Larsen, Jeremy T.

Two Letters to Blood address the risks of COVID-19 in populations with precursors of hematological disease. In the first article, Miller and colleagues report on whether clonal hematopoiesis of intermediate potential (CHIP) is associated with adverse outcomes with COVID-19, finding no association between CHIP and 28-day mortality while providing data indirectly linking IL-6 signaling and patient outcomes. In the second article, Ho and colleagues investigate the outcomes of patients with monoclonal gammopathy of undetermined significance (MGUS) with COVID-19, reporting that one-fourth had a severe infection and that on multivariable analysis, adverse outcomes are more likely if immunoparesis is present.

Abstract Bortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib’s favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01864018.

SummaryBelantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

8022 Background: Bone marrow (BM) assessment of minimal residual disease (MRD) is being considered as a surrogate endpoint in clinical trials and is prognostic for survival in multiple myeloma (MM). Timing of BM assessment is variable across Chimeric Antigen Receptor T cell (CART) therapy trials and differs from standard of care practice. BM myeloma cell clearance can be detected by month 1 post CART, even before serum immunofixation becomes negative. BM is still hypocellular at month 1, thus prognostic value of MRD negative (MRDneg) at this timepoint is unclear. We examined impact of Day 30 MRD status in patients (pts) who received CART at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CART between 8/2016 and 6/2021. PFS and OS were plotted by Kaplan-Meier method. Results: Sixty MM pts received CART and had BM biopsy at month 1. Median age was 62 yrs, 53% were male, and 78% were BM MRDneg by flow cytometry. Baseline demographics were similar between MRDneg and MRD+ (Table). Overall, 85% (40/47) who were month 1 BM MRDneg had i/u FLC<normal. Patients who achieved CR/sCR had higher rates of BM MRDneg (100% vs 61%, p<0.001) and i/u FLC< normal (89% vs 58%, p<0.001). At month 1, 24/60 (40%) pts had hypocellular BM. Serial BM samples at month 3 (n=35), 6 (n=28) and 12 (n=23) showed MRDneg rate of 93% (25/27), 56% (9/16) 58% (7/12), respectively.. Rate of hypocellularity was 54% (19/35), 32% (9/28) and 30% (7/23), respectively. Among the MRDneg/hypocellular pts at month 1, hypocellular BM was seen in 8/11 (73%) pts at month 3 and 2/4 (50%) pts at month 6 and 12. Compared to MRD+, pts who had BM MRDneg at months1 had longer PFS (Table). PFS was not statistically significantly different between pts who had BM MRDneg and were either hypocellular or not. MRDneg pts with i/u FLC<normal at months1 had better median PFS compared to those who did not. (MRD+:2.9 months (1.2-NR). MRDneg/FLC>normal: 4.9 months (2.3-NR). vs MRDneg/FLC<normal:17.9 months (11.8-NR), p<0.0001). Conclusions: Hypocellular BM is common in the 3 months post CART. Regardless of BM cellularity, BM MRDneg at month 1 correlates with deep response and prolonged PFS. Majority of BM MRDneg pts at month 1 also had FLC<normal. BM MRDneg status and FLC normalization were associated with longer survival. Our data support the continued evaluation of BM early post CART infusion as a prognostic tool. [Table: see text]

AbstractWe retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv‐SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM‐AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3–41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM‐AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow‐up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5–123) and response duration 21.5 months (range 2.9–123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.

Abstract INTRODUCTION: Belantamab mafodotin (BLMF) is a first-in-class, antibody-drug conjugate targeting B-cell maturation antigen on myeloma cells. BLMF was approved for use in patients (pts) with advanced multiple myeloma (MM). Due to the risk of ocular toxicity, it is made available through a restricted program under a Risk Evaluation and Mitigation Strategy. It is speculated that monomethyl auristatin F (MMAF), the cytotoxic payload of BLMF may be internalised by the corneal epithelium via an off-target mechanism, leading to epithelial changes. In the pivotal DREAMM-2 trial, only 1% of pts permanently discontinued treatment due to keratopathy. Data regarding BLMF-induced ocular toxicity following its commercial availability since August 2020, are sparse, and in this context, we evaluated our clinical experience with BLMF to determine the impact of its ocular toxicity on outcomes when utilized outside of stringent clinical trial settings. METHODS: We reviewed records of pts with advanced MM who were evaluated at Mayo Clinic between 09/01/2020-07/01/2021 and initiated on BLMF monotherapy following a baseline ophthalmic examination that was also performed prior to each dose, and as needed for worsening ocular symptoms. Data pertaining to ocular symptoms, best corrected visual acuity (BCVA) and corneal examinations were collected and analyzed with respect to patient outcomes. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0. RESULTS: Thirty-four pts, with median age of 67 (range:49-90) years who received BLMF at the approved 2.5 mg/kg dose as their first infusion and completed at least one cycle were included. All patients were instructed to use preservative-free lubricant eye drops at least 4 times a day, starting with the initial infusion and continuing until the end of therapy, and avoid contact lenses. The median number of prior lines of therapy was 8 (range: 2-15). The median time to BLMF initiation from the diagnosis of MM was 7.5 (range: 1.3-19.7) years. The median follow-up from initiation of BLMF was 7 [95% confidence interval (CI): 5.7-8.6] months, and the median number of BLMF doses administered was 2 (range: 1-6). Twenty-seven (79%) pts experienced ocular toxicity, comprising keratopathy [n=25 (74%)] and/or decreased visual acuity [n=21 (62%)]. Table 1 outlines the keratopathy-related details. Thirteen pts (38%) developed symptomatic xerophthalmia. A clinically significant decrease in BCVA of equal or worse than 20/40 in the better-seeing eye was observed in 12 (35%) pts at a median of 1.7 (95%CI: 1.4-2.2) months of commencing BLMF. In 7 (58%) pts, it improved to better than 20/40 within a median of 3 (range: 0.7-4) months from the time of documentation of impaired BCVA following withholding treatment (n=5), with or without subsequent dose reduction or its permanent discontinuation (n=2). Treatment was permanently discontinued in 5 (15%) pts after a median of 3 doses due to grade ≥2 keratopathy. It was withheld in 9 (26%) due to grade ≥2 keratopathy. Four (12%) pts required dose reduction due to keratopathy (Table 1). Of 14 pts in whom BLMF was held or permanently discontinued due to keratopathy, 10 (77%) had disease progression within a median of 1 month (range 0.4-2.5) following BLMF interruption. Among 11 pts (32%) responded to BLMF, 45% developed grade 2 or higher keratopathy after the first dose compared to 13% of pts who were refractory to BLMF (n=23). The median duration of response was 4 (95%CI: 0.7-NR) months. Among responders, 2 pts (18%) had to permanently discontinue BLMF due to keratopathy, with subsequent progression from partial remission at 1.4 and 4.6 months following its discontinuation. Additionally, 73% of responders required dose withholding due to keratopathy and of those, 50% had evidence of disease progression within a median of 1.2 month (range: 0.7-1.7) following BLMF interruption. DISCUSSION & CONCLUSIONS : Despite efficacy in pts with advanced MM, in routine practice, ocular toxicity of BLMF is a major challenge and a deterrent to its continuous use. While frequent ocular toxicity-related interruptions were observed at expected rates, permanent treatment discontinuation due to keratopathy was observed in a higher proportion of pts than that encountered in the DREAMM-2 trial. Larger prospective studies are warranted to accurately discern the effects of ocular toxicities on outcomes of pts treated with BLMF. Figure 1 Figure 1. Disclosures Patel: Emmecell: Consultancy; GlaxoSmithKline: Consultancy; Senju Pharmaceuticals: Consultancy; Santen, Inc.: Consultancy. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: AbbVie: Consultancy; Xencor: Research Funding; Medimmune: Research Funding; Genentech: Consultancy; Ascentage: Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Karyopharm: Consultancy; Beigene: Consultancy. Bergsagel: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Karyopharm: Consultancy; AbbVie: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding.

Abstract Background :COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values &gt; 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406); the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (&gt;250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. Figure 1 Figure 1. Disclosures Munoz: Physicians' Education Resource: Honoraria; Seattle Genetics: Honoraria; Bayer: Research Funding; Gilead/Kite Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Incyte: Research Funding; PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding; GSK: Consultancy; Apellis: Consultancy; Alexion: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Kapoor: Sanofi: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Oncopeptides: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Merck: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Antengene: Consultancy, Honoraria; Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Gamida Cell: Consultancy; Takeda: Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.

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 &gt; 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.

Abstract Background: SUMOylation, a post-translational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in the immune system by regulating type I interferon (IFN-I) expression, thereby functioning to constrain the innate immune response (Decque Nat Immunol 2016), and limit tumor immune surveillance. The SUMOylation pathway is often overexpressed in multiple myeloma (MM) and is associated with poor outcomes (Driscoll Blood 2010). TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme, which blocks the SUMOylation cascade (Langston J Med Chem 2021) and increases IFN-I production and signaling in innate immune cells (Nakamura AACR 2019). In ex vivo assays, TAK-981 activated the IFN-I pathway, increased phagocytic activity of monocyte-derived macrophages, and increased natural killer (NK) cell cytotoxicity via IFN-I signaling (Nakamura AACR 2019). The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1). Patients with MM who have disease refractory to the three most effective classes of anti-myeloma therapies (proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], and anti-CD38 mAbs) have a poor prognosis, with median survival 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complex mechanisms of resistance, continued efforts to better understand MM biology at the time of relapse and to translate this into effective treatment combinations are needed. Combination therapies that engage the immune system to treat MM may offer substantial clinical benefit. Methods: To be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018), patients must have failed at least 3 prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to ≥1 PI and ≥1 IMiD, and refractory to ≥1 anti-CD38 mAb), and have demonstrated disease progression on their last therapy. Prior CAR-T therapy is allowed. Patients will be assigned to TAK-981 plus subcutaneous (SC) meza (Phase 1 Part 1) or SC dara (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary objectives of Phase 1b are to determine safety and tolerability, and to select the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary objectives are to evaluate preliminary antitumor activity, to characterize TAK-981 pharmacokinetics (PK), and to explore pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. Approximately 30 patients will participate in the Phase 1b Part 1 dose escalation of TAK-981 plus meza (~15 patients per dosing schedule), and ~15 patients will participate in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The primary objective of Phase 2 is to evaluate the efficacy of TAK-981 at the RP2D in combination with an anti-CD38 mAb; ~36 patients will be enrolled. In Phase 1b, patients will receive TAK-981 via a 1-hour intravenous infusion either on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or on days, 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. Meza 600 mg SC or dara 1800 mg SC will be given 8x weekly, 8x every other week, then monthly, in a 28-day cycle (Figure 2). Treatment will continue until disease progression or unacceptable toxicity (max. 24 cycles). TAK-981 dose escalation will proceed from 60 mg BIW, a dose shown to be pharmacologically active in a first-in-human, single-agent TAK-981 study (TAK-981-1002; data on file). Dose escalation will be guided by Bayesian Optimal Internal Design with Informative Prior (iBOIN) plus consideration of other safety, clinical, PK, and PD data. The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021. Figure 1 Figure 1. Disclosures Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria. Boccia: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Morphosis: Honoraria, Speakers Bureau. Yimer: Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Levy: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau. Abonour: Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding. Mohan: Medical College of Wisconsin: Current Employment. Girnius: BMS: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Genentech: Honoraria; GSK: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Speakers Bureau. Rosenbaum: Takeda: Honoraria; Akcea: Honoraria; Janssen: Honoraria. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Zhang: Takeda: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Novartis: Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. OffLabel Disclosure: Study of the investigational agent TAK-981 in combination with daratumumab and hyaluronidase-fihj or the investigational agent mezagitamab (TAK-079).