Real-World (RW) Multiple Myeloma (MM) Patients (Pts) Remain Under-Represented in Clinical Trials Based on Standard Laboratory Parameters and Baseline Characteristics: Analysis of over 3,000 Pts from the Insight MM Global, Prospective, Observational Study
Authors: Hungria Vania T.M. , Lee Hans C. , Abonour Rafat , Rifkin Robert M. , Terpos Evangelos , Leleu Xavier , Costello Caitlin L. , van Rhee Frits , Weisel Katja C. , Puig Noemi , Berdeja Jesus G. , Cook Gordon , Usmani Saad Z. , Thompson Michael A. , Boccadoro Mario , Zonder Jeffrey A. , Spencer Andrew , Hajek Roman , Fanning Suzanne R. , Boyd Kevin , Omel Jim , Armour Mira , Morgan Kathryn E. , Patel Ronak S. , Carlson Gary L. , Ferrari Renda H. , Stull Dawn Marie , Ren Kaili , Cherepanov Dasha , Pottala James V. , Chari Ajai 
Published: November 2019

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.