Abstract: Background: Oprozomib (OPZ) is an oral proteasome inhibitor. This phase 1b/2 study (NCT01416428) is evaluating single-agent OPZ in patients with relapsed hematologic malignancies, including those with multiple myeloma (MM) and Waldenström macroglobulinemia (WM). In the phase 1b portion of the study, the maximum tolerated dose (MTD) of single-agent OPZ was 300 mg/day when administered on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or 240 mg/day when administered on days 1-5 of a 14-day cycle (5/14 schedule) (Vij et al. Blood.2014;124:abstr 34). Here, we present final results from the phase 2 portion of the study. Methods: Adults with relapsed MM or WM (≥1 prior therapy) were eligible for the phase 2 portion of the study. The primary objective of the phase 2 portion was to determine the overall response rate (ORR). During phase 2, patients on the 5/14 schedule received OPZ at the MTD of 240 mg/day, or in a step-up dosing scheme where patients received 150 mg/day in cycle 1, and stepped-up to a target dose of 180 mg/day thereafter (ie, 150/180 mg/day). Patients on the 2/7 schedule received OPZ in a step-up dosing scheme of 240/300 mg/day. All patients received premedication with a 5-hydroxytryptamine-3 inhibitor and dexamethasone 4 mg. Results: During phase 2, patients were initially treated on the 5/14 schedule at the MTD of 240 mg/day (MM, n=27; WM, n=17). Three patients with MM died on study: 2 due to treatment-related gastrointestinal (GI) hemorrhage and 1 due to progressive disease. The study protocol was then amended to test alternative regimens and lower doses, and patients were subsequently enrolled on the 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). The phase 2 portion enrolled 56 patients on the 2/7 step-up dosing schedule (MM, n=41; WM, n=15) and 34 patients on the 5/14 step-up dosing schedule (all MM). Median ages in MM patients were 65 years (2/7, 240/300 mg/day), 64.5 years (5/14, 150/180 mg/day), and 63 years (5/14, 240 mg/day); median ages in WM patients were 65 years (2/7, 240/300 mg/day) and 62 years (5/14, 240 mg/day). Median numbers of prior regimens were 4, 3.5, 5, 2, and 3 in these cohorts, respectively. Among MM patients, 68% were bortezomib (BTZ)-refractory, 37% were carfilzomib (CFZ)-refractory, 75% were lenalidomide-refractory, 45% were pomalidomide-refractory, and 71% had received prior transplant. Median treatment durations were 11.4 weeks (MM, 2/7 schedule, 240/300 mg/day), 10.1 weeks (MM, 5/14 schedule, 150/180 mg/day), 5.4 weeks (MM, 5/14 schedule, 240 mg/day), 34.6 weeks (WM, 2/7 schedule, 240/300 mg/day), and 8.1 weeks (WM, 5/14 schedule, 240 mg/day). Across all cohorts, the most common grade ≥3 adverse events (AEs) included diarrhea, anemia, thrombocytopenia, fatigue, nausea, and vomiting (Table 1). Among patients with MM, the proportions of patients who discontinued treatment due to AEs were 44%, 12%, and 48% in the 2/7, 240/300 mg/day; 5/14, 150/180 mg/day; and 5/14, 240 mg/day cohorts, respectively. Among patients with WM, the proportions of patients who discontinued treatment due to AEs were 20% and 47% in the 2/7 and 5/14 schedules, respectively. No on-study deaths occurred in the 2/7 schedule nor in the 5/14 step-up dosing cohorts. Efficacy outcomes are shown in Table 2. Among response-eligible patients with MM, ORRs were 34%, 22%, and 25% in the 2/7, 240/300 mg/day (n=38); 5/14, 150/180 mg/day (n=32); and 5/14, 240 mg/day (n=24) cohorts, respectively. Among BTZ-refractory patients with MM, ORRs were 28% and 17% on the 2/7 (n=29) and 5/14 (n=24) schedules, respectively; among CFZ-refractory patients, ORRs were 8% and 10% on the 2/7 (n=13) and 5/14 (n=21) schedules. For response-eligible patients with WM, ORRs were 71% and 47% on the 2/7 (n=14) and 5/14 (n=17) schedules. Conclusions: Single-agent OPZ appears to have promising activity in patients with relapsed MM or WM, with durable responses overall and responses observed in those refractory to BTZ or CFZ. GI events (primarily diarrhea) were among the most common grade ≥3 AEs with single-agent OPZ. Further exploration of OPZ therapeutic effect is planned with modified formulations and optimized schedule and dosing administration. Disclosures Ghobrial: Noxxon: Honoraria; Novartis: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Vij:Amgen: Honoraria, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Research Funding. Siegel:Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Kaufman:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding. Raje: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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Obreja:Amgen: Employment. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Abstract: Background: Therapeutic advances in multiple myeloma (MM) have greatly improved the rate and depth of response. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that has synergistic activity with carfilzomib (K) and dexamethasone (d), and is currently under investigation as a targeted therapy in relapsed/refractory (R/R) MM. Using next-generation sequencing (NGS) and 18F-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), we aimed to comprehensively evaluate minimal residual disease (MRD) in R/R MM patients (pts) treated with VenKd. Methods: In this phase 2, dose-escalation study (NCT02899052), R/R MM (1 - 3 prior lines of therapy and no prior K exposure) pts received VenKd: Ven 400 mg/day + K 27 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,8,15,22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 d1,8,15 + d 40 mg d1,8,15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,2,8,9,15,16,22,23 (Cohort 4). The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR and cytogenetic abnormalities by interphase fluorescence in situ hybridization. MRD assessments by NGS (clonoSEQ®) were performed on bone marrow aspirates at cycle 3 day 1 in pts achieving VGPR or better, time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR with negativity determined at & lt;10-5 threshold. FDG-PET/CT imaging was performed on a subset of pts at baseline, cycle 3 day 1, and confirmation of CR or sCR, which corresponded to the bone marrow MRD evaluations by NGS. Lesions assessed by PET/CT were guided by standard of care imaging (i.e., x-ray, CT), and FDG-uptake was measured by maximum standardized uptake value. Pts were excluded from subsequent FDG-PET imaging based on proximity of evaluable lesions to anticipated areas of high normal FDG uptake (e.g., brain), or PET negative based on baseline FDG-PET imaging. MRD negativity (NGS and/or Imaging) was evaluated in the ITT population and key biomarker-defined subgroups (t(11;14) and BCL2high). Pts with missing or indeterminate assessments were considered MRD positive. Correlation with PFS, DOR, OS, and patient-reported outcomes (e.g., physical functioning, pain scores, fatigue) will be presented. Results: As of 14 Feb 2020, 49 pts were enrolled (4 in cohort 1, 3 in cohort 2, 7 in cohort 4 and 35 in cohort 3 + expansion). Pts had received a median of 2 (1-3) prior lines of therapy, 96% were exposed to PI (57% refractory), 90% exposed to IMiD (71% refractory), and 86% exposed to PI + IMiD (45% double refractory). Median age was 60 years (37 - 79), 61% had ISS II/III disease, 27% had t(11;14), and 45% were BCL2high. Of note, 8 out of the 22 (36.4%) BCL2high pts were t(11;14) positive. Overall response rate (ORR) was 80% (≥PR), including 65% ≥ VGPR and 41% ≥CR (Table 1). Among t(11;14) pts, ORR was 92%, ≥ VGPR 85%, and ≥CR 54%; while among BCL2high pts ORR was 86%, ≥ VGPR 77%, and ≥CR 41%. Of the 19 pts assessed for MRD by NGS, 15 (79%) had clonotypes identified at baseline. Of these 15 pts, 6 (40%) achieved MRD negativity ( & lt;10-5) by NGS in the bone marrow after VenKd treatment. Of the 12 pts who participated in the FDG-PET sub-study, 10 (83%) were FDG-PET positive at baseline, and 8 (67%) completed post-treatment FDG-PET imaging. Of these 8 pts, 3 (38%) achieved complete metabolic response (CMR) by FDG-PET imaging after VenKd treatment. While only 4 pts were evaluated concurrently for MRD by NGS and FDG-PET/CT imaging, the assessments were concordant for 3 pts (2 positive, 1 negative). The discordant result (NGS negative, FDG-PET/CT positive lymph node) indicated clearance of disease in the bone marrow while the presence of a potential soft tissue plasmacytoma remaining after treatment with VenKd. Of the 19 pts evaluated by either NGS or FDG-PET/CT, 8 (42%) achieved MRD negativity by NGS in the bone marrow or CMR by FDG-PET/CT after VenKd treatment. The highest rates of MRD negativity were observed in t(11;14) and BCL2high subgroups (Table). Conclusions: The combination of VenKd demonstrates promising efficacy in pts with R/R MM, including high rates of MRD, particularly in the t(11;14) and BCL2high subgroups. Overall, MRD assessments by NGS and FDG-PET/CT were highly concordant in this study and may be complementary for assessment of disease clearance in MM. Disclosures Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Burwick:AbbVie: Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Kaufman:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cabanillas:AbbVie: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Masud:AbbVie: Current Employment, Other: may hold stock or stock options . Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Bueno:AbbVie: Current Employment, Current equity holder in publicly-traded company. Mudd:AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Davies:Oncopeptides: Consultancy, 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, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: This is a summary of a publication about Black participants of the GRIFFIN clinical study that was published in Blood Cancer Journal in April 2022. The GRIFFIN clinical study looked at the treatment combination of daratumumab plus a standard therapy for multiple myeloma (called RVd therapy, which stands for lenalidomide, bortezomib, and dexamethasone) in adult patients who had not been treated before for multiple myeloma and so were considered to have newly diagnosed multiply myeloma. Multiple myeloma is a blood cancer of plasma cells. Based on the participants' age, medical history, and indicators of good general health, the participants in the GRIFFIN study were also eligible to receive autologous stem cell transplant as part of their therapy. This summary describes results for the Black participants of the GRIFFIN clinical study who received daratumumab plus RVd therapy (called D-RVd) to see if D-RVd therapy is better than RVd therapy at reducing the amount of multiple myeloma cancer cells in a patient's body. Why did the researchers evaluate the results for Black patients in the GRIFFIN study? Due to racial disparities leading to historically low representation of minority groups in clinical studies, optimal treatments are not defined for Black patients with newly diagnosed multiple myeloma. Since previously published results from the overall population in the GRIFFIN study indicated that D-RVd therapy was better than RVd therapy, the researchers wanted to determine if this was also the case among Black participants. What were the results? Out of 207 participants in the GRIFFIN study, 15% (32 participants) were Black and 78% (161 participants) were White. In both Black and White participants, D-RVd therapy reduced the amount of myeloma cancer cells more than RVd therapy. Additionally, D-RVd and RVd therapy had similar safety results for Black and White participants. What do the results mean? This analysis of GRIFFIN by race shows that Black people benefit from the daratumumab-containing D-RVd therapy as much as White people. Additionally, D-RVd therapy had similar safety results to RVd therapy for both Black and White people. Clinical Trial Registration: NCT02874742 ( ClinicalTrials.gov )

Abstract: Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Abstract: The oral proteasome inhibitor oprozomib has shown preclinical antitumor activity. Here, we report phase Ib/II study results investigating single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia. Patients and Methods: The primary objectives were to determine the MTD, safety, and tolerability of oprozomib (phase Ib) as well as overall response rate (ORR; phase II). Oprozomib was administered once daily on days 1, 2, 8, and 9 (2/7 schedule) or days 1 to 5 (5/14 schedule) of a 14-day cycle. Results: In patients with multiple myeloma or Waldenström macroglobulinemia (n = 71), the determined MTDs were 300 mg/day (2/7 schedule) and 240 mg/day (5/14 schedule). Median oprozomib treatment duration for patients with multiple myeloma was 11.4 weeks (2/7 schedule, 240/300 mg/day), 5.4 weeks (5/14, 240 mg/day), and 10.1 weeks (5/14, 150/180 mg/day). For patients with Waldenström macroglobulinemia, these values were 34.6 weeks (2/7 schedule, 240/300 mg/day) and 8.1 weeks (5/14 schedule, 240 mg/day). The most common grade ≥3 adverse events (AE) in phase Ib included gastrointestinal and hematologic AEs. Three AE-related deaths in phase II prompted enrollment into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). In phase II, ORRs in 95 response-eligible multiple myeloma patients were 41.0%, 28.1%, and 25.0% in the 2/7, 240/300-mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. ORRs in 31 response-eligible Waldenström macroglobulinemia patients were 71.4% and 47.1% for the 2/7 and 5/14 cohorts, respectively. Conclusions: This study demonstrated promising efficacy of single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.