In multiple myeloma, next generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here, we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number changes (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case. Known and novel independent prognostic markers were identified in our cohort of proteasome inhibitor and IMiD-treated patients with long follow-up, including events with context-specific prognostic value, such as deletions of the PRDM1 gene. Taking advantage of the comprehensive genomic annotation of each case, we used innovative statistical approaches to identify potential novel myeloma subgroups. We observed clusters of patients stratified based on the overall number of mutations and number/type of CNAs, with distinct effects on survival, suggesting that extended genotype of multiple myeloma at diagnosis may lead to improved disease classification and prognostication.

Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, 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. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

BACKGROUND: AL amyloidosis is a rare, progressive, and typically fatal disease caused by both soluble and insoluble (amyloid) forms of misfolded immunoglobulin light chain (LC) proteins, with no approved treatments. Production and tissue deposition of LC aggregates result in various organ system dysfunction (most commonly cardiac and renal), causing significant morbidity and mortality. NEOD001 is an investigational humanized IGg1 designed to directly neutralize soluble toxic aggregates of misfolded LCs and promote phagocytic clearance of amyloid deposits. AIM: To evaluate efficacy and safety of NEOD001 + standard of care (SOC) vs placebo + SOC in patients with AL amyloidosis by assessing time to all-cause mortality (ACM) or cardiac hospitalization (CH). METHODS: This Phase 3, double-blind, placebo-controlled study randomized 260 newly diagnosed, untreated AL amyloidosis patients (stratified by Mayo stage (Kumar et al., 2012), renal stage, & 6MWD) with cardiac involvement. Patients were randomized 1:1 to 24 mg/kg IV NEOD001 + SOC or placebo + SOC every 28 days. SOC was concomitant chemotherapy with a first line bortezomib-containing regimen. Primary endpoint (PE) was time to ACM or time to centrally adjudicated CH (CH: >90 days after first study drug infusion). Futility analysis based on 103 adjudicated events favored NEOD001 but was not statistically significant (HR 0.84, 95% CI 0.57-1.204, p=0.386). The study was terminated early and post hoc analyses were performed. To our knowledge, this study was the first randomized, placebo-controlled, Phase 3 study evaluating an amyloid-targeting agent in AL amyloidosis. RESULTS: Study arms were balanced with regard to demographics and baseline clinical characteristics. The final PE results (intent-to-treat, ITT) were consistent with the futility analysis: HR 0.835, 95% CI 0.5799-1.2011, p=0.330. Favorability of HR for NEOD001 was largely attributable to time to all-cause mortality rather than cardiac hospitalization. Study termination was the primary reason for discontinuation (majority occurring after 12 months). The 12-month study period was defined as modified ITT (mITT). Further mITT analyses by prognostic Mayo staging categories suggest benefit favoring NEOD001 for both PE (HR=0.635) and ACM (HR=0.498) in stage IV patients (n=77), who have highest risk of early mortality. Median overall survival in stage IV (mITT) was 8.3 months for placebo + SOC and was not reached (>12 months) for NEOD001 + SOC. One or more treatment-emergent adverse events (TEAEs) were experienced by 257 patients. Of the 88 NEOD001-treated patients with a serious adverse event (SAE), the majority of SAEs (95.5%) were considered not related to study drug. The most common TEAEs (fatigue, nausea, peripheral edema, constipation, and diarrhea) were similar in both arms. Overall safety results were similar within and across Mayo stages. CONCLUSION: After study termination, further calculations supported that the VITAL study as designed would not have achieved statistical significance. No statistically significant differences between NEOD001 + SOC vs. placebo + SOC were observed for the PE. Overall, the incidence, severity, and seriousness of AEs were similar in each arm, suggesting that NEOD001 was generally safe and well tolerated. Post hoc analyses suggest a potential survival benefit of NEOD001 for AL amyloidosis patients with the highest risk of early mortality (Mayo stage IV). This population has historically been the most in need of therapy to improve outcomes, therefore additional clinical studies for NEOD001 are warranted. Disclosures Gertz: Ionis/Akcea: Consultancy; Alnylam: Consultancy; Annexon: Consultancy; Physicians Education Resource: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Medscape: Consultancy, Speakers Bureau; Appellis: Consultancy; Prothena Biosciences Inc: Consultancy; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau. Cohen:Poseida Therapeutics, Inc.: Research Funding. Comenzo:Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Du Mond:Inclin, Inc.: Employment; Prothena: Consultancy. Kastritis:Genesis: Honoraria; Prothena: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Landau:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celator: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Merlini:University of Pavia: Employment. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Prothena: Research Funding; Celgene: Research Funding. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wechalekar:Janssen-Cilag: Honoraria; GSK: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kinney:Prothena Biosciences Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: named inventor on multiple patents and patent applications related to NEOD001.

Background : Rituximab (RTX) is commonly used to treat Waldenström's macroglobulinemia (WM). Treatment options are limited for patients (pts) who fail rituximab therapy. Single-agent ibrutinib (ibr) is highly active in WM and is approved in the United States and Europe for WM. In the phase 3 iNNOVATE study, ibr plus RTX resulted in significantly longer PFS and higher response rates vs RTX alone, both among TN and previously treated pts with WM (Dimopoulos MA, et al. N Engl J Med. 2018). Previous reports from the open-label, single-agent substudy showed sustained responses and a manageable toxicity profile in RTX-refractory WM, with a median follow-up of 18.1 mo (Dimopoulos MA, et al. Lancet Oncol. 2016). Follow-up data from both the randomized portion (median follow-up of 30.4 mo) and substudy (median follow-up of 38.7 mo) of iNNOVATE are presented. Methods : Pts had confirmed, symptomatic WM requiring treatment. Pts in the randomized portion (Arms A and B) with prior RTX therapy required a response (≥MR) to their last RTX-based regimen. Pts were randomized to daily 420 mg ibr (Arm A; IR) or placebo (Arm B; R) plus RTX (375 mg/m2/week IV at weeks 1-4 and 17-20). In Arm C, pts who failed to achieve ≥MR or relapsed <12 mo of their last RTX-containing therapy received daily 420 mg ibr until PD/unacceptable toxicity. Endpoints included PFS, response rates, OS, hemoglobin (Hb) improvement, time to next treatment (TTnT), pt-reported outcomes (PROs) and safety. Results : A total of 150 pts were randomized to Arms A and B (n=75/arm; Table 1). Median age was 69 y. High IPSSWM was reported in 38% of pts; 45% of pts were treatment naïve. With prolonged follow-up and a median duration of treatment of 29.5 mo with IR and 15.5 mo with R, investigator-assessed major response rates (≥PR) were 77% with IR vs 33% with R (P<0.0001); ORRs (≥MR) were 95% vs 48% (P<0.0001), respectively. With continued IR treatment, 27% of pts achieved a VGPR compared to only 3% in the R arm. Major responses with IR stayed robust independent of MYD88/CXCR genotype, with time to major response of 1.8, 2.9, and 5.7 mo for MYD88L265P/CXCR4WT, MYD88L265P/CXCR4WHIM, and MYD88WT/CXCR4WT, respectively. Median investigator-assessed PFS was not reached (NR) with IR vs 20.3 mo (95% CI: 11.6-31.3) with R (HR=0.219 [0.122-0.393]; P<0.0001); estimated 30-mo PFS was 79% vs 41%. Importantly, among pts receiving IR, 30-mo PFS estimates did not show any major differences among the different genotypes. The 30-mo OS estimate was 93% with IR vs 90% with R; 31 pts on R crossed over to IR after IRC-confirmed PD. Treatment with IR was ongoing in 73% of pts; the most common reasons for discontinuation of ibr were disease progression and pt withdrawal of consent (9% each); 35% of pts who received R were in response follow-up after the interim analysis. The AE profile in the IR arm was consistent with previous reports. Overall, grade ≥3 AEs occurred in 61% of pts in both arms. Incidence of grade ≥3 AEs was 53% during the first 12 months of treatment in the IR arm and increased 8% with longer follow up. Serious AEs occurred in 43% of IR pts vs 33% of R pts. Similarly, incidence of serious AEs was 39% during the first 12 months of treatment with IR and increased 4% with longer follow up. In Arm C, 31 pts received single-agent ibr (Table 1). Median age was 67 y. Most (71%) pts had ≥3 prior therapies; all patients were RTX-refractory and 90% had prior treatment with cyclophosphamide. High IPSSWM was reported in 42% of pts. With longer follow-up, median investigator-assessed PFS was NR (95% CI: 27.6-NR); estimated 36-mo PFS was 61%. Major response rate by investigator assessment was 77% and ORR was 90%. The estimated 36-mo OS was 84%. Improved Hb level was seen in 71% of pts. Treatment was ongoing in 52% of pts. Median duration of ibr treatment was 37.0 mo, with no major hemorrhagic or atrial fibrillation events reported. Grade ≥3 AEs occurred in 74% of pts and 39% had serious AEs. No fatal AEs were reported. Conclusions : IR showed continued superiority over R, in treatment-naïve and previously treated pts with WM, regardless of genotypic factors. Similarly, in heavily pretreated, RTX-refractory pts with follow-up >3 y, single-agent ibr was highly active and response improved over time. Alone or in combination, ibr had a manageable safety profile and no new safety signals were identified with longer follow-up. Disclosures Buske: Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Trotman:Beigene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; PCYC: Research Funding; Roche: Research Funding; Jassen: Research Funding. García-Sanz:Spanish Government: Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Honoraria; Hospira: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. MacDonald:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Seattle Genetics: Honoraria. Leblond:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sandoz: Honoraria; Gilead: Honoraria, Speakers Bureau. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Tam:Beigene: Honoraria, Other: Travel funding; Roche: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Janssen: Honoraria, Research Funding. Palomba:Seres: Honoraria, Patents & Royalties; Juno: Honoraria, Patents & Royalties; Merck: Consultancy; Pharmacyclics: Consultancy; Therakos: Consultancy. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Shustik:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kastritis:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Genesis Pharma: Consultancy; Prothena: Consultancy. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Lih:Abbvie: Employment, Equity Ownership; Abbvie/Pharmacyclics: Other: Travel, Accommodations, Expenses. Li:Pharmacyclics: Employment; Abbvie: Equity Ownership; BMS: Equity Ownership; Pfizer: Equity Ownership; Abbott: Equity Ownership; Amgen: Equity Ownership; Gilead: Equity Ownership; Biogen: Equity Ownership; Celgene: Equity Ownership; Medivation: Equity Ownership; Merck: Equity Ownership; Exelixis: Equity Ownership; Juno: Equity Ownership; Isis: Equity Ownership; Aduro: Equity Ownership; Merrimack: Equity Ownership. Salman:Pharmacyclics LLC: Employment, Equity Ownership; Abbvie: Equity Ownership. Graef:Abbvie: Equity Ownership, Patents & Royalties; Pharmacyclics: Employment, Other: Leadership, Patents & Royalties. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria.

