Citations

Abstract Background Clinical practice guidelines for MM list many alternative therapeutic options with an equivalent category of evidence but lack recommendations on the best approaches for individual patient cases. To provide clinicians with expert guidance on treatment options for defined patient scenarios, we developed and updated an interactive, online decision aid that allows users to enter specific disease and patient characteristics, enter their planned treatment, and then compare their choice of therapy with those of an MM expert panel for that scenario. Here we report data from the most recent version (2015) of this tool, capturing changes in expert recommendations and treatment trends for MM over time and evaluating the impact of this online tool on clinical care. Methods Each of 3 annual updates to the tool were developed with input from a panel of 5 MM experts. The individual experts provided treatment recommendations for multiple patient scenarios across the settings of induction therapy, maintenance therapy, and therapy for relapsed/refractory MM. A series of pull-down menus allowed users to select individual patient and disease characteristics identified by experts as important to consider when making treatment choices. These characteristics included: eligibility for autologous stem cell transplantation (for induction therapy only), results of chromosome analysis (cytogenetics/FISH), ECOG performance status, risk of renal insufficiency or peripheral neuropathy, previous therapy and depth of response (for maintenance and relapsed/refractory settings), and cardiac or pulmonary dysfunction (for relapsed/refractory setting). Users were then asked to state their intended management approach for that particular patient scenario. Once completed, recommendations for that scenario from each of the experts were displayed, and users were asked to indicate the impact of the expert recommendations on their treatment choice. Results Expert recommendations spanning the continuum of care were compiled in October 2012, November 2013, and March 2015 for the 3 different MM tool updates. As for earlier versions of the MM tool, each of the experts in the 2015 update provided recommendations for 32 case scenarios for induction therapy, for a total of 160 possible induction recommendations. Comparing overall induction therapy recommendations the use of bortezomib/lenalidomide/dexamethasone was approximately 40% in both 2013 and 2015, whereas the use of carfilzomib-containing regimens increased from 5% to 17%. None of the experts chose regimens with melphalan as induction therapy in 2015. In the relapsed/refractory setting, the use of newer therapeutic approaches continued to grow especially in the setting of patients who did not respond to induction therapy or relapsed within 6 months. For example, in those with prior proteasome inhibitor (PI) therapy, the selection of carfilzomib/lenalidomide/dexamethasone by experts rose from 11% to 38% from 2013 to 2015 with pomalidomide and lenalidomide selected for 20% to 25% of cases in the most recent tool. For prior IMiD and PI, the experts selected a new combination of pomalidomide with a PI (either bortezomib or carfilzomib) and dexamethasone in 55% of the case scenarios in 2015. To date, 170 different clinicians sought guidance on more than 259 patient case scenarios using the 2015 decision support tool. In the subset of cases (n = 104) in which users reported how the tool affected their management of patients with MM, 68% indicated the expert recommendations either confirmed or changed their intended treatment (22% changed; 46% confirmed), whereas 17% indicated that there would be barriers to implementing the expert recommendations, and 5% said they disagreed with the experts' recommendations. Conclusions Expert opinions regarding optimal MM therapy continue to evolve with new evidence. Our data show that interactive online therapy decision aids that provide expert recommendations to clinicians for specific case scenarios can aid decision making and capture practice trends in this rapidly evolving environment. Preliminary data suggest that most clinicians using the online decision aid either confirmed or changed their treatment approaches for specific MM patient case scenarios based on expert recommendations. A detailed and updated analysis of expert and user data will be presented. Disclosures Kumar: Janssen: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding. Lentzsch:BMS: Consultancy; Novartis: Consultancy; Axiom: Honoraria; Janssen: Consultancy; Celgene: Consultancy. Lonial:Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Roodman:Amgen: Consultancy; Eli Lilly: Research Funding. Mortimer:AstraZeneca: Other: spouse is an employee of and has equity ownership in.

Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required to have a diagnosis of VOD by Baltimore criteria (total bilirubin > 2.0 mg/dL with > 2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.

