Closing the Efficacy and Effectiveness Gap: Outcomes in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Ixazomib-Lenalidomide-Dexamethasone (IRd) in Routine Clinical Practice Remain Comparable to the Outcomes Reported in the Phase 3 Tourmaline-MM1 Study
Authors: Hajek Roman , Minarik Jiri , Straub Jan , Pour Ludek , Jungova Alexandra , Berdeja Jesus G. , Boccadoro Mario , Brožová Lucie , Spencer Andrew , van Rhee Frits , Vela-Ojeda Jorge , Thompson Michael A. , Abonour Rafat , Chari Ajai , Cook Gordon , Costello Caitlin L. , Davies Faith E. , Hungria Vania T.M. , Lee Hans C. , Leleu Xavier , Puig Noemi , Rifkin Robert M. , Terpos Evangelos , Usmani Saad Z. , Weisel Katja C. , Zonder Jeffrey A. , Bařinová Magda , Kuhn Matyáš , Silar Jiri , Capkova Lenka , Galvez Kenny , Lu Jin , Skacel Tomas , Elliott Jennifer , Demers Brittany , Stull Dawn Marie , Ren Kaili , Maisnar Vladimir 
Published: November 2019

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.