Lin, Jianchang

AbstractObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537

Background CD38 is highly expressed on MM cells, hence anti-CD38 agents are of interest as a therapeutic approach in MM. The anti-CD38 monoclonal antibody, dara, as mono- or combination therapy, has substantially improved efficacy outcomes in RRMM, including in heavily pretreated pts. However, many pts relapse and new therapeutic approaches are needed, particularly for pts R/R to dara. TAK-169 is a dimeric fusion protein of an anti-CD38 antibody single chain variable fragment fused to a modified Shiga-like toxin-A subunit. Its unique mechanism of action involves specific binding to CD38+ cells, forced internalization into the target cells, retrograde transport to the cytosol, and irreversible, enzymatic inactivation of target cell ribosomes to cause apoptosis. TAK-169 showed potent, rapid in vitro activity on CD38-expressing cell lines and in vivo efficacy in MM mouse xenograft tumor models with a wide CD38 expression range when administered intravenously (IV) once weekly (QW) or once every 2 weeks (Q2W). Activity was also shown in ex vivo assays from 6 pt bone marrow aspirate (BMA) samples, including from a dara-resistant pt (EC50 5 nM). TAK-169 retained in vitro activity in the presence of dara with modest shifts in EC50 noted at higher dara concentrations. In contrast to dara, TAK-169 has direct tumor cell kill activity that is independent of a pt's immune function status and may therefore be effective in a dara-resistant setting. Accordingly, this phase 1 study will assess safety, tolerability, preliminary efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-169 in RRMM. Methods This first-in-human, multicenter, open-label study (NCT04017130; Figure) comprises dose escalation (Part 1) and expansion (Part 2). Eligible pts must be aged ≥18 years with a confirmed diagnosis of MM. Pts enrolled in Part 1 should not be candidates for available therapies known to confer clinical benefit in RRMM. In part 2, pts enrolled should have received ≥3 prior lines of therapy, or ≥2 if one included a PI and IMiD combined. Prior anti-CD38 therapy (including dara) is permitted, except in the Part 2 anti-CD38 therapy-naive expansion cohort. In Part 1, the primary objective is to assess safety/tolerability of TAK-169 in pts with RRMM, and determine maximum tolerated dose/recommended Phase 2 dose (MTD/RP2D). Secondary objectives include efficacy, PK, PD and immunogenicity of TAK-169. Approximately 60 pts are planned to be enrolled to receive IV TAK-169 QW on Days 1/8/15/22 in 28-day cycles. Dosing will start at 50 μg/kg, with subsequent dose levels of 100, 200, 335, 500, 665 μg/kg. A 2nd Q2W dose escalation cohort may be initiated, starting at the QW MTD. The Bayesian Logistic Regression Model with overdose control will be used for dose escalation cohort 2 and for all subsequent dose escalation cohorts, and other non-DLT-safety, clinical, PK, and PD data will be considered. In Part 2, the primary objective is preliminary evaluation of TAK-169 clinical activity in RRMM. Secondary objectives include further evaluating safety, efficacy, PK, PD, and immunogenicity of TAK-169. Part 2 will enroll approximately 54 pts into dara RR (QW and Q2W dosing) and anti-CD38 therapy-naïve (QW dosing) cohorts. TAK-169 will be administered at the MTD/RP2D (QW and Q2W) determined in Part 1. Response will be monitored longitudinally using orthogonal approaches. M-protein levels in serum and urine will be measured each cycle to determine objective responses by International Myeloma Working Group (IMWG) criteria. Minimal residual disease status in pts suspected to be at complete response will be assessed. Circulating free DNA (cfDNA) will be collected from longitudinal plasma samples for disease monitoring. Baseline cytogenetic data will be collected, and TAK-169 efficacy will be assessed in pts with high-risk cytogenetics. Serial blood samples will be used to characterize PK and PD of TAK-169 after IV administration, and to assess the presence of antidrug antibodies. BMA samples collected at screening will be used to evaluate baseline expression of candidate biomarkers. Toxicity will be evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Efficacy analyses will use descriptive statistics with a 95% confidence interval and the Kaplan-Meier method. PK parameters and immunogenicity status will be summarized using descriptive statistics. Recruitment is ongoing. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy. Landgren:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ailawadhi:Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Willert:Molecular Templates: Employment. Waltzman:Molecular Templates, Inc.: Employment, Equity Ownership. Lin:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Zhang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lublinsky:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Manoharan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leichter:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ottinger:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Newcomb:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Vorog:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. OffLabel Disclosure: TAK-169 is a dimeric fusion protein of an anti-CD38 antibody single chain variable fragment fused to a modified Shiga-like toxin-A subunit

