Nguyen, Tuong Vi

Abstract Introduction : Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM; in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods : Eligible pts had RRMM; had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; had experienced disease progression within 60 days of last myeloma therapy; and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg; 20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results : As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years; median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts; 29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed; prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table); the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%; and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts; Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions : IBER + DEX demonstrated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy; this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. Figure 1 Figure 1. Disclosures Lonial: Abbvie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, 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; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: 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. Richardson: Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Janssen: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: 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; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Minnema: Cilag: Consultancy; Janssen: Consultancy; Alnylam: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; BMS: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Stadtmauer: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy.

Introduction: IBER is an oral, potent novel cereblon E3 ligase modulator (CELMoD) agent with marked synergistic tumoricidal and immune-stimulatory effects in combination with BORT or DARA in preclinical models. CC-220-MM-001 is a phase 1/2 study evaluating dose escalations of IBER with different treatment combinations in independent cohorts, in patients (pts) with RRMM (NCT02773030); the IBER + DEX cohort showed a favorable safety profile with promising efficacy and a selected IBER RP2D of 1.6 mg 21/28 days (D). Here, we present results from the IBER + DARA + DEX (IberDd) and IBER + BORT + DEX (IberVd) cohorts. Methods: Eligible pts had received ≥ 2 prior regimens in the IberDd cohort, and ≥ 1 prior regimen in the IberVd cohort, containing at least lenalidomide or pomalidomide, and a proteasome inhibitor (PI), and had experienced disease progression on or within 60 days of last MM therapy. Escalating doses of IBER were given orally, in the IberDd cohort on D1-21, with DARA (16 mg/kg) on D1, D8, D15, and D22 (cycles [C]1-2), D1 and D15 (C3-6), and D1 (C ≥ 7), of each 28-day cycle; in the IberVd cohort, on D1-14, with BORT (1.3 mg/m2) on D1, D4, D8, and D11 (C1-8), and on D1 and D8 (C ≥ 9), of each 21-day cycle. In both cohorts DEX was given weekly. Primary objectives were to evaluate MTD, RP2D, and safety separately for each cohort; a key secondary objective was preliminary assessment of efficacy. Immune profiling was evaluated by flow cytometry from pt peripheral blood at C1D1, C2D15, C4D1, and C4D15. Results: As of June 18, 2020, 19 pts had received IberDd and 21 pts IberVd. Baseline characteristics for the 2 independent cohorts are shown in the table. All pts were refractory to their last prior regimen, and exposure to prior regimens was heterogeneous. IBER doses ranged from 1.0 to 1.6 mg; the MTD/RP2D has not been reached in either cohort. Median follow-up was 5 (0-14) and 3 (0-11) months, 10 (53%) and 13 (62%) pts continue on treatment, median cycles received was 5 (1-14) and 4.5 (1-17), with IberDd and IberVd, respectively. Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 14 (78%) pts with IberDd, and in 13 (65%) pts with IberVd. Most frequent Gr 3-4 TEAEs of interest included neutropenia (50%), leukopenia (22%), and anemia (22%) with IberDd; and neutropenia (20%) and thrombocytopenia (20%) with IberVd. In both cohorts, neutropenia was managed with G-CSF. One pt (IberDd; 1.2 mg dose) had Gr 4 neutropenic sepsis. Occurrence of Gr 3-4 non-hematological TEAEs was low in both cohorts. One pt had Gr 2 infusion-related reaction with IberDd, and 3 pts had Gr 1-2 peripheral neuropathy with IberVd. Six (33%) and 4 (20%) pts had IBER dose reductions with IberDd and IberVd, respectively. In the IberDd cohort, with 12/19 (63%) DARA-refractory pts and 11 (58%) quad-class-refractory pts, the overall response rate (ORR) was 35% across all dosing groups (2 very good partial responses [VGPRs], 4 partial responses [PRs]); the clinical benefit rate (CBR) was 47% and disease control rate (DCR) was 88%. In the IberVd cohort, with 16/21 (76%) PI-refractory pts, 9 (43%) BORT-refractory pts, and 10 (48%) quad-class refractory pts, ORR was 50% (1 complete response, 3 VGPRs, 6 PRs); CBR was 65% and DCR was 85%. Responses with IberDd and IberVd were observed irrespective of DARA- and BORT-refractoriness, respectively. Median time to response was 4.1 (4.1-12.0) and 4.9 (3.0-13.1) weeks, in the IberDd and IberVd cohorts, respectively; median duration of response was not reached in both cohorts. Immune profiling showed dose-dependent decreases in B cells and increases in activated and differentiated T cells, in both cohorts. Except for reductions in CD38+ T cells in pts receiving IberDd, these observations were similar in pts treated with IBER + DEX. Conclusions: IberDd and IberVd showed a favorable tolerability profile in heavily pretreated RRMM pts, with promising clinical activity, even among pts refractory to the last prior regimen and previously exposed to IMiD agents, PIs, and CD38 antibodies. Immune-profiling data confirm that IBER + DEX was pharmacodynamically active in triplet combination and not augmented by the addition of DARA or BORT. The study is ongoing with continued enrollment at the 1.6 mg dose level for both cohorts. Updated results, including the MTD/RP2D, will be presented at the meeting. These results support the further development of IBER-based regimens in MM; phase 3 trials are planned to further evaluate these combinations. Disclosures van de Donk: Bristol Myers Squibb: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Ferrer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Popat:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). 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. Minnema:Servier: Consultancy; Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Oriol:Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Zonder:Prothena: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; BMS: Consultancy, Research Funding; Amgen: 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; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Caelum: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Rodriguez-Otero:Sanofi: 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); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Stadtmauer:Sanofi: Consultancy; AbbVie: Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding. Bringhen: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; Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy; Karyopharma: Consultancy, Honoraria. Gamberi:Janssen: Consultancy, Honoraria; GSK: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gironella Mesa:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. Nguyen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Di Micco:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sorrell:Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1; Bristol Myers Squibb: Current Employment. Chen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amatangelo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kueenburg:Celgene International Sàrl, a Bristol Myers Squibb Company, Boudry, Switzerland: Current Employment. Lonial:Onyx: Honoraria; Novartis: Consultancy, Honoraria, Other: Personal fees; Genentech: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Millennium: Consultancy, Honoraria; Karyopharm: Consultancy; Sanofi: Consultancy; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees.

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.

8006 Background: IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and DEX. Methods: A phase 1b/2a multicenter, open-label, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER. Eligible pts had RRMM and must have received ≥ 2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All pts had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in pts age > 75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose escalation committee. Results: As of Jan 2019,58 pts received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) pts and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% pts, respectively. Three pts discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table); 20 of 51 pts remain on treatment (2–27+ cycles). Conclusions: IBER + DEX showed favorable efficacy and safety in heavily pretreated pts with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT. Clinical trial information: NCT02773030. [Table: see text]

Introduction: Despite advances in treatment strategy, multiple myeloma (MM) remains a challenging, incurable disease as patients (pts) often relapse. Here we describe preclinical data of a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD), iberdomide (IBER; CC-220), as well as clinical and translational data from a current phase 1/2 clinical trial (NCT02773030). These data support a differentiated profile for IBER from immunomodulatory agents (IMiD agents), and development of IBER as a foundation of combination therapy for the treatment of relapsed/refractory MM (RRMM). Methods: Preclinical analyses were performed on pomalidomide (POM)-sensitive and acquired-resistant MM cell lines and peripheral blood mononuclear cells from healthy volunteers. Eligible pts enrolled on the clinical trial had RRMM and had received ≥ 2 prior regimens, containing at least an IMiD agent and proteasome inhibitor (PI), and had experienced disease progression within 60 days of last MM therapy. Escalating doses of IBER were given on Days 1-21, in combination with dexamethasone (DEX; 40 mg; 20 mg in pts aged > 75 years) on Days 1, 8, 15, and 22, of each 28-day cycle. Immunohistochemistry (IHC) data on CRBN, Ikaros, Aiolos, and ZFP91 expression was obtained from pt bone marrow specimens at screening and at Cycle 2, Day 15. Immune profiling was evaluated by flow cytometry of peripheral blood at Cycle 1, Day 1 and Cycle 2, Day 15. Primary objectives were to evaluate maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy. Results: Preclinically, IBER exhibited potent tumoricidal anti-MM and immunostimulatory activity. IBER was more potent than lenalidomide (LEN) or POM in overcoming the immunosuppressive activity of bortezomib (BORT), inducing a more than twofold increase in T cell proliferation in the presence of BORT. IBER also enhanced the antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of daratumumab (DARA), leading to deeper responses than combinations with LEN or POM. Further differentiating from both LEN and POM, IBER showed activity alone and in combination with BORT or DARA in POM-resistant MM cell lines. As of June 28, 2019, 69 pts with RRMM had received IBER + DEX. Median age was 65 years (range 33-80), and median number of prior regimens was 5 (range 2-12). Prior therapies included autologous stem cell transplantation (80%), LEN (100%), POM (70%), PIs (100%), DARA (71%) and anti-BCMA (6%), including CAR T cells. Clinical activity was observed across all dose levels with an overall response rate (ORR) of 29%, clinical benefit rate of 45%, and disease control rate of 80%. ORR was 30%, 28% and 29% in IMiD agent-refractory, DARA-refractory and Quad-class (IMiD agents/PIs/steroids/CD-38 antibodies)-refractory pts, respectively. IBER + DEX showed a favorable safety profile, with grade 3-4 neutropenia, infections, and thrombocytopenia, occurring in 29%, 25%, and 12% of pts, respectively. To date, IBER doses range from 0.3 to 1.3 mg and the MTD/RP2D has not yet been reached. Pharmacodynamic immunophenotyping changes were dose-dependent. Treatment with IBER (at doses > 0.75mg) + DEX doubled the percentage of proliferating T cells and NK cells (P < 0.001 for each) and increased activated and effector memory CD8+ and CD4+ T cells by > 50% (P < 0.01 for each subset). Pharmacodynamic changes in pt bone marrow by quantitative IHC scoring showed significant degradation of substrates (Ikaros, P = 0.006; Aiolos, P < 0.001; ZFP91, P < 0.001) and downregulation of c-myc (P = 0.027), including in pts refractory to POM and with low CRBN expression. Conclusions: IBER + DEX has shown notable clinical activity and favorable tolerability in heavily pretreated pts with RRMM, including pts refractory to prior IMiD therapy. Preclinical and translational data suggest a differentiated profile of IBER from IMiD agents in regard to activity in POM-resistant models, potency in combination with BORT and DARA, and by inducing changes in CD4+ T cells that were not observed in pts treated with POM from prior studies. Taken together, these data support a differentiated profile for IBER from IMiD agents, and the clinical development of IBER as a foundation of combination therapy for the treatment of RRMM. This study is ongoing, and includes cohorts evaluating the combinations of IBER + DEX with DARA, BORT, and carfilzomib. Updated results will be presented at the meeting. Disclosures Lonial: Karyopharm: Consultancy; GSK: Consultancy; Takeda: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings. Minnema:Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Servier: Honoraria; Jansen Cilag: Honoraria. Zonder:Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Oriol Rocafiguera:Celgene Corporation: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. Rodriguez Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Bristol-Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; AbbVie: Consultancy; Merck & Co.: Consultancy; Celgene Corporation: Consultancy. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene Corporation: 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; 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; Takeda: Consultancy. Gironella:Amgen: Honoraria; Janssen: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding. Cook:Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Nguyen:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Homan:Celgene Corporation: Employment. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Pierceall:Celgene Corporation: Employment, Equity Ownership. Bensmaine:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Van De Donk:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: 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, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees.