Merlini, Giampaolo

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was >15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff >30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR <15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC<40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC <40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.

SummaryThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated coronavirus disease 2019 (COVID‐19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID‐19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID‐19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID‐19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

Background and purposeHereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO‐TTR study in patients with hATTR polyneuropathy. Here, the long‐term efficacy and safety of inotersen are assessed in an ongoing open‐label extension (OLE) study.MethodsPatients who completed NEURO‐TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL‐DN) questionnaire total score and the Short‐Form 36 Health Survey (SF‐36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed.ResultsOverall, 97% (135/139) of patients who completed NEURO‐TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO‐TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL‐DN and SF‐36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.ConclusionInotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long‐term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

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.

Abstract Background: Amyloid light chain (AL) amyloidosis is caused by the deposition of misfolded light chain (LC) proteins, which may cause organ failure and death. Current treatments, which target the plasma cells that produce LC, induce organ responses in only 30% to 40% of patients. There is a substantial need for a safe and effective amyloid-directed therapy to improve recovery of organ function. NEOD001, a monoclonal antibody that targets misfolded LC, is hypothesized to neutralize circulating LC aggregates and to clear insoluble organ deposits. In an ongoing phase 1/2 study (NCT02613182; Gertz M et al. J Clin Oncol. 2016;34(10):1097-1103) in 27 patients with AL amyloidosis and persistent organ dysfunction, monthly NEOD001 infusions were well tolerated and produced no infusion-related hypersensitivity reactions. In a best response analysis of subjects who fulfilled eligibility criteria at baseline, 57% met cardiac and 60% met renal response criteria. Supported by these positive results, the current study (VITAL; NCT02312206) is a randomized, double-blind, placebo-controlled, phase 3 trial of NEOD001 in patients with cardiac AL amyloidosis. Here we present the study design for this trial in progress. Patients and Methods: Eligible patients (estimated enrollment, 236) with a diagnosis of AL amyloidosis (newly diagnosed, treatment naive) and cardiac dysfunction (N-terminal probrain natriuretic peptide [NT-proBNP] ≥650 and <8500 pg/mL, clinical signs of heart failure, left ventricular wall thickness >12 mm, or cardiac biopsy-detected amyloidosis) and with estimated glomerular filtration rate ≥30 mL/min/1.73 m2 will be randomly assigned (1:1) to receive NEOD001 (24 mg/kg q28d) plus standard of care (SOC) chemotherapy or placebo plus SOC therapy. Subjects will be stratified according to Mayo Clinic stage, renal stage, and 6-minute walk test (6MWT) distance. The primary end point is a composite, evidence-based measure consisting of all-cause mortality or cardiac hospitalization. Key secondary end points include cardiac response measured by NT-proBNP (as defined by Comenzo RL et al. Leukemia. 2012;26(11):2317-2325) and change in 6MWT distance, Short Form-36 Health Survey response, Neuropathy Impairment Score-Lower Limb and renal response (as defined by Palladini G et al. Blood. 2014;124(15):2325-2332). Disclosures Liedtke: Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Merlini:Takeda and Janssen-Cilag: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Comenzo:Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Array Biopharma: Consultancy; Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Corcept: Consultancy; Aduro: Consultancy; Prothena: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Gertz:Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.