Abstract: Background: IRd has been approved for the treatment of RRMM based on the results of the TOURMALINE-MM1 study, (median progression-free survival [PFS] with IRd vs placebo-Rd: 20.6 vs 14.7 months). Several retrospective and prospective observational studies have shown comparable effectiveness of IRd in ≥2 nd line of therapy (LoT) in the real-world setting to that observed in the MM1 trial, with median PFS ranging from 15.6 to 27.6 months. Here we report an analysis of a large, globally representative dataset pooled from 3 observational studies to investigate the effectiveness of IRd in the overall RRMM population, by LoT, and in subpopulations of pts defined by frailty status. Methods: INSIGHT MM is a large, prospective study which has enrolled & gt;4200 MM pts from Europe, Asia, the US, and Latin America, with a planned follow-up of ≥2 years. UVEA-IXA is a multicenter, longitudinal cohort study of ~300 RRMM pts receiving ixazomib-based treatment via an early access program in Europe. It comprises a retrospective phase (chart review of the period from ixazomib initiation to enrolment in UVEA-IXA) followed by a 1-year prospective follow-up period. REMIX is a retrospective/prospective study of ~200 pts receiving IRd via a compassionate use program in France. The INSURE pooled analysis included adult pts with ≥2 prior MM therapy lines, and who had received IRd in ≥2 nd LoT. PFS was a primary outcome measure; secondary outcome measures included duration of treatment (DoT), overall response rate (ORR), time-to-next therapy (TTNT), overall survival (OS), and safety. Using the Kaplan-Meier method, time-to-event endpoints were analyzed in the overall analysis population, by LoT, and in subpopulations of pts defined by a simplified frailty score (0-1 [non-frail] vs ≥2 [frail] ). Adverse events (AEs) and discontinuations/dose reductions due to AEs, were reported separately for each study. Results: In total, 566 pts were identified in this pooled analysis (INSIGHT MM, n=181; UVEA-IXA, n=195; REMIX, n=190), with a median follow-up of 18.5 months overall. Median age at the start of IRd therapy was 68 years (range 36-92), with 21% of pts aged & gt;75 years; 17.6% of pts had an Eastern Cooperative Oncology Group performance status ≥2; pts had received a median of 2 LoT prior to IRd; 41%, 38%, and 21% of pts received IRd as 2 nd, 3 rd, and ≥4 th LoT, respectively. Of 408 pts with frailty scores recorded, 166 (41%) were defined as frail, with similar percentages (39-42%) across all LoTs. Median DoT was 14.0 months overall and decreased with increasing LoT (Table). Median PFS was 20.8 months overall, ranging from 22.1 to 11.6 months with IRd as 2 nd and ≥4 th LoT, respectively (Figure/Table). OS data are not yet mature. Among 406 response-evaluable pts, the ORR was 64.5%, being highest in pts receiving IRd as 2 nd (70.7%) vs 3 rd (63.1%) or ≥4 th LoT (52.1%). In frail vs non-frail pts, median PFS was 11.9 vs 24.0 months, while median DoT was 9.7 vs 16.1 months, respectively; consistent trends for longer DoT/PFS with earlier vs later LoTs were seen in both frail and non-frail pts (Table). Analyses of REMIX AEs are ongoing. In INSIGHT, 30%, 23%, and 18% of pts discontinued ixazomib, lenalidomide, and dexamethasone, respectively, due to AEs; 14%, 19%, and 12% reduced their respective treatment dosage to manage AEs. In UVEA-IXA, discontinuation rates were 17%, 15%, and 10%, respectively; 9%, 9%, and 1%, had dose reductions. The most common AEs leading to ixazomib discontinuation in INSIGHT and UVEA-IXA were thrombocytopenia (19 and 24%, respectively), diarrhea (9 and 18%), infections and infestations/infection (15% and 6%), peripheral neuropathy (7 and 12%), and fatigue in INSIGHT only (11%). Analyses of TTNT, OS, AEs associated with treatment discontinuations in REMIX, and additional analyses of the frail cohort are ongoing and will be presented. Conclusions: The findings from this analysis of a large, global, pooled dataset of 566 pts show that the effectiveness of IRd in routine clinical practice is consistent with the efficacy of IRd observed in TOURMALINE-MM1 (median PFS 20.8 vs 20.6 months), with no new safety concerns. Our results suggest a benefit of treatment with IRd in earlier vs later lines, consistent with reports from previous, smaller real-world studies of IRd in RRMM pts. In addition, this analysis provides important insights on the effectiveness of IRd in frail pts, helping to increase the understanding of the achievable outcomes in this subpopulation. Figure 1 Figure 1. Disclosures Leleu: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Boccadoro: Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees. Lee: Sanofi: Consultancy; Karyopharm: Consultancy; Oncopetides: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy. Zonder: Intellia: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Janssen: Consultancy; Alnylam: Consultancy. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria. Ramasamy: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Celgene (BMS): Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer oncology: 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. Hulin: abbvie: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ren: Takeda: Current Employment. Bent-Ennakhil: Takeda: Current Employment. Bouillie: TAKEDA ONCOLOGIE FRANCE: Current Employment. Cherepanov: Takeda: Current Employment, Current equity holder in publicly-traded company. Stull: Takeda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Abstract: Background Ixazomib (ixa), the first oral proteasome inhibitor, is approved in combination with lenalidomide (len)-dexamethasone in 〉 50 countries globally, including the US and EU, for the treatment of relapsed/refractory MM (RRMM) pts who have received ≥1 prior therapy. Outcomes and tolerability in routine clinical practice often differ from data reported in clinical trials for novel-agent-based MM therapies; however, data directly comparing efficacy in clinical trials with effectiveness in routine clinical practice of new MM agents and regimens are currently limited. To evaluate the effectiveness of IRd in RRMM pts in routine clinical practice, we performed a pooled analysis of individual pt-level data for IRd-treated RRMM pts from the ongoing INSIGHT MM (NCT02761187) study and from the Czech RMG. INSIGHT MM is the largest global, prospective, observational MM study conducted to date, which is currently enrolling ~4200 adult pts with newly diagnosed MM or RRMM from Europe (EUR), the US, Asia, and Latin America. The Czech RMG was established by the Czech Myeloma Group in 2007 and comprises clinical data for 〉 6000 MM pts enrolled at 19 Czech and 4 Slovak centers. Methods RRMM pts with 1-3 (INSIGHT MM) or ≥1 (RMG) prior therapies who had been treated with IRd were identified. INSIGHT MM pts required prospectively collected data on IRd therapy; pts who received another regimen or additional treatment within the same line of therapy as IRd were excluded. RMG pts from Czech centers who received IRd were included using the same eligibility criteria as the INSIGHT MM study. Individual pt-level data on demographics, disease characteristics, treatment history, effectiveness, and safety for IRd-treated RRMM pts from INSIGHT MM and the Czech RMG were integrated and analyzed. Best response and PFS were determined as per the assessment of the treating physician or local investigator, utilizing IMWG criteria. Descriptive analyses were performed on the integrated data as well as on data from INSIGHT MM and from the Czech RMG. PFS, TTNT, DOT, and OS were estimated using Kaplan Meier methodology. Results Overall, 163 IRd-treated RRMM pts from 9 countries were included in the analysis (50 INSIGHT MM, 113 Czech RMG); of these, 146 (90%) were from EUR, 16 (10%) from the US, and 1 (1%) from Taiwan. Median age was 67 (range 39-84) yrs, with 23 (14%) pts aged 〉 75 yrs; 86 (53%) pts were male. At initial diagnosis, 38%/36%/26% of pts had ISS Stage I/II/III disease; median time from diagnosis to initiation of IRd treatment was 42.6 mos; 71% of pts had ECOG PS ≥1. Most pts (65%) had IgG MM, and 14% had extramedullary disease. Overall, 50%/30%/20% of pts received IRd as 2nd/3rd/≥4th-line therapy. The most common reasons for starting IRd therapy were relapse/progression (90%), including bone lesions (53%), and anemia (14%). Overall, 61% of pts had received prior stem cell transplant; prior therapies included bortezomib (bor) in 89% of pts, thalidomide (thal) in 42%, len in 21%, carfilzomib (car) in 11%, daratumumab (dara) in 3%, and pomalidomide (pom) in 2%. Median DOT was 14.0 mos; 101 (62%) pts were on treatment at data cut-off. Data on best response to therapy were available for 105 pts; among these, ORR (partial response or better) was 74%, with 31% ≥VGPR (Table); ORR with IRd as 2nd/3rd/≥4th-line therapy was 91%/57%/47%, including 41%/25%/11% ≥VGPR. Median time to first response was 1.1 mos for Czech RMG pts; median time to best response was 3.7 mos for INSIGHT MM pts. Overall, median PFS was 20.9 (95% CI: 13.0-28.7) mos, with a 12-mo rate of 65% (Table). Median PFS with 2nd/3rd/4th/ 〉 4th-line therapy was NR/23.2/14.2/5.1 mos. Median TTNT was 26.2 (95% CI: 9.6-42.8) mos, with a 12-mo rate of 73% (Table). Overall, 37 (23%) pts received subsequent therapies including bor (24%), pom (24%), thal (16%), dara (16%), car (14%), or len (8%). Median OS was not reached, with 81% of pts alive at 12 mos (Table). Ixa and len dose reductions were required in 15% and 30% of pts, respectively, with 11% and 21% of pts, respectively, requiring dose reductions due to AEs (Table). Conclusions These findings show that the effectiveness of IRd in routine clinical practice, including an ORR of 74% and a median PFS of 20.9 mos, is comparable to the efficacy of IRd reported in the TOURMALINE-MM1 trial (ORR 78%, median PFS 20.6 mos). IRd is well tolerated in RRMM pts treated in routine clinical practice, with low rates of dose reductions due to AEs for ixa (11%) and len (21%). Table. Table. Disclosures Hajek: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: 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, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Takeda: 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; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Array Biopharma: Research Funding. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Puig:Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Leleu:Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Karyopharm: Honoraria. Berdeja:Celgene: Research Funding; Sanofi: Research Funding; Glenmark: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Bluebird: Research Funding; Teva: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Davies:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Hungria:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Boccadoro:Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding. Rifkin:McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; EMD Serono: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Sandoz: Consultancy; Amgen: Consultancy. Zonder:Takeda: Honoraria; Pharmacyclics: Other: DSMC; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Ren:Takeda Pharmaceuticals International Co.: Employment. Cacioppo:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Maisnar:Janssen: 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; Takeda: 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: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background Ixazomib, the first oral proteasome inhibitor, has been approved for 〉 3 years in 〉 70 countries, for the treatment of RRMM pts who have received ≥1 prior therapy, on the basis of the TOURMALINE-MM1 study, which reported an overall response rate (ORR) of 78% and median progression free survival (PFS) of 20.6 mos. Although outcomes and tolerability in routine clinical practice often differ from data reported in clinical trials, growing evidence suggest that outcomes in patients treated with ixazomib-based regimens are comparable to those in the Phase 3 TOURMALINE-MM1 trial. We report on an expanded pooled analysis with longer follow-up of IRd therapy from the INSIGHT MM study (NCT02761187) and the Czech Registry of Monoclonal Gammopathies (RMG) to evaluate the effectiveness of IRd in RRMM pts in routine clinical practice. Methods INSIGHT MM is a large, prospective, observational study which has enrolled over 4,200 adult pts with MM from Europe (plus Israel, EUR), the US, Asia, and Latin America, with a planned follow-up of ≥5 years. The RMG comprises clinical data for 〉 6,000 MM pts enrolled at 19 Czech and 4 Slovak centers. Eligible pts had 1-3 (INSIGHT) or ≥1 prior therapy (RMG) including an IR-based regimen. Individual pt level data on demographics, disease characteristics, treatment history, effectiveness, and safety from INSIGHT and RMG were integrated and analyzed. Best response or time to first response and PFS were determined as per investigator assessment, using IMWG criteria. PFS, duration of treatment (DOT), and overall survival (OS) were estimated using Kaplan Meier (KM) methodology, applying an exclusion criterion to account for immortal time bias (INSIGHT only). Results At data cutoff of 22 Nov 2018, 217 pts (83 in INSIGHT and 134 in RMG) from 11 countries had been included: 191 (88%) from EUR, 17 (8%) from the US, and 9 (4%) from Taiwan; 89% of pts were treated in an academic facility. At diagnosis, 32% of pts had ISS Stage III disease, 78% had bone lesions, 46% had anemia, and 12% had elevated creatinine. At study start, median age was 67 years with 12% 〉 75 years; 58%/14% of pts had ECOG performance status 1/2. The distribution of immunoglobulin (Ig) heavy and light chain MM was as expected; 69% of pts had IgG MM. Overall, 21% of pts had extramedullary disease. Prior therapies included: bortezomib (90%), stem cell transplant (60%), thalidomide (47%), lenalidomide (26%), carfilzomib (8%), daratumumab (6%), and pomalidomide (2%). Median time from diagnosis to start of IRd therapy was 42.1 mos; 43%/35%/22% of pts received IRd at 2nd/3rd/≥4th line. The most common reasons for starting IRd were relapse/progression (87%) and insufficient response (10%). The most common CRAB criteria present were bone lesions (48%) and anemia (18%). Median duration of follow-up was 12.6 mos in all pts. At data cutoff, 117 (54%) pts had discontinued IRd; median DOT was 11.9 (95% CI: 9.4-15.2) mos; at 12 mos, 49% (41.3-56.2) of pts were still on treatment (KM estimates). Data on best response to therapy were available for 152 pts. The ORR was 74%, with 36% ≥VGPR; ORR with IRd at 2nd/3rd/ ≥4th-line therapy was 82%/71%/59%, including 43%/37%/17% ≥VGPR. Median time to first response was 1.2 mos (RMG); median time to best response was 3.7 mos (INSIGHT). Median PFS was 21.6 (95% CI: 13.6-26.7) mos across all lines. PFS rate at 12 mos was 62%, and 86 (40%) pts had progressed at data cutoff. Median time to next therapy (TTNT) was 31.5 (95% CI: 24.5-35.9) mos, with a 12-month rate of 74% across all lines. Overall, 60 (28%) pts received subsequent therapies including daratumumab (22%), pomalidomide (22%), bortezomib (20%), carfilzomib (17%), lenalidomide (15%), and thalidomide (12%). At data cutoff, 53 (24%) pts had died. Median OS was 36.7 (95% CI: 24.4-NR) mos, with 79% of pts alive at 12 mos (Figure). Regarding safety, ixazomib and lenalidomide dose reductions were required in 16% and 36% of pts, respectively, including 10% and 21% who required dose reductions due to AEs. Conclusions These findings show that the effectiveness of IRd in routine clinical practice (ORR 74%, median PFS 21.6 mos) is comparable to the efficacy of IRd reported in the registrational TOURMALINE MM1 trial (ORR 78%, median PFS 20.6 mos). IRd is well tolerated with no new safety signals, and low rates of dose reductions due to AEs for ixazomib (10%) and lenalidomide (21%). Outcomes should be interpreted with caution due to limited maturity of data. Disclosures Hajek: Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding. Minarik:Celgene: Consultancy, Honoraria, Research Funding; Amgen, BMS, Janssen-Cilag, Takeda: Consultancy, Honoraria. Straub:Amgen, Takeda, Celgene: Consultancy. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Boccadoro:AbbVie: Honoraria; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Spencer:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. van Rhee:Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; EUSA: Consultancy; Castleman Disease Collaborative Network: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Thompson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties: Myeloma reviewer; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; BMS: Research Funding; Lynx Bio: Research Funding. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: 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; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cook:Karyopharm: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Abbvie: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lee:Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Puig:Takeda: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rifkin:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Patents & Royalties, Research Funding; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Skyline DX: Consultancy. Weisel:Sanofi: Consultancy, Honoraria, Research Funding; Juno: Consultancy; GSK: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. 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; 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; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Skacel:Millennium Pharmaceuticals, Inc., subsidiary of Takeda Pharmaceutical Company Limited: Employment. Elliott:Takeda: Employment. Demers:Takeda: Employment. Stull:Takeda: Employment. Ren:Takeda: Employment. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria.

Abstract: Graphical abstract [Formula: see text]

Abstract: Background Multiple groups of pts, including elderly/frail pts and those with comorbidities, are typically under-represented in randomized controlled trials (RCTs). A recent study found an average of 16 eligibility criteria per cancer trial, 60% of which were related to comorbidity or performance status (PS; Unger, JNCI 2014). Phase 3 RCTs in MM have similar extensive eligibility criteria, resulting in populations that are not reflective of RW MM pts. Data from CONNECT-MM (Shah, CLML, 2017) and CoMMpass (Fiala, IMW 2017) suggest that 22-40% of RW pts are ineligible for MM RCTs, and an analysis of US RW relapsed/refractory MM (RRMM) pts showed that only 25-47% of pts would have been eligible for the phase 3 ASPIRE, TOURMALINE-MM1, ELOQUENT-2, and POLLUX studies, based on their differing eligibility criteria (Chari, EHA 2018). Further, data from CONNECT MM show that clinical trial ineligibility is associated with poorer long-term outcome (Shah, CLML, 2017). Thus, it is important to characterize RW MM pts and understand the discrepancies vs RCT populations. INSIGHT MM (NCT02761187) is the largest prospective, observational study in MM to date, following ~4,200 pts from 15 countries. Here we analyze RCT eligibility in INSIGHT MM pts, with a focus on the treatment of frail MM pts in the real world. Methods INSIGHT MM is following newly diagnosed (≤3 mos since treatment initiation) MM (NDMM) and RRMM (≤3 prior lines) pts. Demographics and disease characteristics, including medical history, comorbidities, PS, and frailty status (per IMWG Frailty Index criteria, Palumbo, JCO 2015), are collected using electronic case report forms at study baseline visit. For this analysis, pt data were reviewed vs 20 standard RCT eligibility criteria, using a conservative approach of classifying 'not available' data as 'eligible'; laboratory/PS and medical history exclusion criteria are summarized in the Table. Presence of hypertension was reviewed but omitted, as INSIGHT MM only collected data on 'hypertension requiring treatment' vs the standard RCT exclusion criterion of 'uncontrolled hypertension'. Results Data from 3,201 pts (1,761 NDMM, 1,440 RRMM) were analyzed. The proportions of pts who would be ineligible for RCTs based on each individual parameter, and the overall rate of ineligible pts, are shown in the Table. Overall, 39.2% of pts would have been ineligible for RCTs based on not meeting at least one of the 20 standard eligibility criteria included in this analysis, including 38.8% of NDMM and 39.7% of RRMM pts. The most common criteria excluding pts overall were another prior malignancy (7.5%), CrCl ≤30 mL/min (6.4%), cardiac arrhythmias (5.4%), platelets ≤75,000/mm3 (5.1%), and hemoglobin 〈 8.0 g/dL (4.8%). Common criteria were similar in NDMM and RRMM pts, except for higher rates of CrCl ≤30 mL/min (7.3%) and hemoglobin 〈 8.0 g/dL (5.9%) in NDMM pts, and higher rates of platelets ≤75,000/mm3 (7.4%) in RRMM pts. Frail pts are particularly likely to be ineligible for RCTs based on these standard criteria. Per study team evaluation applying the IMWG Frailty Index parameters, 320/1,685 evaluable pts (19%) were determined to be frail in INSIGHT MM. Of these 320 frail pts, applying the 20 standard eligibility criteria used in this analysis, 74.7% would have been ineligible for RCTs. Of 126 evaluable frail 1st line pts, 30 (24%) and 83 (66%) received doublet and triplet therapy, respectively, with median duration of treatment (DoT; Kaplan-Meier analysis) of 5.4 and 6.2 mos. Of 48 evaluable 2nd to 4th line pts, 26 (54%) and 21 (44%) received doublet and triplet therapy, respectively, with median DoT of 4.4 and 5.3 mos. Additional analyses of treatments received, reasons for treatment discontinuation, and DoT by frailty status and RCT eligibility will be presented. Conclusions A high proportion of INSIGHT MM pts (39.2%) were RCT-ineligible, consistent with or higher than previous reports. Common reasons for ineligibility included prior history of malignancy, low CrCl, and cardiac arrhythmias; more RRMM vs NDMM pts were excluded due to low platelet count. Analysis of frail pts suggests that these pts are particularly under-represented in RCTs using standard eligibility criteria. These findings emphasize the discrepancy between RW and RCT pt populations and the importance of RW data for evaluating effectiveness of treatment options. Initiatives are also ongoing to broaden oncology clinical trial eligibility criteria. Disclosures Hungria: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Research Funding. Abonour:Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy. Rifkin:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Leleu:Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Costello:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; EUSA: Consultancy; Castleman Disease Collaborative Network: Consultancy; Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy. Weisel:Juno: Consultancy; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Puig:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Pharmacyclics: Patents & Royalties, Research Funding; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Skyline DX: Consultancy. Thompson:GSK: Membership on an entity's Board of Directors or advisory committees; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; UpToDate: Patents & Royalties: Myeloma reviewer; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Adaptive: 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; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Lynx Bio: Research Funding. Boccadoro:Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria. Zonder:Oncopeptides: 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; 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. Spencer:Servier: 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; Specialised Therapeutics Australia: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: 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, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: 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, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding. Fanning:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Armour:Millennium Pharmaceuticals: Other: Financial relationship; Janssen: Other: Financial relationship; Amgen: Other: Financial relationship; Celgene: Other: Financial relationship. Morgan:Myeloma Patients Europe, a non-profit organisation, which receives unrestricted grants from the following pharmaceutical companies: Amgen, Bristol Myers Squibb, Takeda, Janssen, Karyopharm, Novartis, Celgene and Sanofi.: Employment. Patel:Takeda: Employment. Carlson:Takeda: Employment. Ferrari:Takeda: Employment. Stull:Takeda: Employment. Ren:Takeda: Employment. Cherepanov:Takeda: Employment. Pottala:PPD, Inc., research organization contracted by Millennium Pharmaceuticals, Inc.: Employment. Chari:Sanofi: 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; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: 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; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Bristol-Myers Squibb: Consultancy.

Abstract: Background The introduction of multiple novel agents and regimens for NDMM and relapsed/refractory MM (RRMM) has improved outcomes while increasing the complexity of treatment selection and disease management. The real-world effectiveness of many novel-agent-based regimens remains to be elucidated. INSIGHT MM (NCT02761187) is the largest global, prospective, observational MM study to date. It aims to understand global NDMM/RRMM disease and pt characteristics, treatment patterns, and clinical outcomes, as well as regional variations. Here we report data for 1056 NDMM pts enrolled from July 1, 2016 to April 27, 2018. Methods INSIGHT MM is enrolling ~4200 adult pts with NDMM/RRMM (1-3 prior therapies) from 15 countries; 9 in Europe (EU), 3 in Latin America (LA), the United States (US), and 2 in Asia. Pts will be followed prospectively for ≥5 yrs. Data are collected from hospital/clinic records at baseline (MM-specific disease characteristics, prior therapies) and every 3 mos (disease management, effectiveness, safety). Results At data cut-off, 1056 NDMM pts had been enrolled from 14 countries, including 495 (47%) from EU, 361 (34%) from the US, 112 (11%) from LA, and 88 (8%) from Taiwan. Median age at enrollment was 64 (range 32-89) yrs and 139 (13%) pts were aged 〉 75 yrs (14%/12%/11%/13% in EU/US/Taiwan/LA); 57% of pts were male (60%/58%/61%/39% in EU/US/Taiwan/LA); 72%, 13%, and 8% were White/Caucasian, Asian, and Black/African American, respectively. Overall, 62% of pts were treated at academic centers and 38% in community settings. Based on accrual at data cut-off, regional differences were observed, with more pts treated at academic centers in EU/Taiwan (88%/91%) vs the US/LA (30%/25%). 87% of pts were treated outside of clinical trials (88%/82%/95%/98% in EU/US/Taiwan/LA). Bone pain (32%, including 33%/28%/40%/37% in EU/US/Taiwan/LA), weakness/fatigue (anemia; 11%, including 12%/10%/6%/18% in EU/US/Taiwan/LA), and kidney problems (5%, including 3%/3%/17%/2% in EU/US/Taiwan/LA) were the most common reasons for pts seeking care; 32% (36%/32%/22%/24% in EU/US/Taiwan/LA) were asymptomatic at diagnosis. At diagnosis, 27%/26%/31% of pts had physician-reported ISS Stage I/II/III MM, and 88% had ECOG PS 0-1; 8% of pts had hypercalcemia, 34% creatinine clearance 〈 60 ml/min, 56% anemia, and 30% 〉 3 bone lesions. The most common reasons for initiating therapy were the presence of CRAB criteria, e.g. bone involvement (54%) and anemia (37%). At start of treatment, fixed-duration therapy, treat-to-best-response, and treat-to-progression approaches were planned for 38%, 29%, and 31% of pts, respectively. The most frequently administered regimens are shown in the Table; 20%/66% of pts received a doublet/triplet. V-based regimens were the most frequently used. Regional differences in regimen selection are emerging: among IMiDs, T is most commonly prescribed in EU, Taiwan, and LA; R is more common in the US. After a median follow-up of 9.3 mos, 72 (7%) pts had discontinued the study, most often due to death (57%), consent withdrawal (14%), or change of treatment provider (11%). At data cut-off, data for 236 (22%) pts who received 1st-line ASCT were available (median age 60 yrs; 12%/63%/25% of pts aged 〈 50/50-65/ 〉 65 yrs). Of these, 64% received ASCT at academic centers; 42% of pts each in EU and the US received ASCT vs 11% in Taiwan and 4% in LA. The most frequently administered regimens in ASCT-eligible (n=429) vs ASCT-ineligible (n=571) pts were VC±d (21% vs 21%), VR±d (19% vs 17%) and VT±d (17% vs 10%). At data cut-off, 115 NDMM pts had progressed to 2nd-line therapy; 99 pts received a PI with 1st-line therapy, of whom 33 (33%) then received a PI-based regimen in 2nd line; 61 pts received an IMiD with 1st-line therapy, of whom 35 (57%) then received an IMiD-based regimen in 2nd line. Among 1st/2nd-line pts, 2%/12% received monoclonal antibody therapy. Conclusions PIs and IMiDs remain the global backbones of MM therapy, with V-based regimens most commonly used in NDMM pts, regardless of intended transplant status. These data from INSIGHT MM are beginning to elucidate regional differences in disease presentation and treatment selection, including higher numbers of pts receiving ASCT in the US/EU vs Taiwan/LA, which are likely reflective of differences in healthcare systems and access to MM treatments in the participating countries. Future studies will evaluate the impact of these regional variations on outcomes. Table. Table. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Hungria:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Leleu:Karyopharm: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Davies:Abbvie: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; ASH: Honoraria; MMRF: Honoraria. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Rifkin:Takeda: Consultancy; EMD Serono: Consultancy; McKesson: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy; Sandoz: Consultancy; Boehringer Ingelheim: Consultancy. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Chari:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; The Binding Site: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Berdeja:Teva: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Zonder:Takeda: Honoraria; Coelum: Honoraria; BMS: Research Funding; Celgene: Consultancy, Honoraria; Alnylam: Honoraria; Janssen: Honoraria; Pharmacyclics: Other: DSMC. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Demers:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ren:Takeda Pharmaceuticals International Co.: Employment. Skacel:Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Terpos:Novartis: Honoraria; Celgene: 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, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding.