Citations

Introduction: Iberdomide (IBER; CC-220) is a potent, novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a phase 1/2 dose-escalation study in relapsed/refractory multiple myeloma (MM) (CC-220-MM-001; NCT02773030). IBER modulates CRBN to induce ubiquitination and proteasome-dependent degradation of Ikaros/Aiolos, resulting in anti-myeloma and immunomodulatory activity. Compared with immunomodulatory drugs (IMiDs), IBER binds to CRBN with 20-fold higher affinity and is more efficient at degrading Ikaros/Aiolos. Additionally, IBER can overcome IMiD drug resistance. Here, we evaluate the preclinical activity of IBER in combination with monoclonal antibodies (mAbs) and assess immune pharmacodynamic changes of IBER + daratumumab (DARA) among patients in the CC-220-MM-001 study. Methods: Preclinical analyses were performed on MM cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. In co-culture assays, cell lines and immune cells were treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), and IBER (20 nM) alone, and in combination with DARA or elotuzumab (ELO). Clinical biomarker data were obtained from blood samples of patients enrolled in IBER + dexamethasone (DEX) and IBER + DARA + DEX cohorts of the CC-220-MM-001 study. Immune profiling was evaluated by flow cytometry on Cycle (C) 1 Day (D) 1, C2D15, C4D1, and C4D15. Results: Treatment of CD3-stimulated PBMCs with IBER increased cytokine secretion more potently than with IMiD drugs, promoting natural killer (NK) cell proliferation and increasing NK cell numbers by > 30% in cultures. Treatment of CD3-stimulated PBMCs with IBER also promoted immune-mediated killing of MM cell lines, and pretreatment of MM cell lines for 48 h followed by washout sensitized cells to immune-mediated clearance. IBER treatment of MM cells increased protein expression of CD38, but had no discernable effect on SLAMF7 expression. IBER in combination with DARA or ELO enhanced the immune-mediated killing of MM cell lines and resulted in deeper cell killing compared with LEN or POM when combined with the same mAbs. Analogous to preclinical data, immune profiling of patients treated with IBER + DEX demonstrated an immune-stimulatory effect, including increased proliferating NK and T cells. Notably, patients coming on trial directly after a DARA-containing regimen showed depleted NK cell counts, which rebounded by nearly 2-fold after 1 cycle of IBER + DEX. Additionally, the effects of IBER on T and NK cell proliferation were similar in patients treated with IBER + DEX + DARA and IBER + DEX, except for overall reduction in CD38-expressing NK and T cells in patients receiving DARA. Conclusions: IBER induced immune-stimulatory activity more potently than LEN or POM, enhancing cytokine release and NK cell proliferation. MM cells treated with IBER were also sensitized to immune-mediated clearance. These data suggest that IBER may enhance the activity of biologics that exert anti-malignant activity through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Accordingly, IBER enhanced the activity of DARA and ELO in co-culture. IBER also induced an immune-stimulatory effect on NK and T cells in vivo, confirming immune-stimulatory effects of IBER in patients with MM. Notably, the effect of IBER on NK cells was more pronounced in patients whose last treatment regimen contained DARA, suggesting IBER treatment may contribute to NK cell recovery after DARA treatment. Furthermore, immune changes observed by the addition of DARA to IBER + DEX were similar, suggesting IBER was the primary agent promoting immunomodulation in this triplet therapy. Together, these data support continued clinical development of IBER in combination with CD38- and SLAMF7-directed mAbs as well as other immune-directed therapies for the treatment of MM. Disclosures Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ma:Bristol Myers Squibb: Current Employment. Wollerman:Bristol Myers Squibb: Current Employment. Pierceall:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Onyx: Honoraria; Millennium: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. van de Donk:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ferrer: Membership on an entity's Board of Directors or advisory committees. Popat:Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Zonder:Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; Prothena: Consultancy; Janssen: Consultancy, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Caelum: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Minnema:Kite, a Gilead Company: Speakers Bureau; Servier: Consultancy; Amgen: Consultancy; Celgene: Other: travel support, Research Funding. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larsen:Janssen Oncology: 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. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Rodriguez-Otero:Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Nguyen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hong:Bristol Myers Squibb: Current Employment. Sorrell:Bristol Myers Squibb: Current Employment; Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1. Thakurta:Bristol Myers Squibb: Current Employment; Oxford University: Other: Visiting professor.