Background: Advances in the anti-plasma cell therapy with the introduction of bortezomib-based therapies have improved the outcomes of patients with systemic light chain (AL) amyloidosis. However, patients with more severe cardiac involvement, (i.e., those with stage 3B disease defined as increased troponin levels with NT-proBNP level > 8500 pg/ml) still have a dismal prognosis with a median survival of 4-9 months. A delay in hematologic response and potential treatment related toxicities, may not allow for improvement in the outcome of these high-risk patients. Unfortunately, patients with stage 3B disease are excluded from clinical trials; their management remains a challenge and new treatment options are urgently needed. Daratumumab is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope on CD38. It acts on plasma cells that express CD38 via different mechanisms, including direct apoptotic activity and immune system mediated responses. In patients with relapsed or refractory AL amyloidosis, daratumumab monotherapy has shown rapid, deep and high response rates, which are durable. Moreover, daratumumab has shown an excellent toxicity profile and no signal of cardiotoxicity. An ongoing prospective randomized trial evaluates the addition of daratumumab to standard bortezomib-based therapy in previously untreated patients with AL amyloidosis but patients with stage 3B are excluded. In order to offer high risk AL patients a new treatment option we designed this phase 2 trial aiming to enroll exclusively patients with stage 3B disease. Study Design and Methods: This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B AL amyloidosis. Approximately 40 subjects will receive primary therapy with daratumumab. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase. A safety run-in will include 6 subjects treated with daratumumab for at least 1 cycle to establish safety of the study drug in stage 3B AL amyloidosis patients. Dosing of these 6 patients will be staggered so that no subject will receive their first dose sooner than 48 hours after the previously enrolled subject. Safety evaluation will be performed by a Data Safety Monitoring Board after at least 1 cycle is completed for all 6 patients. If no safety signal is observed, the enrollment of the rest of the patients will begin. Subjects will initially receive daratumumab IV at a dose of 16 mg/kg, and by the end of 2019 will switch to daratumumab SC at a fixed dose of 1800 mg. Daratumumab will be administered weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Each Cycle will last 28 days. The treatment will continue until disease progression according to Major Organ Deterioration Progression-Free Survival (MOD-PFS) criteria, start of subsequent therapy, or a maximum of 2 years. Patients who after 3 cycles of daratumumab monotherapy, have not achieved at least a hematologic VGPR or a hematologic PR with improved major organ function (i.e., cardiac or renal response per updated response criteria) may receive at the Investigator's discretion, bortezomib (1.3 mg/m2 weekly, for a maximum of 6 cycles) with low dose dexamethasone, in addition to daratumumab (Figure 1). The primary objective is to evaluate the overall survival (OS) rate at 6 months. The secondary objectives include evaluation of overall, VGPR and CR hematologic response rates at 3 and 6 months, MOD-PFS, PFS, organ response rate, treatment effects on patient-reported outcomes, time to and duration of response, safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis. Minimal residual disease (MRD) may be monitored in subjects who achieve hematologic CR using high sensitivity methodologies (such as the Clonoseq NGS assay, or NGF based on the EuroFlow protocol). Safety will be measured by adverse events, laboratory tests, electrocardiograms, echocardiograms, vital sign measurements, physical examination and ECOG performance status. Health-related quality of life will be assessed via patient-reported outcome questionnaires. The study will run in 3 countries (Italy, Greece, and Netherlands), and will open for enrollment in August 2019. The recruitment is expected to last for 18 months, and the maximum time of treatment under the study protocol is 24 months. Disclosures Kastritis: Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Minnema:Servier: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Palladini:Janssen-Cilag: Other: Travel grant; Sebia: Honoraria; Janssen-Cilag: Honoraria; Celgene: Other: Travel grant. OffLabel Disclosure: Daratumumab in AL amyloidosis