Terpos, Evangelos

ABSTRACT Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN‐related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m 2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30–59, 15–29, and < 15 mL/min/1.73 m 2 , respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard‐risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.

Abstract Introduction: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved in the United States (US) and Europe as a monotherapy for triple-class refractory adult patients with relapsed or refractory multiple myeloma (RRMM). This hypothesis-generating post-hoc analysis of DREAMM-2 trial (NCT03525678) data examined relationships between corneal exam findings (superficial punctate keratopathy and/or microcyst like epithelial changes), best-corrected visual acuity (BCVA), and direct patient-reported ocular symptoms per the Ocular Surface Disease Index (OSDI) questionnaire. This approach could provide insight into the relationship between corneal exam findings, BCVA, and ocular symptoms and their impact on quality of life to help determine if BCVA decline and symptoms could guide dosing. Currently, in the US, eye exams with eye-care professionals (ECPs) are required for each belamaf treatment, which can add to patients' therapy-related burden. Identifying a surrogate marker for results from corneal exam findings would help providers determine if dosing adjustments are necessary. Methods: Eye exams (including a corneal exam and BCVA assessment using the Snellen chart) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ECPs at baseline (BL) and before each dose, administered q3w. Corneal exam findings (keratopathy) and BCVA were assessed per protocol-defined criteria, and grade (GR) assessment was based on the worst finding in the worse eye. BCVA and keratopathy grading were relative to BL. Patient-reported ocular symptoms and vision-related functioning, as per the OSDI, were used to evaluate the impact of treatment-related ocular toxicity. The OSDI is a patient-reported outcome questionnaire that assesses eye symptoms and effects on vision-related function in the past week and was performed in all patients before each belamaf dose. Items 1-5 address the frequency of eye-related symptoms (eg, painful or sore eyes, blurred vision) while items 6-9 address the frequency of functional limitations (eg, driving at night or reading). OSDI was considered positive, clinically meaningful, and potentially associated with treatment when at least one question 1-5 (ie, sensitivity to light, gritty or painful eyes, blurred or poor vision) was reported as experienced "all of the time" and at least one question 6-9 (ie, driving at night, reading, working with PC, or watching TV) was reported as experienced "most of the time." Results: Overall, GR 3-4 (severe) keratopathy was observed only 5% of the time in patients who did not report frequent ocular symptoms as measured by the OSDI questionnaire (no items 1-9 ≥ "most of the time"). A further breakdown of the questions revealed that, in patients who reported no items 1-5 "all of the time" AND no items 6-9 ≥ "most of the time" (OSDI negative), GR 3-4 keratopathy was observed only 6% of the time (Table). When considering individual OSDI items, in patients who reported "no deterioration from BL" for any of the OSDI eye-related symptoms or functional limitations, GR 3-4 keratopathy was observed ~3%-7% of the time while GR 0-2 (mild) keratopathy was observed ~23%-34% of the time. Similar results were observed in patients with BCVA ≤20/30 at BL who reported "no deterioration from BL" for any eye-related adverse events (AEs) or functional limitations (GR 3-4 keratopathy: ~2%-6% of the time; GR 0-2 keratopathy: ~19%-28% of the time); patients with worse visual acuity at BL (BCVA &gt;20/30) who reported "no deterioration" for items 1-9 had lower incidence of GR 3-4 and GR 0-2 keratopathy (~0%-1% and ~3%-8%, respectively). Conclusions: The results from this hypothesis-generating post-hoc analysis suggest that hematologists/oncologists may be able to use clinical indicators/tools (eg, ocular symptoms, the OSDI tool) as potential surrogate markers for eye exam results to help determine whether dosing changes are needed. This approach will be explored in trials with other belamaf dose regimens that are currently under evaluation. If the results are validated, it may be possible for hematologists/oncologists to manage belamaf dose modifications, due to ocular AEs, without a confirmatory eye exam by the ECP, reducing the patient burden. Funding Source: GSK (205678). Drug linker technology licensed from Seagen; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Badros: GlaxoSmithKline: Research Funding; BMS: Research Funding; Janssen: Research Funding; J&J: Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Rodríguez-Otero: Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Cohen: BMS: Research