Updated results highlight the range of differentiated research platforms across BMS’ multiple myeloma pipeline, including cell therapy and protein degradation

Data will be presented for first-in-class GPRC5D CAR T BMS-986393, novel CELMoD™ agent mezigdomide, and unique 2+1 bispecific T cell engager alnuctamab

Bristol Myers Squibb (NYSE: BMY) today announced updated results from three key programs within its broad multiple myeloma research pipeline, highlighting its diverse targets and molecular approaches to address unique patient needs within the disease. These data were presented at the 65^th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

“The data from our multiple myeloma pipeline at ASH this year continue to demonstrate the progress we are making to deliver the best possible outcomes for patients, leveraging an array of targets matched to the right therapeutic modality based on insights from causal human biology,” said Michael Pourdehnad, M.D., senior vice president, Head of Early Clinical Development, Hematology Oncology and Cell Therapy Development, Bristol Myers Squibb. “These programs also represent the strength of our promising pipeline with a growing wave of registrational assets. As we continue to advance these programs, these data provide further evidence of the transformational potential of our cell therapy, protein degradation, and cell engager platforms.”

Results being presented at ASH provide updated evidence for programs including chimeric antigen receptor (CAR) T cell therapies, novel CELMoD™ agents from our leading protein degradation research platform, and bispecific T cell engagers (TCE):

• Updated data from the Phase 1 study of CAR T BMS-986393, a potential first-in-class cell therapy targeting GPRC5D, show deepening responses, a tolerable safety profile, and activity across both B-cell maturation antigen (BCMA)-naïve and -exposed patients (Oral Presentation #219)
• New results from the Phase 1 CC-92480-MM-002 study of oral CELMoD agent mezigdomide, including first results for cohorts evaluating mezigdomide and dexamethasone with monoclonal antibodies (anti-CD38 mAbs) daratumumab and elotuzumab (Oral Presentation #1013)
• Updated results of the Phase 1 study of alnuctamab, a 2+1 BCMA x CD3 bispecific TCE, show deepening and durable responses, including minimal residual disease (MRD) negativity, along with manageable safety (Poster Presentation #2011)

“Despite continuing advances in care for multiple myeloma, critical unmet needs remain as patients reflect a diverse spectrum of characteristics. Moreover, the disease remains marked by eventual relapse, making the long-term management of the disease paramount,” said Joseph Mikhael, M.D., Professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute and Chief Medical Officer of the International Myeloma Foundation. “Because of this heterogenous profile, having a broad array of options across the treatment path is extremely valuable. Seeing the range of new and updated data being presented at this meeting is encouraging as we look toward the future of myeloma therapy.”

GPRC5D CAR T (BMS-986393) Phase 1 Study Results

BMS-986393 is a first-in-class GPRC5D-directed autologous CAR T cell therapy that has the potential to be a best-in-class option for this emerging target.

This Phase 1, first-in-human, multicenter, open-label study is evaluating BMS-986393 in patients with relapsed/refractory multiple myeloma (RRMM) who had received three or more prior lines of therapy. Prior BCMA-targeted treatment, including CAR T cell therapy, was allowed. Primary objectives of the study were to determine safety and tolerability of BMS-986393 and inform the recommended dose for future development.

At the data cutoff of September 11, 2023 (median follow-up of 8.8 months), BMS-986393 continued to demonstrate an efficacy benefit with deep and durable responses in these heavily pretreated patients, including those with prior exposure to BCMA-targeted treatment. The overall response rate (ORR) was 91% (48% complete response rate) among patients treated with the recommended Phase 2 dose (RP2D, n=23), including an ORR of 100% (n=8) in patients with previous exposure to anti-BCMA targeting therapy. Minimal residual disease-negativity was observed in 86% (n=14) of evaluable patients.

BMS-986393 demonstrated a well-tolerated safety profile, and the RP2D was declared as 150 x 10⁶ CAR T cells without reaching the maximum tolerated dose. The benefit-risk profile remained consistent with earlier, previously presented data cuts. Overall, most patients regardless of treatment dose experienced a treatment emergent adverse event (n=84; any Grade: 91.7%, Grade 3/4: 82.1%). Cytokine release syndrome (CRS) was common with the majority of events being manageable and low grade (any Grade: 76.2%, Grade 3/4: 3.6%) including in patients treated at RP2D where all CRS events were Grade 1 (88.5%). ICANS-type neurotoxicity events were not common across all dose levels (any Grade: 9.5%, Grade 3: 2.4%) and were reversible with or without intervention; among patients treated at RP2D all ICANS events were low grade (any Grade: 3.8%, Grade 3/4: 0%). The incidence of non-ICANS neurotoxicity was similar for patients treated at RP2D as compared with all patients (15.4% vs. 10.7%, respectively). On-target/off-tumor skin, nail, and oral adverse events (AEs) were all low-grade, transient, and the majority (86%) did not require treatment.

These early clinical data suggest a single infusion of BMS-986393 is tolerable and efficacious in RRMM, including in those with prior exposure to BCMA-targeted therapy​, and a single-arm Phase 2 trial of BMS-986393 in patients with RRMM exposed to four or more classes of therapy (quadruple-class exposed) is planned to open in the first half of 2024.

Novel oral CELMoD™ agent mezigdomide Phase 1/2 Study Results

Cereblon E3 ligase modulators (CELMoDs), representing one of three modalities from the company’s leading protein degradation platform, are a class of oral therapeutics that are optimized to both stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. The CELMoD agents, mezigdomide and iberdomide, are adaptable combination and sequencing partners being investigated in multiple myeloma.

The mezigdomide CC-92480-MM-002 trial is an ongoing open-label, international Phase 1/2 study evaluating the safety and efficacy of mezigdomide with different treatment combinations in patients with RRMM. At ASH, first results were presented for combinations of mezigdomide and dexamethasone plus monoclonal antibodies (anti-CD38 mAbs) elotuzumab (MeziEd, Cohort H=21/28 days) or one of three dosing schedules of daratumumab (MeziDd, Cohort B1= 21/28 days, Cohort B2=14/21 days, Cohort B3=7/14 days x2). Patients had a median of 3 (range 2-5) prior therapies including stem cell transplantation, proteasome inhibitors, anti-CD38 agents or IMiD agents. The primary objectives of the study were to determine the RP2D, safety, and preliminary overall response rate (ORR).

Results at ASH showed mezigdomide combined with anti-CD38 mAbs showed encouraging efficacy in previously treated patients. Patients treated with MeziDd achieved a response regardless of dose and schedule, with ORR observed in 82.6% of patients in Cohort B1 (n=23), 62.1% of patients in Cohort B2 (n=18) and 88.9% of patients in Cohort B3 (n=18). MeziEd was active in patients who were refractory to prior anti-CD38 mAb therapy, with an ORR of 45% in Cohort H (n=20). MeziDd and MeziEd were pharmacodynamically active at all schedules and dose levels tested. Further investigation is underway to determine the optimal dose and schedule for MeziDd based on Cohort B3.

The safety profile of mezigdomide in combination with anti-CD38 mAbs was manageable and consistent with prior reports. Most Grade 3/4 treatment-emergent adverse events (TEAEs) following treatment with MeziDd or MeziEd were hematologic, with neutropenia being the most common and ranging from 40-70% across cohorts. The occurrence of Grade 3/4 non-hematologic TEAEs was relatively low with either combination.

Mezigdomide is currently being evaluated in two randomized pivotal Phase 3 studies, including SUCCESSOR-1 (NCT05519085: mezigdomide, bortezomib and dexamethasone vs. pomalidomide, bortezomib and dexamethasone in patients with lenalidomide-exposed RRMM) and SUCCESSOR-2 (NCT05552976: mezigdomide with carfilzomib and dexamethasone vs. carfilzomib and dexamethasone in patients with anti-CD38 and lenalidomide exposed RRMM).

Alnuctamab (BMS-986349/CC-93269) Phase 1 Study Results

Alnuctamab is a bispecific T cell engager (TCE) that simultaneously binds myeloma cells expressing BCMA and T cells (via CD3) in a unique 2:1 fashion. This interaction aims to drive myeloma cell death by inducing T cell activation and release of proinflammatory cytokines and cytolytic enzymes.

In the ongoing alnuctamab CC-93269-MM-001 open-label, Phase 1 study, 78 patients with RRMM were treated with subcutaneous (SC) alnuctamab in two step-up doses (3 mg and 6 mg) followed by escalating target doses of 10, 15, 30, and 60 mg, given every one week for three months, then every two weeks for three months, followed by every four weeks after those six months.

In updated results, SC alnuctamab showed durable responses with high anti-tumor activity observed at target dose of 30 mg (n=32), the dose selected for Phase 3. In the efficacy-evaluable patients treated with SC alnuctamab (n=73), the ORR was 53% across all doses and 67% at the 30 mg target dose. Median time to response was 1.2 months (range, 0.9–4.0) and responses deepened over time. Median progression-free survival (PFS) was 10.1 months (95% CI, 2.8–17.8) across all dose levels and 11.4 months (95% CI, 1.8 to not estimable) in the 30 mg target dose. Median duration of response (DOR) had not been reached at the time of data cutoff. All patients who achieved a response at the 30 mg target dose (14/14) were MRD-negative.

The safety profile was manageable and no Grade 3/4 CRS was observed. The most common Grade 3 or higher hematologic TEAEs across target doses (n=78) were neutropenia (46%), anemia (26%) and thrombocytopenia (17%) with the most common non-hematologic Grade 3 or higher TEAE being infections (17%).

A Phase 3 study of alnuctamab in patients with RRMM exposed to lenalidomide and an anti-CD38 monoclonal antibody is planned and will be initiated in the first half of 2024.

Bristol Myers Squibb: Transforming the Multiple Myeloma Treatment Paradigm

At BMS, we believe that every patient deserves a tailored treatment approach to achieve the best possible outcome for their disease, from extended survival and reduced treatment burden to the possibility of cure. Over two decades of trailblazing work in multiple myeloma, we have driven significant scientific and clinical advancements. As we look forward, we are leveraging our deep immunotherapy experience to progress an industry-leading pipeline across targets, molecular approaches and combinations (including BCMA-targeted therapies, targeted protein degradation, CAR T cell therapies and NK-cell engagers). Understanding that continued partnership with the multiple myeloma community is key to advancing scientific progress, we pride ourselves on an openness to collaborate, which is reflected in our ongoing research fueled by academic and industry partnerships. While multiple myeloma remains a relentless disease, we continue to transform the multiple myeloma treatment paradigm by dramatically improving outcomes for every patient.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. Learn more about the science behind cell therapy and ongoing research at Bristol Myers Squibb here.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

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This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that the product candidates described in this release may not receive regulatory approval for the indications described in this release, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidates for such indications will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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$BMY announces new data from its broad #multiplemyeloma pipeline at #ASH23.