Introduction: Iberdomide (IBER; CC-220) is a potent, novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a phase 1/2 dose-escalation study for relapsed/refractory multiple myeloma (MM) (CC-220-MM-001; NCT02773030). IBER modulates CRBN to induce ubiquitination and proteasome-dependent degradation of Ikaros/Aiolos, resulting in antimyeloma and immunomodulatory activity. Compared with immunomodulatory drugs (IMiDs); IBER binds to CRBN with 20-fold higher affinity and is more efficient at degrading Ikaros/Aiolos. Additionally, IBER can overcome IMiD drug resistance. Here, we compare the preclinical activity of IBER versus IMiD drugs + proteasome inhibitors (PIs), and assess the pharmacodynamic (PD) activity of IBER in patients treated with IBER + dexamethasone (DEX), IBER + DEX + bortezomib (BORT), and IBER + DEX + carfilzomib (CFZ). Methods: MM cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were analyzed. Cell lines treated with PIs (BORT and CFZ) were pulsed with drug for 1 h, and then treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), or IBER (20 nM). Biomarker data for PD analyses were obtained from blood samples of patients enrolled in the IBER + DEX, IBER + DEX + BORT, and IBER + DEX + CFZ cohorts of the CC-220-MM-001 study. Degradation of Ikaros/Aiolos in peripheral blood was analyzed on Cycle (C) 1 Day (D) 1, pre-dose, and post IBER/IBER + PI dose by flow cytometry. Immune profiling was evaluated by flow cytometry from peripheral blood at C1D1, C2D15, C4D1, and C4D15. Results : Proteasome inhibition in cell lines after 1 h pulse of PI was maintained after washout. However, substrate degradation by IBER was affected only minimally by combination with PIs, and was more potent than by LEN or POM. These results correlate with synergistic antiproliferative activity and more potent tumoricidal activity in cell lines treated with IBER + PI than IMiD + PI combinations. Furthermore, ex vivo treatment of PBMCs with IBER + PIs minimally affected cytokine induction by IBER. Analysis of patient samples from the CC-220-MM-001 study confirmed preclinical observations showing minimal inhibition of IBER PD with the addition of PIs to the treatment regimen. In patient T cells, Ikaros and Aiolos protein levels decreased by > 50% and > 70%, respectively, with IBER + DEX, and by > 30% and > 45% (at lower IBER doses) with IBER + DEX + BORT or IBER + DEX + CFX. In all cohorts, the nadir of substrate expression was determined to be 6 h. After repeated dosing (mid-C1) patients treated with IBER + PIs showed > 70% decreases in both Ikaros and Aiolos expression. Furthermore, immune profiling of patients showed that the addition of PIs to the IBER treatment regimen did not inhibit immune-stimulatory activity of IBER, including induction of NK and T cell proliferation. Conclusions: Preclinically, IBER induced substrate degradation in the presence of PIs, and treatment with IBER + PIs resulted in substantially increased tumoricidal activity. Deeper substrate degradation and increased apoptosis were also observed when PIs were combined with IBER versus IMiD drugs. Clinically, IBER led to rapid decreases in substrate levels, even in the presence of PIs, and levels were reduced further with repeated dosing, suggesting that concurrent administration of PIs minimally affects proteasomal degradation of substrates mediated by IBER. Furthermore, increases in NK and T cell proliferation in IBER-treated patients were consistent whether or not they also received a PI, further confirming that IBER has immune-stimulatory activity in combination with PIs. These data support continued clinical development of IBER in combination with PIs for the treatment of MM. Disclosures Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kang:Bristol Myers Squibb: Current Employment. Mukhopadhyay:Bristol Myers Squibb: Other: Contract scientist, Research & Early Development. Jiménez Nuñez:CITRE, a Bristol-Myers Squibb Company: Current Employment. Wong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lonial:Merck: Consultancy, Honoraria, Other: Personal fees; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Millennium: Consultancy, Honoraria; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria. van de Donk:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Popat:GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Zonder:Caelum: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Minnema:Celgene: Other: travel support, Research Funding; Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau. Oriol:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larsen:Janssen Oncology: 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. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Rodriguez-Otero:Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Oncopeptides: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Nguyen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hong:Bristol Myers Squibb: Current Employment. Sorrell:Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1; Bristol Myers Squibb: Current Employment. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Background: Multiple myeloma (MM) occurs most commonly among the older population, with a median age of 69 years at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options for patients with hematologic malignancies, including MM. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated deep and durable responses in the pivotal phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory MM (RRMM; Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall response rate (ORR), complete response (CR) rate, median duration of response (DOR), and median progression-free survival (PFS) were 73%, 33%, 10.7 months, and 8.8 months, respectively, among all 128 patients treated across the target dose levels of 150-450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells. The safety profile of ide-cel was consistent with the mechanism of action of CAR T cell therapies, with the most common toxicities across all dose levels being cytopenia (97%) and cytokine release syndrome (84%). In the present analyses, the efficacy and safety of ide-cel in elderly patients in the KarMMa study were evaluated. Methods: Patients enrolled in the KarMMa trial (NCT03361748) were required to have ≥3 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to their last regimen per International Myeloma Working Group (IMWG) criteria. Patients received ide-cel at target doses of 150, 300, or 450 × 106 CAR+ T cells after 3 days of lymphodepletion with cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) followed by 2 days of rest. The primary endpoint was ORR, and the key secondary endpoint was CR rate. Additional secondary endpoints included DOR, PFS, and safety. Patients were classified into ≥65 years and ≥70 years subgroups for analysis. Responses were assessed according to IMWG guidelines, and DOR and PFS were analyzed using Kaplan-Meier methods. Results: Of the 128 patients treated with ide-cel, 45 (35%) were aged ≥65 years and 20 (16%) were aged ≥70 years. The median age within these age groups was 69 years (range, 65-78) and 73 years (range, 70-78), the median number of prior antimyeloma regimens was 6 and 5, and the median time since initial diagnosis was 6.7 years and 6.1 years, respectively. Baseline characteristics were generally similar between age groups with the exception of tumor burden. Response rates for both age groups were comparable with those of the overall ide-cel treated population, with ORRs of 84% to 90% and CR rates of 31% to 35% (Table). Likewise, median DOR among responders in both age groups (10.9 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. At the time of analysis, overall survival data were still immature. No new safety signals were observed in either of the older age groups compared with those in the overall ide-cel treated population (Table). Conclusions: These results demonstrate deep and durable responses with ide-cel treatment together with a manageable safety profile in triple-class exposed patients with RRMM aged ≥65 years and ≥70 years. Outcomes were comparable with those observed in the overall ide-cel treated population. These data suggest ide-cel is safe and effective in older patients and provide further evidence supporting ide-cel as a promising treatment option in RRMM. Figure 1 Disclosures Berdeja: Karyopharm: Consultancy; Kite Pharma: Consultancy; Cellularity: Research Funding; Acetylon: Research Funding; Genentech, Inc.: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Lilly: Research Funding; Janssen: Consultancy, Research Funding; EMD Sorono: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glenmark: Research Funding; Kesios: Research Funding; Legend: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; CURIS: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Poseida: Research Funding. Raje:Takeda: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Immuneel: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Research Funding; Amgen: Consultancy. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Lin:Gamida Cells: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rodriguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Manier:Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene/BMS: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Jenssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Consultancy; Takeda: Consultancy. Einsele:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Sanford:BMS: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Jagannath:Takeda: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

Background: Ide-cel, a BCMA-directed CAR T cell therapy, showed tolerability and promising efficacy in patients with relapsed and/or refractory multiple myeloma (RRMM) in the first-in-human phase 1 CRB-401 study (Raje et al. N Engl J Med. 2019;380:1726) and the pivotal phase 2 KarMMa study (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). Ide-cel demonstrated a favorable benefit-risk profile with an overall response rate (ORR) of 85%, a complete response (CR) rate of 45%, and a median progression-free survival (PFS) of 11.8 months in the first 33 patients treated in CRB-401. Reported here are updated safety and efficacy results for 62 patients who received ide-cel in the ongoing CRB-401 study. Methods: CRB-401 (NCT02658929) is a 2-part, phase 1 dose-escalation and -expansion study. The expansion phase enrolled patients who had received ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody, and were refractory to their last line of therapy. Eligibility criteria for the dose-escalation phase were described previously (Raje et al. N Engl J Med. 2019;380:1726). After lymphodepletion with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) for 3 days followed by 2 days of rest, patients received ide-cel at target doses of 50, 150, 450, or 800 × 106 CAR+ T cells in the dose-escalation phase and 150 to 450 × 106 CAR+ T cells in the dose-expansion phase. The primary endpoint was safety. Secondary endpoints included tumor response according to the International Myeloma Working Group criteria. Exploratory endpoints included PFS, overall survival (OS), and minimal residual disease (MRD). Results: As of January 14, 2020, 21 patients had received ide-cel in the dose-escalation phase, and 41 patients received ide-cel in the dose-expansion phase. The median age was 61 years, and 44% of patients had high tumor burden (≥50% bone marrow CD138+ plasma cells). Of the 62 patients, 45% received >6 prior regimens, 90% were daratumumab-exposed, and 77% were daratumumab-refractory. As of the cutoff date, 13 patients were ongoing, and 49 patients had discontinued the study. Reasons for study discontinuation were progressive disease (58%), withdrawal by patients (10%), and death (10%). Based on safety and efficacy in the dose-escalation phase, target dose levels of 150 to 450 × 106 CAR+ T cells were selected for the dose-expansion phase. The most frequent adverse events (AEs) were neutropenia (92%), cytokine release syndrome (CRS; 76%), anemia (76%), and thrombocytopenia (74%). The most frequent grade 3/4 AEs were neutropenia (89%), leukopenia (61%), anemia (57%), and thrombocytopenia (57%). Most CRS events were grade 1 or 2 (Table). Four patients (7%) had grade 3 CRS; there were no grade >3 CRS events. The incidence of CRS generally increased with target dose level. Neurologic toxicity (NT; clustered term) occurred in 27 patients (44%) and was primarily grade 1/2 with 1 patient having grade 3 and 1 patient having grade 4 NT. Among all 62 patients in the dose-escalation and -expansion phases, the ORR was 76%, including 24 patients (39%) with a CR or better and 40 patients (65%) with a very good partial response or better. The median duration of response was 10.3 months. Of 37 responders evaluable for MRD, 30 were MRD negative (≤10−4 nucleated cells) at 1 or more time point, and 7 responders were MRD positive. With a median follow-up of 14.7 months for all patients in the dose-escalation and dose-expansion phases, median PFS was 8.8 months and median OS was 34.2 months. Overall, a dose-dependent effect was observed on responses and survival outcomes, with greater efficacy reported at ≥150 × 106 CAR+ T cells (Table). Conclusions: Ide-cel demonstrated deep and durable responses in heavily-pretreated RRMM patients. Efficacy and safety reflect prior reports and support a favorable clinical benefit-risk profile for ide-cel at target dose levels ≥150 × 106 CAR+ T cells. Table Disclosures Lin: Novartis: Consultancy; Janssen: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Raje:Caribou: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Takeda: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Astrazeneca: Consultancy; Amgen: Consultancy. Berdeja:Abbvie: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Vivolux: Research Funding; Genentech, Inc.: Research Funding; Bluebird: Research Funding; Lilly: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bioclinica: Consultancy; EMD Sorono: Research Funding; Acetylon: Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Kesios: Research Funding; CURIS: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Jagannath:Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Madduri:Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Foundation Medicine: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Liedtke:Pfizer: Honoraria; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Celgene: Research Funding. Maus:arcellx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; kite: Consultancy, Research Funding. Massaro:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Caia:Celgene a BMS company: Current Employment, Current equity holder in publicly-traded company. Yang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Celgene: Ended employment in the past 24 months. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; C4: Current equity holder in private company; Amgen: Consultancy; Legend: Consultancy. Kochenderfer:Celgene: Patents & Royalties, Research Funding; bluebird, bio: Patents & Royalties; Kite, a Gilead company: Patents & Royalties, Research Funding.

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM). bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007 during ex vivo culture to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. To investigate whether DP properties correlate with clinical outcomes including duration of response (DOR), we conducted extensive molecular characterization of patient DPs. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in RRMM patients who received ≥3 prior regimens, including proteasome inhibitor and immunomodulatory agent, or are double-refractory to both classes. In the expansion cohort, patients additionally required prior exposure to an anti-CD38 antibody and were required to be refractory to last line. Planned enrollment is 74 patients, including 50 in the expansion cohort. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive a single infusion of bb21217 at 150, 300 or 450 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. We profiled DP and apheresis starting material (PBMC) by RNAseq and cyTOF and correlated expression of memory/senescence markers from apheresis to DP with clinical outcomes, including DOR. Results: Asof March 1, 2020, 46 patients (median age 62 [33-74]) received bb21217, 24 in escalation (12 at 150, 6 at 300 and 6 at 450) and 22 in expansion (8 at 300 and 14 at 450); median follow up for all patients is 8.5 (<1-29) months. Patients had a median of 6 (3-17) prior lines of therapy with 26/46 (57%) triple refractory. Cytokine release syndrome (CRS) developed in 31/46 (67%) patients and included one death (14 G1, 15 G2, 1 G3 and 1 G5). Median time to first onset was 3 days (1-20); tocilizumab (18 pts) +/- corticosteroids (6 pts) was used to manage CRS. Ten (22%) patients developed neurotoxicity [5 G1, 2 G2, 2 G3, 1 G4] with median time to first onset of 7 (3-24) days. Response was assessed per investigator for 44 patients with ≥ 2 months of follow up or PD/death within 2 months. Twenty-four (55%) patients had confirmed response per IMWG criteria including 8 (18%) with ≥CR and 13 (30%) with VGPR. Median time to CR was 2.5 (1-24) months. The median DOR was 11.9 (95% CI: 8.1-17.0) months across target dose levels of 150-450 x106 CAR+ T cells. The 450 target dose was selected as the RP2D and dose expansion is ongoing. bb21217 DPs from 44 patients were characterized. Paired analysis of T cells from PBMC and DP showed bb21217 DP is significantly enriched for memory-like T cells (LEF1+, CD27+, CCR7+) and depleted of highly differentiated or senescent CD57+ T cells. Patients with DPs most enriched for early memory markers (LEF1+, CCR7+ and CD27+) and with low expression of effector/exhaustion markers (EOMES+, GZMA+, CD57+) were more likely to have higher peak CAR+ T cell expansion. To evaluate the association of these DP markers with DOR, we split the 24 responders (≥PR) on median marker expression (high vs low) and analyzed DOR in these exploratory subgroups. High CD127 expression, associated with long-lasting memory T cell formation, was positively correlated with DOR, while multiple markers associated with differentiated T cells (e.g. EOMES+, TBET+) were negatively correlated with DOR. Conclusions: The adverse events observed are consistent with known toxicities of CAR T cell therapies. Initial efficacy results with bb21217 are encouraging, with 48% of patients treated across target dose levels of 150-450 obtaining ≥VGPR. The presence of T cell markers associated with memory and the absence of T cells markers associated with differentiation/senescence in DP correlated positively with peak expansion and DOR. These preliminary correlative data support the mechanistic hypothesis that enrichment for memory like T cells in bb21217 DP may result in improved clinical outcomes. Data for approximately 14 additional patients at the 450 target dose will be presented. Disclosures Alsina: Janssen: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Raje:Janssen: Consultancy; Celgene: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Astrazeneca: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Karyopharm: Consultancy; BMS: Consultancy; Amgen: Consultancy. Jagannath:Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy. Kaufman:Janssen: Consultancy, Honoraria; Karyopharm: 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; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Celulatiry: Consultancy. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, 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. Timm:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Turka:bluebird bio: Current Employment. Mao:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences: Divested equity in a private or publicly-traded company in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses, Patents & Royalties: Numerous, Research Funding. Bitter:Novartis AG, Predicant Biosciences, Biospect, F Hofmann-La Roche: Ended employment in the past 24 months; bluebird bio: Current Employment, Current equity holder in publicly-traded company; Novartis: Ended employment in the past 24 months, Patents & Royalties. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Berdeja:Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Kesios: Research Funding; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Vivolux: Research Funding.

SummaryAlthough new multiple myeloma (MM) therapies are effective in alleviating some disease‐associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health‐related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide‐bortezomib‐dexamethasone [RVd (n = 445)], bortezomib‐melphalan‐prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy‐Multiple Myeloma subscale, EuroQol‐5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real‐world, largely community‐based population of patients with NDMM.

BackgroundMultiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard‐risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent.MethodsThis study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187).ResultsAfrican Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation–Comorbidity Index (HCT‐CI). Fewer African Americans with t(11;14) (21%) had a coexistent high‐risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression‐free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30‐0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT‐CI, and receipt of maintenance.ConclusionsRace may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

8537 Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had > 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range >1.9 to >9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (>8.5 mos) (range >1 d to >8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM. [Table: see text] [Table: see text]

8504 Background: CFZ is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of proteasome selectivityand demonstrates antitumor activity in bortezomib (BTZ)-resistant MM pts in phase I studies. Methods: PX-171–003-A0 was an open-label, multicenter study that enrolled MM pts who relapsed from >2 prior therapies, failed BTZ and at least 1 immunomodulatory agent [thalidomide (THAL) or lenalidomide (LEN)], and were refractory to last treatment [progressing on or within 60 d of last therapy or <25% response to last therapy]. Pts received CFZ 20 mg/m2 IV d 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C). Clinical benefit response (CBR) was defined as MR or better. Results: 46 pts were enrolled, including 78% with progression on or within 60 d of last therapy and 22% with no response to last therapy. 39 pts completed at least 1 C of CFZ, had measurable M-protein, and were evaluable for response. Median prior therapies was 5 (range 2–15). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplant (SCT) and all had failed combinations including anthracyclines (80%) and/or alkylating agents (94%). Pts received a median of 3 C (range 1–12); 13 pts completed ≥6 C. CBR was 26% (10/39 eval pts), including 5 pts achieving PR and 5 pts achieving MR. 5 BTZ-refractory pts achieved MR or PR. Median TTP was 6.2 mo, the median DOR for the MR + PR was 7.4 mo. 8/10 pts achieved response during C1. 16 additional pts achieved SD for at least 6 wks. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine and diarrhea. Peripheral neuropathy occured in < 10% of pts with 1 Gr 3 in a pt with pre-existing Gr 2. Conclusions: Single-agent CFZ achieved a TTP of > 6 mo in relapsed and refractory MM pts who failed available therapies. 26% of patients had at least an MR and median duration of >7 mo with this steroid- and anthracycline-sparing regimen. CFZ toxicities were manageable and importantly, exacerbation of pre-existing PN was rare. The study has been expanded to enroll an additional 250 pts in this unmet medical need population at an escalated dose, and treatment has been extended beyond a year. [Table: see text]