Funding; GlaxoSmithKline: Other: Personal fees and other association with, Research Funding; Novartis: Research Funding; Celgene: Honoraria, Other: Personal fees and other association with; Janssen: Honoraria; Kite Pharma: Honoraria; Oncopeptides: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Manier: Regeneron: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, 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, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees: Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay: 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; Janssen: 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; Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Martin: Janssen: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Farooq: Five Prime Therapeutics/Amgen: Consultancy; GlaxoSmithKline: Consultancy. Jeng: OysterPoint: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Eyegate: Current equity holder in publicly-traded company. Chng: Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Novartis: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy; Antengene: Consultancy; Pfizer: Consultancy; Aslan: Research Funding. Lee: Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Berdeja: BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Celularity: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend Biotech: Consultancy; SecuraBio: Consultancy; EMD Serono: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Bluebird bio: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; Sanofi: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Lilly: Research Funding. Jadhav: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Tosolini: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Palumbo: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dimopoulos: Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Lonial: Merck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Trudel: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen Canada: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Karyopharm: Honoraria. Richardson: Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Introduction: Lenalidomide is increasingly used for the treatment of newly diagnosed multiple myeloma. However, most patients experience relapse during treatment or after prolonged exposure to lenalidomide, therefore, there is an emerging unmet need for new, highly efficacious lenalidomide-sparing regimens at relapse. CANDOR is an ongoing phase 3 randomized clinical trial (RCT) that compares the lenalidomide-free KdD regimen with carfilzomib 56mg/m2 twice-weekly with dexamethasone (Kd) in patients with relapsed and/or refractory multiple myeloma (RRMM). Based on the primary analysis, KdD was associated with a 37% reduction in the risk of progression or death compared to Kd (HR: 0.63, p=0.001).(Dimopoulos et al. 2020 Lancet) Besides the trial-based comparator Kd, DVd is considered as an additional relevant comparator. DVd is the most similar lenalidomide-free triplet regimen comprising a proteasome inhibitor, daratumumab, and dexamethasone. DVd was assessed in the phase 3 CASTOR RCT and demonstrated superior PFS versus 8 cycles (24 weeks) of bortezomib in combination with dexamethasone (Vd) (HR: 0.31, p&lt;0.001).(Weisel et al. 2019 ASH) In the absence of a direct head-to-head trial comparing these treatments and an assessment suggesting that network meta-analysis is not feasible, matching-adjusted indirect comparisons (MAIC) were used (Signorovitch et al. 2010) to assess the efficacy of KdD relative to DVd. MAIC leverages all available data and compares outcomes across balanced populations. Method: Baseline characteristics and PFS data from the CANDOR and CASTOR trials were used in the analyses. Outcomes were compared in three steps. First, after aligning patient selection criteria of both trials, KdD patients in CANDOR were matched to the average characteristics of DVd patients in CASTOR using matching-adjusted indirect treatment comparisons methodology. The matching variables reflected tumor stage, disease burden, and treatment history, and were generally consistent with validated prognostic markers used in stratifying patients into different risk groups. Second, the published Kaplan-Meier PFS curves for DVd were digitized to generate virtual patient-level data that reconstructed the curves. Third, Cox regression models were fitted to the matched CANDOR data and the reconstructed virtual patient-level CASTOR data to estimate the efficacy of KdD versus DVd. The outcome measure was the hazard ratio (HR) for PFS. Outcomes were also compared for the first 24 weeks and for the period beyond 24 weeks to assess the impact of stopping Vd in DVd after 24 weeks on the HRs. Scenario and subgroup analyses were conducted to assess the robustness of results. Results: KdD patients in the CANDOR trial who were proteasome inhibitor-refractory (n=102) were removed from the data so that the KdD population was aligned with that of DVd in the CASTOR trial. Following the matching procedure, the effective sample size for KdD reduced to 82. In matched populations, PFS at 12 months was 73.1% for KdD and 59.9% for DVd. The MAIC results showed that treatment with KdD decreases the risk of progression or death versus DVd, with an overall HR of 0.61 (95% CI: 0.45-0.82). The time-dependent analysis demonstrated similar PFS for the two treatments for the first 24 weeks and a larger benefit for KdD over DVd after 24 weeks. Similar results were obtained in scenario analyses; in bortezomib-exposed patients the overall HR was 0.46 (95% CI: 0.33-0.64). Conclusions: After adjusting for cross-trial differences, KdD was associated with a significant reduction in the risk of progression or death compared with DVd. Although based on an approach in agreement with methods guide, the results are associated with inherent limitations due to the decreased sample size for KdD, and due to known (longer follow-up for DVd, different duration of proteasome inhibition) or unobserved differences in the trials (potential unobserved heterogeneity in patient characteristics). A comparison of overall survival was not considered due to immature data in CANDOR. The results are in line with those of the head-to-head ENDEAVOR trial that directly compared carfilzomib with bortezomib (HR for PFS for Kd vs Vd 0.53; 95% CI: 0.44-0.65) supporting the clinical validity of this study. The present analysis suggests that KdD improves outcomes compared with DVd in patients with RRMM and may provide a rationale for a preferential treatment. Disclosures Weisel: Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Nooka:Sanofi: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive Technologies: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Terpos:Janssen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Spencer:AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; Celgene, Janssen and Takeda: Speakers Bureau. Goldschmidt:Merck Sharp and Dohme (MSD): Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Incyte: Research Funding; Mundipharma GmbH: Research Funding. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. DeCosta:Amgen Ltd: Current Employment, Current equity holder in publicly-traded company. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yusuf:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Kumar:Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Tenebio: Other, Research Funding.

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl < 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

8095 Background: Multiple myeloma (MM) remains incurable and invariably relapses after initial therapy. There is no uniform approach to management of relapsed MM and is dictated by type of initial therapy and the response seen, and availability of new drugs. The outcomes associated with current approaches have not been systematically examined. Methods: We enrolled 383 patients (pts) with myeloma who had a documented relapse between Jan 2007 and June 2010, including 220 from Europe, 106 from Asia, and 31 from South America and 26 from North America. Time Zero (T0) was defined as date of treatment after first relapse. Results: Across the study, 61% were male and 49% were over 65 years at T0. ISS stage distribution at diagnosis included 26, 40 and 33% of patients in stages 1, 2 and 3, respectively. Among regimens used at first relapse; bortezomib (Btz) containing regimens were most common (54%), followed by lenalidomide (Len, 25%) and cyclophosphamide (21%). The overall response rate (>=PR) to first therapy after relapse was 58% including 14% with a CR. There was a progressive decrease in the response rates with successive regimen; 45%, 30% and 15% for regimens 2, 3 and 4 respectively. Len use was considerably lower in the Asian cohort, while Btz use was comparable across the regions. The median PFS from T0 was 13 mos and OS was 35 mos, for the entire cohort. The PFS to first salvage regimen was similar across the regions, while OS was shorter for the Asian and South American cohorts. In a univariate analysis, ISS stage 3, presence of cytogenetic abnormalities, history of plasma cell leukemia or extramedullary disease (EMD), bone marrow PC% > 33% and presence of renal insufficiency were all associated with a shorter PFS as well as shorter OS (P<=0.01). In a multivariate model, ISS stage 3 and presence of EMD were most associated with short OS. Conclusions: Median PFS for current second line regimens, typically containing Btz or Len appear to be 1 yr with an OS from first relapse of about 3 yrs. The OS from first relapse is nearly double that seen in a cohort of patients in first relapse prior to introduction of new drugs. Clear-cut regional differences can be seen in terms of patterns of drug use and likely reflect drug availability and healthcare costs.