with a caliper width 25% of the standard deviation of the logit-transformed propensity score, using sampling without replacement. For the regression analysis, the covariates included in the multivariate proportional hazards regression model were age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to POM and CAR, and PI/IMiD refractory status. Clustering of observations at the treatment-line level within patients was controlled for using the robust sandwich estimate for the covariance matrix, making confidence intervals (CIs) more conservative. For both PSM and regression, statistical significance testing was performed using a two-tailed p-value of <0.05, and all comparisons between treatment groups were reported with hazard ratios (HRs) and 95% CIs. Results: Prior to PSM, imbalances between the DARA and SOC groups were significant for prior lines of therapy and proportions of patients refractory to POM, CAR, BOR, and LEN. After PSM, the DARA and SOC groups were well balanced for all covariates included in propensity score calculations. After PSM, comparisons found significant improvement in favor of DARA relative to SOC for OS (HR=0.44 [95% CI 0.31-0.63]) (Figure 1). Regression analyses revealed consistent results. After adjustment for differences in all covariates included in regression between the DARA and SOC groups, results showed significant improvement in favor of DARA compared with SOC for OS (HR=0.43 [95% CI 0.32-0.59]) (Figure 2). Conclusions: Findings from both PSM and regression analyses were consistent and suggest that DARA is associated with significant gains in OS compared with SOC therapies for patients with heavily pre-treated and highly refractory MM. References: 1. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A et al. (2016) Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128 (1): 37-44. 2. Kumar SK, et al. (2016) Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. The 58th Annual Meeting of the American Society of Hematology: submitted. Disclosures Kumar: Celgene: Consultancy, Research Funding; Noxxon: Consultancy, Honoraria; Janssen: Research Funding; AbbVie: Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria. Durie:Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Su:Janssen: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Hutton:Essai Canada: Consultancy; Cornerstone Research Group: Consultancy; Janssen: Research Funding. Lam:Janssen: Employment. Tetsuro:Johnson & Johnson: Equity Ownership; Janssen: Employment.