Abstract Introduction Polycythemia vera (PV) is characterized by excessive production of erythroid cells and in most cases a point mutation (V617F) in the Jak2 cytokine signaling kinase. We investigated whether a selective JAK2 inhibitor decreased Jak2 V617F induced erythroid differentiation. Methods Wild-type and mutant Jak2 V617F genes were excised from the retroviral Jak2-mus-MSCV-neo vector (Levine et al), cloned into the lentiviral vector pLV CMV IRES2 GFP and their presence verified by DNA sequencing. Lentiviral vectors bearing the wild-type and mutant Jak2 genes or vector alone were used to transduce human peripheral blood CD34+ cells, which were then divided for plating into megacult medium for megakaryocytic colony growth and methylcellulose culture for enumeration of all other progenitor cell types. Normal cord blood HSC (CD34+/CD38−/CD90+) were clone sorted with the FACS Aria and transduced with no vector, backbone vector, wild-type JAK2 or mutant JAK2 vector in methocult media (Stem Cell Technologies Inc, GF+ H4435) +/− 300 nM of a selective JAK2 inhibitor, TG101348. Colonies were scored at day 14. RNA was isolated from the colonies (Qiagen RNeasy kit) and RT-PCR was performed with wild-type and mutant JAK2 allele specific primers. Results Transduction of cord blood HSC with the mutant Jak2 vector resulted in skewed erythroid colony formation compared to wild-type Jak2, vector alone and untransduced HSC (Figure 1; n=3). RT-PCR with murine Jak2 specific primers resulted in ~900 bp fragments corresponding to murine Jak2 from colonies transduced with the wild-type and mutant Jak2 and confirmed by sequencing, but not those from colonies transduced with the vector alone or the untransduced cells. Like the results in cord blood cells, adult peripheral blood CD34+ cells transduced with the mutant Jak2 developed a skewed developmental pattern, with far greater erythroid colony formation compared to wild-type Jak2 or vector alone. In megacult assays, CD34+ cells transduced with the mutant Jak2 had similar megakaryocytic potential as wild-type Jak2 or vector alone. Addition of TG101348 (300 nM), inhibited mutant kinase-induced erythroid colony formation (Figure 1) in 3 experiments while 100– 300 nM was inhibitory to PV (n=2 patients) HSC and progenitors. Current experiments focus on inhibition of Jak2 in a bioluminescent highly immunocompromised mouse model of Jak2V617F-induced myeloproliferation (Figure 2). Conclusion JAK2 V617F skews differentiation of HSC toward the erythroid lineage and may be inhibited with a selective JAK2 inhibitor - TG101348. Figure 1. In vitro JAK2 Inhibition. Figure 1. In vitro JAK2 Inhibition. Figure 2. Bioluminescent JAK2 V617F-induced Myeloproliferation Model. Figure 2. Bioluminescent JAK2 V617F-induced Myeloproliferation Model.

Abstract The t[4;14] simultaneously deregulates fibroblast growth factor receptor 3 (FGFR3) and MMSET in 15% of patients (pts) with Multiple Myeloma (MM). Although oncogenic, FGFR3 expression is lost in ~25% of t[4;14] pts on gene expression profiling while MMSET is always retained. The t[4;14] is highly associated with poor prognosis, furthermore FGFR3 kinase inhibitors are in Phase I trials, thus detection of t[4;14] pts is increasingly important. The Multiple Myeloma Research Consortium (MMRC) therefore evaluated 4 competing methodologies for the diagnostic detection of t[4;14]. Bone marrow (BM) samples were collected in uniform fashion from 85 pts. FGFR3 immunocytochemistry (ICC) and flow cytometry (FC) were performed at the retrieval site, while split samples were shipped to the MMRC tissue bank and processed under GLP conditions. Processed samples were analyzed by cIg-FISH and quantitative IgH-MMSET RT-PCR (QPCR) on unsorted BM and blood. Of 60 samples with sufficient plasma cells for analysis, 8 were FISH +ve [13.3%]. Low % BM plasma cells prevented successful FISH in 25% of samples reflecting large volume harvests and hemodilution. Analysis was conducted in a blinded fashion. With FISH as the gold standard for detection of t[4;14] the sensitivity and specificity of the other diagnostic tests are: BM QPCR is most sensitive (7 of 8 FISH positive detected) and specific (42/43 negatives correctly identified). QPCR on peripheral blood is ongoing. FC is more sensitive to the detection of FGFR3 protein than ICC. Correlation between FC and ICC was only 0.46. Interestingly, 6 of 7 evaluable pts here and 13/14 (92%) in an expanded analysis of FISH +ve patients also expressed the FGFR3 protein. Given the discrepancy between this finding and previously reported loss of FGFR3 expression in 25% of pts we further explored t[4;14] stability. Clonal selection/heterogeneity was determined by the % plasma cells in each pt. with an unbalanced translocation (loss of one der chromosome). In 42 t[4;14] pts, 13 (31%) had a balanced translocation(>75% of cells with a double fusion), 14 (33%) had an unbalanced translocation (>75% cells with only one signal), and 15 (36%) had a chimeric picture. This heterogeneous pattern is suggestive of an evolution towards an unbalanced translocation. Despite this survival did not differ between pts with balanced or unbalanced translocation. Conclusions: These results indicate that the t[4;14] is highly heterogeneous with respect to balanced versus unbalanced translocations, which likely evolve over time. For detection, cIg-FISH continues to be the gold standard diagnostic methodology but may be limited by low plasma cell numbers in dilute BM or during MM remission. QPCR and FC appear most sensitive and specific for presence of t[4;14] and FGFR3 protein expression respectively. Surprisingly (given prior evidence of loss of FGFR3 expression in 25% of pts) 92% of t[4;14] pts in this series expressed FGFR3 protein. # Analyzed % Positive Sensitivity Specificity FISH 60 13 - - QPCR 65 14 87.5 97.6 Flow 82 15 85.7 91 ICC 85 15 62.5 92

Abstract Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance. Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma. Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB. Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB. Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease. Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Abstract Multiple myeloma is a disease of the antibody producing plasma cells in the bone marrow. It has been characterized by frequent genomic alterations including gains and losses of chromosomes. Some of these alterations result in poor clinical prognosis. Bortezomib, a first in class proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma. To better understand how the genome wide changes observed in myeloma relate to prognosis and treatment response, we have used single nucleotide polymorphism (SNP) array technology to assess genotypes and DNA copy number at up to 100,000 genomic loci. DNA from 147 bone marrow tumor biopsies collected in multi-center phase II and III clinical trials of relapsed multiple myeloma patients prior to treatment with Bortezomib were hybridized on SNP arrays to assess genomic aberrations. Commonly seen genomic alterations in myeloma were observed, including deletions of chromosome 13 (37%), 1p (25%), 6q (23%), and amplifications on 1q (35%). We found that 35% of this relapsed myeloma population exhibited a hyperdiploid genome characterized by gains of chromosomes 3, 5, 7, 9, 11, 15, and 19. Other notable genomic deletions included 17p (22%), 8p (27%) and 10p (16%). A correlation of response to bortezomib therapy in patients with differential gains and losses at the chromosomal level is ongoing. Consistent with previous reports, response to bortezomib was observed in patients with poor prognostic chr 13 deletions. A more in-depth analysis of specific loci associated with clinical outcome will be discussed. In summary, this data will help further define genomic aberrations in multiple myeloma and their association with treatment outcome.

Abstract Background In 2015, the FDA approved 5 new agents and/or combination regimens for the treatment of patients with relapsed/refractory (R/R) MM. In addition, new clinical data support using new regimens in the first-line setting. This rapid expansion of available treatment options has greatly increased the complexity of treatment decisions for patients in this disease setting. Clinical practice guidelines list multiple preferred treatment options for MM and can be challenging to apply to specific patients with a mixture of presenting features. Since 2013, we have developed and updated an MM online decision support tool designed to provide clinicians with expert guidance on optimal treatment for defined patient scenarios. An analysis of the tool over the years has shown that experts rapidly integrate new data and available agents into practice whereas many tool users do not. Here we report data from the most recent version (2016) of this tool, capturing the impact of the rapid expansion of new therapies on expert treatment recommendations. Methods In June 2016, a panel of 5 experts provided treatment recommendations for 688 case scenarios across 3 settings: induction, maintenance, and R/R disease. These distinct scenarios were defined by key patient and disease characteristics that the experts considered important when making treatment choices, including: eligibility for autologous stem cell transplantation, results of chromosome analysis (cytogenetics/FISH), ECOG performance status, previous therapy and response, and preexisting comorbidities. To use the tool, these patient and disease factors and the intended treatment for that specific patient were entered through drop-down menus to display the expert choices for that case. Users were then asked to indicate the impact of the expert recommendations on planned treatment. Results We compared expert recommendations from the 2 most recent versions of our MM tool, compiled in March 2015 and June 2016, to assess the impact of the new data and FDA approvals on treatment patterns. The experts are generally not recommending these agents as induction or maintenance therapy. Three out of 5 experts recommended carfilzomib/lenalidomide/dexamethasone as induction therapy for preexisting peripheral neuropathy (PN) and 1 expert recommended ixazomib-based regimens as induction and maintenance therapy for patients with high-risk cytogenetics and both renal insufficiency and PN. The new agents did have a substantial impact on expert recommendation in the R/R setting. In the 2016 tool, the type of previous therapy was the primary factor affecting expert selections, whereas the number of previous lines of therapy (1-3 vs >3) had minimal impact in the R/R setting. For example, in patients refractory to previous proteasome inhibitor (PI) therapy, regimens containing either elotuzumab (30%) or daratumumab (25%) were selected frequently by experts with pomalidomide-containing regimens recommended in another 40% of these specific cases. In the 2016 tool, the use of lenalidomide/dexamethasone alone without a newly approved agent was not recommended by any expert in the R/R setting, although it had been recommended by experts in 25% of R/R case scenarios in the 2015 tool. For patient scenarios refractory to previous immunomodulatory drugs and PIs, the experts recommended daratumumab-based regimens in 67.5% of the cases in the 2016 tool whereas the use of carfilzomib/pomalidomide/dexamethasone fell from 45% in 2015 to 10% of the cases in 2016. None of the experts recommended regimens with panobinostat as their preferred choice in any patient scenario in either 2015 or 2016. Conclusions Expert opinions regarding optimal MM therapy continue to evolve with new evidence and FDA approvals. Our data show that newly approved therapies are having a large impact on expert recommendations for specific case scenarios in the relapsed/refractory MM setting. A detailed and updated analysis of expert and user data that captures practice trends in this rapidly evolving environment will be presented. Disclosures Kumar: Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; BMS: Consultancy; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Lonial:Merck: Consultancy; Novartis: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy. Roodman:Amgen: Consultancy. Anderson:Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: In the pivotal FIRST trial, at the pre-specified planned analysis for progression-free survival (PFS), treatment (Tx) with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) improved outcomes for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) compared with melphalan, prednisone, and thalidomide (MPT), as well as Rd for 18 cycles (Rd18; Benboubker, NEJM 2014). Rd18 was added as a third arm to investigate whether Rd continuous Tx would control progression of NDMM longer than Rd18. Here, we present the final analysis of the overall survival (OS) data from the trial. Methods: Transplant-ineligible pts with NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles); both Rd18 and MPT were 72 weeks in duration. The primary endpoint was PFS and the key secondary endpoint was OS; the primary comparison was Rd continuous vs MPT. Other secondary endpoints included time to second therapy (TTST) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Results: At the time of cutoff for the final OS analysis (January 21, 2016), 52 of the 535 pts in the Rd continuous arm and none of the pts in the Rd18 (n = 541) and MPT (n = 547) arms continued to receive Tx. The median follow-up for surviving pts was 67.0 months (range, 0-86.8 months). In the pre-specified final OS analysis for the primary comparison, a statistically significant advantage in OS was shown with Rd continuous over MPT (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92; P = .00234; Table). OS for Rd continuous vs Rd18 was evaluated (HR, 1.02; 95% CI, 0.86-1.20). In this updated analysis, a PFS advantage continued to be seen for Rd continuous vs MPT (HR, 0.69; 95% CI, 0.59-0.79; P < .00001) and vs Rd18 (HR, 0.70; 95% CI, 0.60-0.81). Median TTST was longer for Rd continuous vs MPT (HR, 0.63; 95% CI, 0.54-0.73; Table). More pts in the Rd18 and MPT arms started second-line therapy (n = 377 and 381, respectively) compared with the Rd continuous arm (n = 299). Pts received a variety of Tx at progression, with bortezomib-based regimens the most common in the Rd continuous (n = 179; 59.9%), Rd18 (n = 208; 55.2%), and MPT (n = 170; 44.6%) arms. Pts who received bortezomib after Rd continuous or Rd18 had better outcomes than those who received it after MPT. PFS2 for Rd continuous was improved vs MPT (HR, 0.74; 95% CI, 0.64-0.85). Grade 3/4 adverse events (AEs) occurred in 86.3%, 80.2%, and 88.7% of the 532, 540, and 541 pts in the safety populations of the Rd continuous, Rd18, and MPT arms, respectively; the most common grade 3/4 AEs were neutropenia (29.5%, 26.5%, and 44.9%) and infections (31.6%, 21.9%, and 17.2%), and no new safety signals were seen compared with earlier analyses. Study discontinuation was most commonly due to disease progression and was less common in the Rd continuous vs Rd18 and MPT arms (50.7% vs 66.9% and 61.6%, respectively). Discontinuation due to AEs was similar across the Rd continuous, Rd18, and MPT arms (12.0%, 13.1%, and 13.9%). Solid tumor second primary malignancies (SPMs) occurred in 6.0, 6.9%, and 5.9% of pts, and hematologic malignancies occurred in 0.8%, 0.4%, and 2.6% of pts in the Rd continuous, Rd18, and MPT arms, respectively. Conclusions: Rd continuous significantly prolonged PFS and OS, and improved other secondary endpoints compared with MPT in transplant-ineligible pts with NDMM. Rd continuous also showed a PFS benefit compared with Rd18, delaying the time to next Tx. PFS2 outcomes suggest that Rd does not induce resistant relapses. Few hematologic malignancies occurred in the Rd arms, and the incidence of SPMs was similar between Rd continuous and Rd18. Rd continuous remains a standard of care for transplant-ineligible pts with NDMM. Disclosures Facon: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding. Belch:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Weisel:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Bahlis:BMS: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Geraldes:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol:Janssen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. De La Rubia:Amgen, Bristol, Celgene, Janssen: Consultancy, Speakers Bureau. White:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria. Attal:janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; sanofi: Consultancy. Ervin-Haynes:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Houck:Celgene: Employment. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Multiple myeloma (MM) is a hematologic cancer that mostly affects elderly patients who are at increased risk for development of cardiac-related comorbidities due to age-, disease-, and treatment-related factors. In real world data, approximately 25-30% of MM patients are hospitalized for a cardiac event after MM diagnosis (Kistler et al. American Society Hematology 2012 Annual Meeting, poster 2916). The proteasome inhibitor, carfilzomib, is approved for treatment of patients with relapsed or refractory MM. In carfilzomib clinical trials, grade 3 or higher cardiac failure was reported for ~4% of patients (Stewart et al. NEJM 2015;372:142-52, Dimopoulos et al. Lancet Oncol 2016;17:27-38). In this retrospective analysis, we sought to evaluate the incidence rate (IR) of cardiac events in MM patients treated with carfilzomib in a real-world setting in the US and to describe differences in baseline characteristics between carfilzomib-treated MM patients who do and do not have cardiac events. Methods: Newly-diagnosed MM patients with symptomatic disease were identified in the Truven MarketScan claims database from 1/1/05 to 6/30/15 using an algorithm validated for ascertainment of MM patients in claims data (Princic et al. Blood 2015;126:4521). All carfilzomib-treated patients were included in the analysis. The first dose of carfilzomib was the index date. The baseline period was 12 months prior to the MM diagnosis date to the index date. Cardiac events (hypertension, heart failure, ischemic heart disease, arrhythmias and conduction disorders, and cardiomyopathy) were identified during baseline by inpatient (IP) or outpatient (OP) claims and after index date by primary diagnosis on IP claims (hospitalized events). Logistic regression was used to estimate baseline covariates associated with any cardiac event. Due to sample size constraints, multivariate regression was not performed. The incidence rate (IR) per 1000 patient-years (PYRs) and associated 95% confidence interval (CI) of hospitalized cardiac events during carfilzomib treatment which included 30 days after the last carfilzomib dose were calculated among patients without a history of the corresponding hospitalized event during the baseline period. Results: The cohort included 498 MM patients treated with carfilzomib; 108 (22%) patients had ≥1 cardiac event identified by both IP and OP claims and 24 (5%) had ≥1 hospitalized cardiac event. Of the 24 hospitalized patients, 14 were hospitalized during carfilzomib treatment (median days to onset = 104) and 8 were hospitalized after carfilzomib treatment (>30 days post dosing; median days to onset = 284). The median age (range) of the 24 patients with hospitalized cardiac events and those with no hospitalized cardiac claims (n=474) was 62 (37, 79) and 61 (36, 96) years, respectively (Table). Baseline medical history of any cardiac event was evident for 92% of hospitalized patients and 84% of non-hospitalized patients. Among hospitalized patients, 25% were over 75 years as compared with 13% of non-hospitalized patients. In univariate analysis, patients with baseline amyloidosis, hypertensive chronic kidney disease, and chronic kidney disease had higher odds of having a hospitalized cardiac event. No significant differences were seen in the proportion of patients with or without a hospitalized cardiac event when evaluated by line of therapy or by carfilzomib treatment regimen (monotherapy or combination). Among patients aged 75+ years, 8.7% were hospitalized, while 2.5% and 4.9% of 65-74 and 18-64 year old patients were hospitalized, respectively (Table). IR per 1000 PYRs [95% CI] among the 14 carfilzomib-treated MM patients hospitalized for any cardiac event during the carfilzomib treatment period was 89.7 (49.0; 150.5) - see Figure for IRs of specific cardiac events. Conclusions: Among carfilzomib-treated patients in a US claims database, hospitalization for a cardiac event was uncommon (~5%) and does not exceed what has been observed in MM patients. Patients at highest risk for cardiac hospitalizations had a history of amyloidosis or chronic renal failure. Additional analyses in much larger populations are needed to better understand risk factors for these events. Disclosures Chari: Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding. Aggarwal:Amgen: Employment, Equity Ownership. Mezzi:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Zhu:Amgen Inc.: Consultancy. Braunlin:Amgen Inc.: Employment, Equity Ownership. Werther:Amgen Inc.: Employment, Equity Ownership. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding.