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 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: The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. “Continuous therapy” commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients’ quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

Abstract: Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the ‘efficacy’ of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual’s composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.

Abstract: Pomalidomide is a distinct immunomodulatory agent with significant activity in relapsed/refractory multiple myeloma (RRMM). The optimal treatment schedule in patients with RRMM who have received multiple lines of treatment, including bortezomib and lenalidomide, is 4 mg/day on days 1–21 of a 28-day cycle in combination with weekly low-dose dexamethasone. Improved responses and outcomes relative to traditional therapies continue to be confirmed in recently completed and ongoing trials. Pomalidomide exhibits direct tumoricidal, immunomodulatory, anti-angiogenic and anti-inflammatory activities, which facilitate combination therapy with agents with complementary mechanisms of action, resulting in greater anti-myeloma effects than single-agent therapy or previous combination therapies. For example, in combination with proteasome inhibitors and traditional chemotherapeutic agents in doublet or triplet regimens, pomalidomide provides high rates of durable response, and represents an important new treatment option for patients with RRMM requiring effective new therapies. Additionally, pomalidomide maintains its efficacy and tolerability profile in difficult-to-treat patients, including the elderly, patients with poor cytogenetics and those with renal impairment. This review summarises the clinical development of pomalidomide and discusses this effective agent for the treatment of patients with RRMM in the context of current myeloma treatment options, as well as potential future directions to further improve patient outcomes.