Abstract Abstract 332 Background: The high response rates seen with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen (Kumar S, et al. Blood 2012; Richardson PG, et al. Blood 2010) highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM). MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy (PN). Here we report phase (Ph) 1 and preliminary Ph 2 results of the first study of MLN9708 in combination with lenalidomide and dexamethasone in patients with previously untreated MM (NCT01217957). Methods: Patients aged ≥18 yrs with measurable disease, ECOG performance status 0–2, and no grade ≥2 PN, received oral MLN9708 (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then maintenance therapy with MLN9708 (same schedule) every 28 days until progression. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. In Ph 1, dose escalation (1.68–3.95 mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities (DLTs). Ph 1 primary objectives were determination of safety, maximum tolerated dose (MTD), and recommended Ph 2 dose (RP2D); the Ph 2 primary objective was CR+VGPR rate. Secondary and exploratory objectives included characterization of MLN9708 pharmacokinetics (PK) and measurement of minimal residual disease using multiparameter flow cytometry. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: From 22 November 2010 (Ph 1) and 14 October 2011 (Ph 2) to data cut-off (June 27, 2012), 65 patients (36 male) have been enrolled, 15 in Ph 1 and 50 in Ph 2. Median age was 66 yrs (range 34–86); 43% and 13% had ISS stage II and III. Patients have received a median of 5 cycles (range 1–15) – 6 cycles (range 1–15) in Ph 1 and 5 cycles (range 1–8) in Ph 2. 42 (65%) patients remain on treatment, 4 (27%) in Ph 1 and 38 (76%) in Ph 2. At 10 August 2012, 22 patients have discontinued: 16 to receive ASCT, 4 due to AEs (3 drug-related, 1 not drug-related GI bleed), 2 for other reasons (1 disease progression, 1 due to investigator decision). Of those who have undergone stem cell mobilization, a median yield of 9.1 × 106 CD34+ cells/L was reported. MLN9708 MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 mg/m2; RP2D converts to a 4.0 mg fixed dose based on population PK results. At 27 June, all-grade AEs related to any regimen drug and seen in ≥25% of patients were fatigue (32%), nausea (31%), and vomiting (25%). Grade 3 any-drug-related AEs were reported in 26 (40%) patients, including erythematous rash, nausea and vomiting (5% each). Grade 4 any-drug-related AEs were end-stage renal disease (related to progressing MM) and deep vein thrombosis in 1 patient each. One patient experienced grade 3 PN at the RP2D. At 10 August, 3 patients discontinued due to drug-related AEs – 1 in Ph 2 who stopped due to grade 1 resting tremor, grade 2 occasional memory loss (neurologic work-up was negative), and grade 2 peripheral sensory neuropathy, 1 patient in Ph 2 due to drug-related RSV pneumonia who subsequently died on study due to this AE, and 1 patient in Ph 1 with syncope (a DLT). Among all 65 patients (at 10 August), median patient follow-up was 3.88 months (Ph 1: 9.03 months, Ph 2: 3.68 months). The overall response rate (ORR; ≥PR, confirmed/unconfirmed) was 88% (100% in Ph 1 and 84% in Ph 2); this includes 40% ≥VGPR (53% in Ph 1 and 36% in Ph 2) and 18% CR (33% in Ph 1 and 14% in Ph 2). Median cycle number is limited, but 50 patients have received ≥4 cycles: ORR was 96%, with 44% ≥VGPR and 26% CR. Analyses by cytogenetic status will be presented at the meeting. At data cut-off, 50 of 52 responders remained in response, with responses durable for up to 13.2+ months. Median time to first response was 0.92 months (range 0.89–6.44). Conclusions: The combination of weekly oral MLN9708 plus lenalidomide and dexamethasone appears generally well tolerated, with one grade 3 PN at the RP2D. Preliminary data show antitumor activity at the RP2D in patients with previously untreated MM, and at data cut-off, 96% of patients had achieved ≥PR, including a ≥VGPR rate of 44% and a CR rate of 26%, with responses consistent with those reported with VRD/RVD. Disclosures: Kumar: Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding; Genzyme: Research Funding; Cephalon: Research Funding; Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Off Label Use: A study of the investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the treatment of patients with previously untreated multiple myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Hari:Celgene: Consultancy. Vescio:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Berg:Millennium Pharmaceuticals, Inc.: Employment. Lin:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals and Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background Ixazomib, the first oral proteasome inhibitor, is approved by the US FDA, in combination with Rd, for the treatment of MM patients (pts) who have received at least 1 prior therapy. Approval was based on the double-blind, placebo-controlled phase 3 TOURMALINE-MM1 study (NCT01564537) in 722 pts with RRMM (Moreau et al, N Engl J Med 2016), in which IRd showed superior PFS versus placebo-Rd (HR 0.74) at the final prespecified analysis, with limited additional toxicity. Prespecified subgroup analyses showed a consistent PFS benefit with IRd, but with a differential treatment effect according to prior therapy exposure. An exploratory study objective was to evaluate potential relationships between treatment outcomes and tumor gene expression patterns. c-MYC is a proto-oncogene that encodes a transcription factor regulating cell proliferation, growth, protein translation, metabolism, and apoptosis, and increased c-MYC expression is involved in MM pathogenesis/progression. We analyzed the impact of c-MYC expression on PFS in RRMM pts treated with IRd or placebo-Rd. Methods Pts with RRMM after 1-3 prior lines of therapy were randomized 1:1 to receive oral ixazomib or placebo, plus lenalidomide and dexamethasone, until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 vs 2-3), proteasome inhibitor exposure, and ISS disease stage. The primary endpoint was PFS by independent review committee assessment. Data reported here are from the final prespecified statistical analysis of PFS (median follow-up ~15 months). Bone marrow aspirate samples were collected at screening for tumor gene expression analysis. Whole transcriptome sequencing (RNAseq) of bone marrow-sorted CD138+ cells was performed using the Illumina Truseq protocol on the Illumina HiSeq platform; this generated a median of 50 million paired-end reads (100 bp length) per sample. c-MYC expression was evaluated by treatment arm and according to number of prior therapies (1 vs 2-3). PFS was analyzed in subgroups dichotomized according to median c-MYC expression (c-MYC-high/c-MYC-low). Results RNAseq data were available for 59% (427/722) of enrolled pts; 213 (50%) had high and 219 (50%) had low c-MYC expression (dichotomized according to the median). Impact of c-MYC expression (high vs low) on PFS, irrespective of treatment arm, was not significant (p=0.98). However, a significant treatment effect of IRd vs placebo-Rd was only seen in pts with high c-MYC expression (interaction p=0.024); in these pts (IRd: n=109; placebo-Rd: n=104) a significant PFS benefit was seen with IRd (HR 0.41; 95% CI: 0.26-0.65, p=0.00011). Impact of c-MYC expression was then analyzed by number of prior therapies. In the overall TOURMALINE-MM1 population, per stratification, 212/213 pts in the IRd/placebo-Rd arms had 1 prior therapy, and 148/149 had 2-3 prior therapies. After median follow-up of ~15 months, median PFS in pts with 1 prior therapy was 20.6 vs 16.6 months with IRd vs placebo-Rd (HR 0.88; 95% CI: 0.65-1.20), and in pts with 2-3 prior therapies was not reached vs 12.9 months (HR 0.58; 95% CI: 0.40-0.84, p=0.0033). The level of c-MYC expression was shown to be significantly higher in pts with 2-3 prior therapies vs 1 prior therapy, with median expression of 6.94 (SD=1.71, n=177) vs 6.52 (SD=1.74, n=250) (log2 scale), t-test p-value 0.0153. In pts with 1 prior therapy, no differences in PFS were observed between pts with low c-MYC expression (HR 1; 95% CI: 0.59-1.8, p=0.934), while a prolonged PFS benefit was observed in pts with high c-MYC expression (HR 0.48; 95% CI: 0.26-0.88, p=0.0146) (Figure, A and B). In pts with 2-3 prior therapies, both the c-MYC-high and c-MYC-low pts showed improved PFS with IRd vs placebo-Rd; the difference in PFS was statistically significant only in c-MYC-high pts (HR 0.36; 95% CI: 0.18-0.72, p=0.00269) (Figure, C and D). Conclusions In TOURMALINE-MM1, c-MYC expression was higher in MM tumor samples from pts with 2-3 vs 1 prior therapies. The IRd regimen was active in c-MYC-high and c-MYC-low pts, but its impact on PFS vs placebo-Rd was greater in c-MYC-high pts, thus providing a potential explanation for the enhanced PFS benefit with IRd vs placebo-Rd in pts with 2-3 prior therapies. The PFS benefit with IRd in c-MYC-low pts with 2-3 prior lines suggests that, in advanced MM, further genomic alterations may also be contributing to ixazomib sensitivity. Disclosures Di Bacco: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bahlis:BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau. Avet-Loiseau:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Speakers Bureau. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ganly:Medipics: Equity Ownership; Novartis: Honoraria; Roche: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Kumar:Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Berg:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lin:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Li:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Badola:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shen:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda: Equity Ownership; Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson and Johnson: Equity Ownership. Luptakova:Takeda Oncology: Employment. van de Velde:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria.

Key Points IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standard-risk cytogenetics. The addition of ixazomib to Rd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.

SummaryThe oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double‐blind, placebo‐controlled Phase III TOURMALINE‐MM1 study of ixazomib‐Rd (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression‐free survival versus placebo‐Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.