Labotka, Richard

AbstractDeeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression‐free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0–4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE‐MM2 receiving ixazomib‐lenalidomide‐dexamethasone (IRd) (n = 351) or placebo‐Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo‐Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo‐Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor‐immunomodulatory drug‐steroid combination is not a negative predictor of outcome.

AbstractPatient‐reported outcomes in AL amyloidosis have not been well‐studied. We analyzed health‐related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE‐AL1 trial (NCT01659658) (ixazomib‐dexamethasone, n = 85; physician's choice of chemotherapy [PC], n = 83). HRQOL and symptom burden were measured with the SF‐36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG‐Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated‐measures linear mixed models; analyses were not adjusted for multiplicity. Least‐squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib‐dexamethasone at several cycles for SF‐36v2 Role Physical and Vitality subscales (p < .05); no subscales demonstrated significant differences favoring PC. For FACT/GOG‐Ntx, small but significant differences in LS mean changes favored ixazomib‐dexamethasone over PC at multiple cycles for seven items and both summary scores; significant differences favored PC for one item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib‐dexamethasone over PC at some cycles (p < .05). Patients with relapsed/refractory AL amyloidosis treated with ixazomib‐dexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy.

Abstract Introduction: A number of cytogenetic abnormalities (CAs) are associated with poorer prognosis in MM, including del(17p), t(4;14), t(14;16), and amp1q21. There is a general consensus that treatment with proteasome inhibitors (PIs) benefits pts carrying these CAs (Sonneveld Blood 2016). This meta-analysis of four phase 3 studies assesses PFS benefit in pts receiving the oral PI ixa vs pbo regarding the specific adverse CAs. Methods: Pts in TOURMALINE-MM1 (N=722; relapsed/refractory MM; Moreau N Engl J Med 2016) and MM2 (N=705; newly diagnosed MM; Facon Blood 2021) received ixa plus lenalidomide-dexamethasone (Rd) vs pbo-Rd (1:1). Pts in TOURMALINE-MM3 (N=656; Dimopoulos Lancet 2019) and TOURMALINE-MM4 (N=706; Dimopoulos J Clin Oncol 2020) received ixa vs pbo (3:2) as maintenance following autologous stem cell transplant or as post-induction maintenance in transplant-ineligible pts, respectively. In TOURMALINE-MM1/MM2, CAs were centrally assessed on CD138 positive sorted cells from bone marrow samples collected at study entry using fluorescence in situ hybridization (FISH). Cutoff values for defining the presence of del(17p), t(4;14), and t(14;16) were 5%, 3%, and 3% positive cells, respectively, based on the false-positive rates (technical cutoffs) of the FISH probes used, and cutoff values of 3% (MM1) and 20% (MM2) were used for amp1q21. In TOURMALINE-MM3/MM4, cytogenetic assessment was performed locally using FISH or conventional karyotyping with locally defined thresholds for positivity. Results: 270/1227 (22%) vs 227/1019 (22%) evaluable pts receiving ixa-based vs pbo-based therapy had high-risk CAs [del(17p), t(4;14), t(14;16)]: 75 vs 62 in MM1, 60 vs 63 in MM2, 61 vs 54 in MM3, and 74 vs 48 in MM4. 957/1227 (78%) vs 792/1019 (78%) had complementary standard-risk CAs: 200 vs 216 in MM1, 231 vs 234 in MM2, 252 vs 152 in MM3, and 275 vs 190 in MM4. 555/1142 (49%) vs 479/955 (50%) evaluable pts receiving ixa-based vs pbo-based therapy had expanded high-risk CAs (high-risk CAs ± amp1q21): 155 vs 154 in MM1, 134 vs 146 in MM2, 116 vs 88 in MM3, and 150 vs 91 in MM4. 587/1142 (51%) vs 476/955 (50%) had complementary standard-risk CAs: 122 vs 126 in MM1, 164 vs 153 in MM2, 154 vs 89 in MM3, and 148 vs 108 in MM4. After a median follow-up in the pooled analysis of 25.6 months (mos; 12.7, 54.6, 29.7, and 21.3 mos in MM1, MM2, MM3, and MM4, respectively), the hazard ratio (HR) for PFS with ixa-based vs pbo-based therapy in pts with high-risk CAs was 0.74 (95% confidence interval [CI] 0.59-0.93; median 17.8 vs 13.2 mos) and 0.70, (95% CI 0.62-0.80; median 26.3 vs 17.6 mos) in pts with standard-risk CAs. In the subgroup analyses of expanded high-risk CAs, the HR for PFS with ixa-based vs pbo-based therapy in pts in the expanded high-risk group was 0.75 (95% CI 0.64-0.87; median 18.1 vs 14.1 mos; Figure 1) and 0.71 (95% CI 0.59-0.85; median 36.1 vs 21.4 mos) in the complementary standard-risk group. Analyses of PFS according to the presence of individual CAs (Figure 2) indicated differing magnitudes of PFS benefit. Notably, in pts with t(4;14) (n=124 vs n=102), the HR for PFS with ixa-based vs pbo-based therapy was 0.68 (95% CI 0.48-0.96; median 22.4 vs 13.2 mos), while for pts with amp1q21 (n=380 vs n=312), the HR was 0.77 (95% CI 0.63-0.93; median 18.8 vs 14.5 mos) and for pts with del(17p) (n=141 vs n=107) the HR was 0.80 (95% CI 0.59-1.09; median 15.7 vs 13.2 mos). Conclusions: This pooled analysis demonstrated a PFS benefit with ixa-based therapy vs pbo-based therapy regardless of the presence of specific adverse CAs, with a similar magnitude of benefit in pts with (expanded) high-risk CAs and the respective complementary standard-risk groups. However, due to the differences in study eligibility criteria and pt populations, ixa combined with Rd or as single-agent maintenance therapy may not abrogate the negative impact of high-risk CAs. Analyses of PFS in subgroups with specific CAs indicated that the greatest magnitudes of benefit (lowest HRs) with ixa-based vs pbo-based therapy were in pts with t(4;14) (HR 0.68) and pts with amp1q21 (HR 0.77), suggesting that the improved outcome with ixa-based vs pbo-based therapy in the expanded high-risk subgroup was primarily driven by PFS differences in pts with these more common CAs. Further study is needed, and additional sensitivity analyses will be presented in subsequent publications. Figure 1 Figure 1. Disclosures Chng: BMS/Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Lonial: BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Morgan: Takeda: Honoraria. Iida: Amgen: Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Abbvie: Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Moreau: Sanofi: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Oncopeptides: Honoraria. Kumar: Bluebird Bio: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Oncopeptides: Consultancy; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Twumasi-Ankrah: Takeda: Current Employment. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Dash: Takeda: Current Employment, Current equity holder in publicly-traded company. Vorog: Takeda: Current Employment. Zhang: Takeda: Current Employment. Suryanarayan: Takeda: Current Employment. Labotka: Takeda: Current Employment. Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib for the initial treatment of multiple myeloma and as maintenance treatment following stem cell transplantation or induction therapy in newly diagnosed patients

Abstract Background: Two global, randomized, placebo (pbo)-controlled phase 3 studies of single-agent ixazomib (ixa) maintenance therapy are currently ongoing for newly diagnosed MM patients following primary therapy that included autologous stem cell transplantation (ASCT) (MM3, NCT02181413) or excluded ASCT (MM4, NCT02312258). Both trials have demonstrated statistically significant and clinically meaningful improvement in their primary endpoint of progression-free survival (PFS): for MM3, median 26.5 months (mos) ixa vs 21.3 mos pbo (hazard ratio [HR] 0.720, 95% confidence interval [CI] 0.582-0.890, P=0.002); for MM4, median 17.4 mos for ixa vs 9.4 mos for pbo (HR 0.659, 95% CI 0.542-0.801, P&lt;0.001). Data for the key secondary endpoint, OS, have not previously been published. Methods: Full methods have previously been reported (Dimopoulos, Lancet 2019; Dimopoulos, J Clin Oncol 2020). Eligible patients (MM3, N=656; MM4, N=706) were randomized 3:2 to receive maintenance therapy with single agent ixa or pbo for a maximum of approximately 24 mos (26 cycles, to the nearest complete cycle) or until progressive disease or unacceptable toxicity, whichever occurred first. Results: At the most recent data cut-off (MM3, 29 January 2021; MM4, 15 October 2020), with median follow up of 64 mos and 36 mos, respectively, 27% (MM3, 174/656) and 29% (MM4, 203/706) of the intention-to-treat (ITT) population had OS events. In MM3, the 5-year Kaplan-Meier estimate for OS was 74% for ixa and 73% for pbo, though the median OS had not yet been reached in either arm (HR 1.008, 95% CI 0.744-1.367, P=0.958; Figure). In MM4, the 5-year Kaplan-Meier OS estimate was 55% for ixa and 56% for pbo, though the median OS had also not yet been reached in either arm (HR 1.136, 95% CI 0.853-1.514, P=0.382; Figure). No new safety signals were identified, and the incidence of new primary malignancies in both studies was similar between ixa and pbo. Conclusions: These most current OS data for MM3 and MM4 have not demonstrated a statistically significant difference for the ixa or the pbo arm to date. After 64 mos of follow-up in MM3, the risk of OS does not differ between the study arms. After 36 mos of follow-up in MM4, the OS HR shows a trend that favors the pbo arm. Because interim analyses of OS may be overrepresented by deaths in patients who did not benefit from maintenance therapy, it is not known to what extent these results will be reflective of the ITT population at the time of the final analyses. As treatment options, including anti-CD38 mAb and other new mechanisms of action, for salvage therapies following progression continue to expand, OS is increasingly being confounded by subsequent therapies. Hence, demonstrating OS advantage for early line MM therapies is becoming increasingly challenging. OS data continue to be collected in these studies for later analyses. Figure 1 Figure 1. Disclosures Dimopoulos: Takeda: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria. Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Chng: Johnson and Johnson: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Iida: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Suryanarayan: Takeda: Current Employment. Vorog: Takeda: Current Employment. Fergus: Takeda: Current Employment. Labotka: Takeda: Current Employment. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance treatment for multiple myeloma following stem cell transplantation or induction therapy in newly diagnosed patients.

Abstract Introduction: Depth of response is associated with long-term outcomes in multiple myeloma (MM); however, the effect of response kinetics on outcomes in NDMM is variable and less clear. Although some studies have shown that achieving a ≥very good partial response (VGPR) at 4 months (mos) from diagnosis is associated with increased overall survival (Garderet Leukemia 2018), other reports have shown worse outcomes in pts with early vs late responses (Yan Blood Adv 2019). The double-blind, randomized TOURMALINE-MM2 (NCT01850524) trial (Facon Blood 2021) showed a clinical meaningful progression-free survival (PFS) benefit with IRd vs pbo-Rd (median 35.3 vs 21.8 mos; hazard ratio, 0.830; 95% confidence interval, 0.676-1.018; P=0.073; median follow-up, 53.3 and 55.8 mos, respectively) in NDMM pts. Safety data were consistent with the established toxicity profile of IRd. We evaluated PFS and duration of response (DOR) by depth of best confirmed response and time to best response in TOURMALINE-MM2. Methods: Pts were randomized to receive oral ixazomib 4 mg (n=351) or placebo (n=354) on days 1, 8, and 15, plus oral lenalidomide 25 mg (10 mg if creatinine clearance ≤60 mL/min) on days 1-21 and oral dexamethasone 40 mg (20 mg in pts aged &gt;75 years) on days 1, 8, 15, and 22 in 28-day cycles. After 18 cycles, treatment was continued without dexamethasone and reduced doses of ixazomib (3 mg) and lenalidomide (10 mg) until progressive disease (PD)/toxicity. Response assessments were performed every cycle until PD, or every 4 weeks in pts who discontinued treatment prior to PD. PFS and DOR were analyzed post-hoc in subgroups defined by depth of response and in subgroups defined by time to best confirmed response; 'early' and 'late' responses were defined by time to best confirmed response of 0-4 and &gt;4 mos, respectively (additional analyses were performed by time to best confirmed response of 0-6 and &gt;6 mos). Pts in either subgroup could have recorded an initial response prior to their best response. PFS and DOR were evaluated from randomization to progression and time of initial response to progression, respectively. To address potential guarantee-time bias in the PFS analysis, and to eliminate potential bias due to transient responses in DOR analysis, sensitivity analyses were conducted in pts with PFS / DOR of ≥6 mos. Results: Among the 705 pts in the intention-to-treat (ITT) population, 20% (26% IRd vs 14% placebo-Rd) had a best confirmed response of complete response (CR) or stringent CR, 35% (37 vs 34%) had VGPR, 26% (19 vs 32%) had PR, 10% (9 vs 10%) had stable disease (SD), 3% (1 vs 4%) had PD. 7% (8 vs 6%) of pts were not evaluable. In a pooled analysis of both arms, achieving a deeper response was associated with longer PFS (Figure, A) and DOR (median not reached [NR], 42.8, and 15.0 mos for pts with ≥CR, VGPR, and PR, respectively). In 570 pts with ≥PR (288 IRd; 282 pbo-Rd), 152 (53%) and 136 (47%) in the IRd arm and 143 (51%) and 139 (49%) pts in the pbo-Rd arm were defined as early (0-4 mos) and late (&gt;4 mos) responders, respectively. For early vs late responders, 46% vs 40% were aged ≥75 years, 21% vs 12% had International Staging System stage III MM, and 44% vs 33% had expanded high-risk cytogenetic abnormalities. Median PFS was prolonged among late vs early responders with IRd (65.7 vs 21.2 mos) and pbo-Rd (62.6 vs 18.2 mos), as was median DOR (IRd, NR vs 22.6 mos; pbo-Rd, 64.1 vs 17.2 mos). The PFS sensitivity analysis among pts with PFS of ≥6 mos confirmed the association of late response with improved outcomes; among late vs early responders achieving ≥PR, median PFS was 65.7 vs 23.9 mos with IRd and 62.6 vs 18.4 mos with pbo-Rd (Figure, B), and among late vs early responders achieving ≥VGPR, median PFS was 65.7 vs 35.3 mos with IRd and 64.4 vs 21.7 with pbo-Rd. Conclusions: Achieving a deeper response was associated with prolonged PFS and DOR in NDMM patients in TOURMALINE-MM2. PFS benefit on the ITT analysis was driven by the higher rates of deep responses (≥VGPR) with IRd vs pbo-Rd. PFS and DOR were also longer in pts achieving a late vs early best confirmed response of ≥PR or ≥VGPR. Consistent with results from a similar analysis in relapsed/refractory MM in the TOURMALINE-MM1 trial (Garderet Leukemia 2018), our findings support the continuation of therapy with the aim of achieving a deeper response over time. Additional sensitivity analyses will be presented. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Venner: Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; GSK: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. White: Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Forus: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Karlin: Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; oncopeptide: Honoraria; Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Takeda: Honoraria, Other: member of advisory board. Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees. Suzuki: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria. Shibayama: Mundi Pharma: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Fujimoto: Honoraria; Daiichi Sankyo: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Essentia Pharma Japan: Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Avvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Research Funding. Zhang: Takeda: Current Employment. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Twumasi-Ankrah: Takeda: Current Employment. Labotka: Takeda: Current Employment. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Lonial: AMGEN: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria. Kumar: Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Moreau: Amgen: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib in newly diagnosed multiple myeloma patients who are ineligible for transplant.

Abstract Introduction Systemic immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys. Management of the disease relies primarily on off-label use of multiple myeloma therapies. No treatments are approved for AL amyloidosis in the relapsed/refractory setting. In the phase 3, open-label TOURMALINE-AL1 trial (NCT01659658), patients with relapsed/refractory AL amyloidosis were randomized 1:1 to receive either oral ixazomib plus dexamethasone (Id) or physician's choice (CH) in 28-day cycles, and followed until progression or unacceptable toxicity. An interim analysis demonstrated that Id was well tolerated and, although the primary endpoint of hematologic response rate was not met, time-to-event efficacy analyses consistently favored Id. We report an analysis of patient-reported outcome (PRO) data on health-related quality of life (HRQOL) and AL amyloidosis symptoms from TOURMALINE-AL1; such data for AL amyloidosis in general have been limited. Methods Four PRO instruments were used to collect data to support PRO-related secondary endpoints during the treatment period: the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), an amyloidosis symptom questionnaire (ASQ), the EuroQoL 5-Dimension 3-Level (EQ-5D-3L), and the Visual Analogue Scale (EQ VAS) were collected at screening, day 1 of each cycle, and end of treatment (EOT), and the 36-item Short Form General Health Survey version 2 (SF-36v2) was collected at screening, day 1 of every third cycle, and EOT. Analysis of PRO data included descriptive summaries of means and change from baseline and a linear mixed model (LMM) for repeated measures for patients in the intent-to-treat (ITT) population with a baseline and at least one postbaseline PRO-specific assessment. No adjustment was made for multiple comparisons. Data cutoff date was 20 February 2019. Results The ITT population included 168 patients (Id: n=85; CH: n=83), who completed up to 58 cycles (Id) and up to 43 cycles (CH); median treatment duration was 11.7 vs 5.0 months, respectively. PRO compliance in the treatment period was high for all instruments (Figure). Baseline HRQOL as measured by the SF-36v2 and EQ VAS was similar between treatment arms. During the treatment period, SF-36v2 Mental and Physical Component Summary (MCS and PCS) scores remained stable relative to baseline and were similar between arms; the 8 subscale scores were also generally maintained over time, and mostly similar between arms. Least-squares (LS) mean changes from baseline were significantly higher (better HRQoL) for Id compared with CH at several cycles in the SF-36v2 Role Physical and Vitality subscales (p&lt;0.05) (Figure); no subscales demonstrated significant differences favoring CH. Symptom burden as measured by the FACT/GOG-Ntx and ASQ was low at baseline, leaving little room for improvement. FACT/GOG-Ntx scores were generally maintained over time. In the treatment period, there were small but significant differences in LS mean changes from baseline favoring Id over CH at multiple cycles for 7 of the 11 individual items and the neurotoxicity and sensory summary scores; there were small but significant differences favoring CH over Id for 1 individual item (trouble hearing) at a few later cycles. The ASQ total score trended downward slightly (lower burden) during treatment after the first few cycles in both arms. There were significant differences per the LMM favoring Id over CH at cycles 7 and 21 (p&lt;0.05). In both arms, EQ VAS scores trended upward (better HRQoL) during treatment and then declined slightly at EOT. (LMM analyses were not conducted for EQ-5D.) At EOT, a slight deterioration from baseline was observed in actual scores for SF-36v2 domains and summary scales, FACT/GOG-Ntx neurotoxicity and sensory subscales, and ASQ items and total score for both Id and CH. Conclusions Relapsed/refractory AL amyloidosis patients treated with Id experienced HRQOL and symptoms that were similar to or trended better than patients treated with CH. These data suggest that treatment with Id, although with a substantially longer treatment duration, did not have a negative impact on HRQOL in patients with relapsed/refractory AL amyloidosis, a population with currently no approved treatment options. Figure 1 Figure 1. Disclosures Sanchorawala: Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Janssen: Consultancy; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria. Kim: Janssen, BMS: Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Fiona: Pfizer: Research Funding. Suzuki: Janssen: Consultancy, Honoraria; Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Comenzo: Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding. Cherepanov: Takeda: Current Employment, Current equity holder in publicly-traded company. Hayden: Takeda: Current Employment, Current equity holder in publicly-traded company. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Labotka: Takeda: Current Employment. Faller: Takeda Pharmaceuticals Co.: Current Employment; Viracta Therapeutics, Inc: Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Briacell, Inc: Current holder of stock options in a privately-held company. Kastritis: Amgen, Genesis Pharma, Janssen, Takeda: Consultancy; Amgen, Janssen, Pfizer: Research Funding; Amgen, Genesis Pharma, Janssen, Takeda, Pfizer: Honoraria.

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

8020 Background: MM patients (pts) often receive several lines of therapy with multiple drug combinations and, as lenalidomide (R)-containing regimens are commonly used as first-line therapy, R-free options for subsequent lines are necessary. Additionally, as pts age and become less tolerant to treatment, more convenient regimens, such as all-oral options, with less toxicity are needed. Dexamethasone (dex)-based doublets are effective and tolerable in this setting. Methods: Proteasome inhibitor (PI)-exposed and/or intolerant and R-refractory pts who had ≥2 prior therapies (N = 122) were randomized 3:2 to receive: ixazomib (ixa) 4 mg (5.5 mg from cycle 2 if tolerated) on day (d) 1, 8, 15, and dex 20 mg (≥75 years [yrs], 10 mg) on d 1, 2, 8, 9, 15, 16, 22, 23; or pomalidomide (pom) 4 mg on d 1–21, and dex 40 mg (≥75 yrs, 20 mg) on d 1, 8, 15, 22, in 28-d cycles until progressive disease (PD) or unacceptable toxicity. Pts were stratified by age ( < 65 vs ≥65 yrs), International Staging System (ISS) disease stage at study entry (I/II vs III), and prior lines of therapy (2 vs ≥3). The study was powered to test the primary endpoint of progression-free survival (PFS). Results: In the ixa-dex (n = 73) vs pom-dex (n = 49) arms, median age was 72 vs 68 yrs (36% vs 18% ≥75 yrs), 25% vs 22% of pts had ISS stage III MM, and 52% vs 53% had received ≥3 prior therapies (per stratification). At data cutoff (5/31/2020), 19% vs 20% of pts were ongoing on treatment with ixa-dex vs pom-dex; primary reasons for discontinuation were PD (47% vs 57%) and adverse events (AEs; 23% vs 12%). With median follow-up of 15.3 vs 17.3 months (mos), median PFS (mPFS) was 7.1 vs 4.8 mos with ixa-dex vs pom-dex (hazard ratio [HR] 0.847; 95% confidence interval [CI] 0.535–1.341; p = 0.477); the Table shows mPFS by prior lines, and secondary endpoints. Pts received a median of 6 cycles with both ixa-dex (range 1–25) and pom-dex (range 1–27); 64% of ixa-dex pts were able to escalate to a 5.5 mg dose of ixa. 69% vs 81% of ixa-dex vs pom-dex pts had grade (G) ≥3 AEs, 51% vs 53% had serious AEs, 39% vs 36% had an AE leading to drug discontinuation, 44% vs 32% had an AE leading to dose reduction, and 13% vs 13% died on study. Health-related quality of life (HRQoL; EORTC QLQ-C30/MY20, and EQ-5D-5L) was maintained, and similar between arms. Conclusions: Ixa-dex prolonged PFS vs pom-dex in these heavily pretreated, PI-exposed and/or intolerant, R-refractory pts, but the difference was not statistically significant. Ixa-dex was well tolerated, with lower G≥3 AE rates vs pom-dex, and comparable HRQoL. Clinical trial information: NCT03170882.

Abstract Background There is increasing evidence for the clinical benefit of long-term, continuous therapy for NDMM pts. Proteasome inhibitors (PIs) form a backbone of therapy in MM; however, long-term therapy with some PIs may be limited due to toxicity and the need for regular parenteral administration, increasing the treatment burden. Ixazomib, the first oral PI, has been studied in NDMM pts in 4 phase 1/2 studies in which approximately 1 year of induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd) was followed by single-agent ixazomib maintenance. Here we report an integrated analysis of pts from these studies who did not undergo autologous stem cell transplant (ASCT) and received ixazomib maintenance therapy. Methods Pts from 4 studies were included: 1) weekly IRd, 12x28-d cycles IRd (weekly ixazomib 1.68-3.95 mg/m² in phase 1, recommended phase 2 dose [RP2D] 4.0 mg; C16005, NCT01217957; ASCT-eligible/-ineligible pts); 2) twice-weekly IRd, 16x21-d cycles IRd (twice-weekly ixazomib 3.0-3.7 mg in phase 1, RP2D 3.0 mg; C16008, NCT01383928; ASCT-eligible/-ineligible pts); 3) IMP, 9x42-d or 13x28-d cycles IMP (weekly/twice-weekly ixazomib 3.0-5.5/3.0-3.7 mg in phase 1, RP2D of weekly ixazomib 4.0 mg; C16006, NCT01335685; ASCT-ineligible pts); 4) ICd, 13x28-d cycles ICd (weekly ixazomib 4.0 mg; C16020, NCT02046070; ASCT-ineligible pts). In all 4 studies, pts completing induction without progressive disease (PD) and, in the IRd studies, not withdrawn for ASCT, could receive single-agent ixazomib maintenance at the last tolerated dose during induction until PD or unacceptable toxicity. Results 121 pts received ixazomib maintenance (25, 18, 35, and 43 in weekly IRd, twice-weekly IRd, IMP, and ICd studies, respectively). Median age was 72 yrs (range 34-90 yrs; 83% aged ≥65 yrs), 62% had IgG myeloma, 47/34/19% had ISS disease stage I/II/III, 40/49% had Eastern Cooperative Oncology Group performance status 0/1. Combined median progression-free survival (PFS) was 33.8 months from time of study entry and 21.4 months from start of maintenance (Figure). Median PFS from the start of maintenance seemed to be longer for the two IRd studies than for IMP, while median PFS for ICd had not yet been reached. 4-yr OS from time of study entry/3-yr OS from the start of maintenance was 82%. Overall response rate was 93% after induction and 94% after maintenance. Best response rate of CR+VGPR after induction was 57% (22% CR), which increased to 63% (35% CR/sCR) after maintenance; 24 pts (20%) improved their response during maintenance (4 pts with CR improved to sCR; 14 VGPR to CR/sCR; 5 partial response [PR] to VGPR/CR; 1 stable disease to PR). Combined mean dose intensity during maintenance was 89.1%. At time of analysis, median duration of maintenance therapy was 2.2 yrs for weekly IRd, 1.0 yr for twice-weekly IRd, and 0.9 yr for IMP and ICd; maximum duration was 4.8, 3.8, 3.9, and 1.6 yrs respectively. 78% of pts had discontinued maintenance, primarily due to PD (55%), and only 7% due to adverse events (AEs). 15% of pts had ixazomib dose reductions during maintenance. Grade ≥3 AEs (48% vs 74%), drug-related grade ≥3 AEs (24% vs 62%), serious AEs (SAEs; 21% vs 43%), and drug-related SAEs (5% vs 19%) were less common during maintenance than during induction. Common grade ≥3 AEs are shown in the Table. Other AEs of clinical interest were also generally similar or less common during maintenance than during induction, including cardiac arrhythmias (13% vs 21%), pneumonia (12% vs 17%), acute renal failure (7% vs 8%), hypotension (4% vs 7%), myocardial infarction (0 vs &lt;1%), and heart failure (2% vs 2%). Only 6 pts (5%) reported a new primary malignancy. There was only 1 on-study death during maintenance, which was not considered related to ixazomib; due to pulmonary edema in an 81-yr old pt with a history of cardiovascular co-morbidities. Conclusions In this integrated analysis, single-agent ixazomib maintenance therapy following an ixazomib-based induction regimen was associated with deepening of responses and good long-term outcomes in NDMM pts not undergoing ASCT. Single-agent ixazomib is feasible for long-term administration, with limited new-onset grade ≥3 AEs. These outcomes appear similar to other studies involving maintenance approaches in NDMM and support the ongoing phase 3 investigation of ixazomib maintenance therapy. Disclosures Dimopoulos: Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding. Laubach: Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Hofmeister: Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. San Miguel: Roche: 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: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Lu: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng: Array Pharmaceuticals: Equity Ownership; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Liu: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Byrne: Oncopeptides AB: Consultancy; Takeda: Consultancy. Berg: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. van de Velde: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson: Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (&lt;75 vs 75-80 vs &gt;80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; &gt;4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (&gt;5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged &lt;65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged &lt;65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged &lt;65 years, 0.615 (95% CI 0.467-0.810, p&lt;0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were &lt;20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (&lt;10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation