Bristol Myers Squibb Announces First Disclosures and New Data at ASH 2022, Demonstrating Commitment to Raising Standards in Treatment Through Broad Multiple Myeloma Portfolio

Studies highlight the range of targets and molecular approaches within the BMS multiple myeloma portfolio including bispecific T cell engager alnuctamab, first-in-class anti-BCMA CAR T cell therapy Abecma, GPRC5D CAR T (BMS-986393/CC-95266) and novel oral CELMoD^TM agents mezigdomide and iberdomide

PRINCETON, N.J.--(BUSINESS WIRE)--$BMY #BMS--Bristol Myers Squibb (NYSE: BMY) today announced the first disclosure of results and presentation of new research from its multiple myeloma portfolio across targets and molecular approaches at the 64^th American Society of Hematology (ASH) Annual Meeting and Exposition, underscoring the company’s commitment to raising standards to transform multiple myeloma outcomes for every patient.

“At ASH this year, we are highlighting the next wave of advances from our diverse multiple myeloma portfolio, reflecting our strategy of leveraging an array of approaches and targets against the disease,” said Samit Hirawat, M.D., executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb. “Through continued partnership with the multiple myeloma community, we are working to push toward a reality in which every patient would have an opportunity to receive a tailored treatment option that offers the best possible outcomes.”

Results being presented at ASH highlight scientific progress across bispecific T cell engagers (TCE), chimeric antigen receptor (CAR) T cell therapies and novel CELMoD^TM agents in advancing the treatment of relapsed/refractory multiple myeloma and include:

• First multicenter results from the Phase 1 study of bispecific TCE alnuctamab, administered subcutaneously every four weeks after six months, showing a reduction in inflammatory toxicity relative to intravenous administration, while maintaining anti-tumor activity with deep responses (Oral Presentation #162)
• First disclosure of Phase 1 results for GPRC5D CAR T (BMS-986393/CC-95266), demonstrating deep and durable responses with a manageable safety profile across all dose levels, including patients previously treated with a B-cell maturation antigen (BCMA)-directed CAR T cell therapy (Oral Presentation #364)
• Two first disclosures of results from cohorts 2a and 2c of the Phase 2 KarMMa-2 trial evaluating Abecma^® (idecabtagene vicleucel), demonstrating durable responses and predictable safety in patients with multiple myeloma after early relapse or suboptimal response to stem cell transplant (Oral Presentation #361, Poster Presentation #3314)
• First results from the dose expansion cohort of the mezigdomide Phase 1/2 study evaluating the novel oral CELMoD agent with dexamethasone (DEX), showing durable efficacy and a manageable safety profile in patients who were highly refractory to multiple prior therapies (Oral Presentation #568)
• New results from a cohort with patients previously exposed to a BCMA-targeted therapy of the iberdomide Phase 1/2 study, evaluating the novel oral CELMoD agent with DEX, demonstrating clinically meaningful efficacy and safety regardless of type of prior anti-BCMA treatment (Poster Presentation #1918)

“Multiple myeloma continues to be an immensely challenging disease which affects patients across a number of demographics, fitness levels and comorbidities. While scientific advances have driven significant improvements in survival, the disease remains characterized by relapses and a disease burden that greatly impacts a patient’s quality of life,” said Brian Durie, M.D., chairman of the board of the International Myeloma Foundation. “These promising data at ASH represent important progress, and I am encouraged by the next wave of potential advances across a diverse range of targets and platforms, which may provide treating physicians with many options that can be tailored for unique patient needs.”

Alnuctamab (BMS-986349/CC-93269) Phase 1 Study Results
Alnuctamab is a bispecific T cell engager (TCE) that simultaneously binds myeloma cells expressing B-cell maturation antigen (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, 138 patients with relapsed/refractory (R/R) multiple myeloma were enrolled (as of November 1, 2022) to receive escalating doses of alnuctamab administered either intravenously (IV) (n=70) or subcutaneously (SC) (n=68). Intravenous alnuctamab was administered as previously reported at target doses of 0.15–10 mg, with both fixed and step-up dosing, while SC alnuctamab was given to patients 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 interim results, SC alnuctamab (n=68) showed an improved safety profile compared to IV delivery, with cytokine release syndrome (CRS) limited to low-grade, short-lived events, allowing for dose escalation to higher target doses. Intravenous and SC alnuctamab both exhibited promising pharmacodynamic effects, triggering the release of the hallmark cytokines of TCEs(e.g., IL-1 and IL-6). However, SC alnuctamab triggered reduced and delayed cytokine production compared to more potent CRS induced by IV delivery. Subcutaneous alnuctamab also demonstrated encouraging dose-dependent anti-tumor activity across all target doses, particularly in patients who received the 30 mg target dose.

GPRC5D CAR T (BMS-986393/CC-95266) Phase 1 Study Results
GPRC5D has been identified as an orphan receptor that is highly expressed on multiple myeloma cells, with limited expression in other tissues. BMS-986393 is a GPRC5D-directed autologous CAR T cell therapy.

This Phase 1, first-in-human, multicenter, open-label study is evaluating BMS-986393 in patients with R/R multiple myeloma 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 time of the interim analysis, BMS-986393 demonstrated a well-tolerated safety profile with mostly low-grade and short-lived occurrences of CRS and neurotoxicity across all tested dose levels. Neurotoxicity was infrequent and low-grade, with no Grade 3 or 4 events reported, and events were reversible with steroid treatment. All on-target off-tumor adverse events were Grade 1, and the majority (78.6%) did not require treatment. Preliminary efficacy also supports the potential of BMS-986393 to elicit deep and durable responses.

Abecma^® (idecabtagene vicleucel) KarMMa Phase 2 Cohorts 2a and 2c Study Results
KarMMa-2 (NCT03601078) is a multi-cohort, open-label, multicenter Phase 2 trial evaluating Abecma in patients with relapsed and refractory multiple myeloma (Cohort 1), patients with multiple myeloma who have progressive disease within 18 months of initial treatment including autologous stem cell transplant (ASCT) (Cohort 2a), or in patients with inadequate response following ASCT during initial treatment (Cohort 2c). Based on results from Cohorts 2a and 2c, Abecma demonstrated complete and durable responses in a significant proportion of patients, alongside a well-established and predictable safety profile with mostly low-grade occurrences of CRS and neurotoxicity. Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio.

Novel CELMoD™ agents mezigdomide (CC-92480) and iberdomide (CC-220) Phase 1/2 Study Results
Cereblon E3 ligase modulators (CELMoD) are a class of oral immunomodulatory therapeutics that are designed to stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. Bristol Myers Squibb is investigating two novel CELMoD agents, mezigdomide and iberdomide, for multiple myeloma that were intentionally designed to improve upon the demonstrated efficacy of the IMiD^® agents, along with manageable tolerability, ease of administration, and the potential to improve patient outcomes. These agents co-opt cereblon to induce degradation of target proteins Ikaros and Aiolos, which inhibits tumor cell proliferation, promote tumor cell death, and induce immune-stimulatory effects.

The mezigdomide CC-92480-MM-001 trial is an ongoing open-label, international Phase 1/2 study to investigate the safety and efficacy of mezigdomide in combination with dexamethasone (DEX) in patients with relapsed/refractory (R/R) multiple myeloma. As part of the expansion cohort phase, 101 highly refractory patients that had received three or more prior lines of therapy, including an IMiD agent, a proteasome inhibitor (PI), and an anti-CD38 mAb, were given mezigdomide for 21 of 28 days in combination with weekly DEX at the recommended Phase 2 dose selected in part 1 of the study (1 mg once daily). The primary objective was efficacy as determined by objective response rate (ORR), while safety, tolerability and additional efficacy measures were included as the secondary objectives.

Based on interim results, mezigdomide, in combination with weekly DEX (40 mg; 20 mg if >75 years of age), showed promising efficacy in a highly refractory patient population. As of the data cut-off date, mezigdomide plus DEX showed a manageable safety profile.

The iberdomide CC-220-MM-001 study is an ongoing Phase 1/2 multicenter, open-label and multi-cohort trial evaluating orally administered iberdomide in several combinations and segments of patients ​with R/R multiple myeloma. Results at ASH are being presented from the dose-expansion cohort evaluating iberdomide in combination with DEX in patients with multiple myeloma who have heavily-pretreated refractory disease and also received anti-BCMA therapy.

Iberdomide was given orally, 1.6 mg once daily for 21 of 28 days, plus weekly DEX (40 mg; 20 mg if >75 years of age). The primary objectives were preliminary efficacy measured by ORR and safety. Patients treated with iberdomide with DEX demonstrated meaningful clinical activity, regardless of modality (TCE, CAR T cell or antibody-drug conjugate therapy), suggesting that iberdomideretains its activity in these patients.

Important Safety Information
BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
• Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
• Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
• Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
• ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.

Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA. Grade 3 or higher CRS (Lee grading system) occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 - 23 days) and the median duration of CRS was 7 days (range: 1 - 63 days) in all patients including the patient who died. The most common manifestations of CRS included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab; 35% (45/127) received a single dose while 18% (23/127) received more than 1 dose of tocilizumab. Overall, across the dose levels, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab.

Overall rate of CRS was 79% and rate of Grade 2 CRS was 23% in patients treated in the 300 x 106 CAR+ T cell dose cohort. For patients treated in the 450 x 106 CAR+ T cell dose cohort, the overall rate of CRS was 96% and rate of Grade 2 CRS was 40%. Rate of Grade 3 or higher CRS was similar across the dose range. The median duration of CRS for the 450 x 106 CAR+ T cell dose cohort was 7 days (range: 1-63 days) and for the 300 x 106 CAR+ T cell dose cohort was 6 days (range: 2-28 days). In the 450 x 106 CAR+ T cell dose cohort, 68% (36/53) of patients received tocilizumab and 23% (12/53) received at least 1 dose of corticosteroids for treatment of CRS. In the 300 x 106 CAR+ T cell dose cohort, 44% (31/70) of patients received tocilizumab and 10% (7/70) received corticosteroids. All patients that received corticosteroids for CRS also received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. CAR T cell-associated neurotoxicity occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 - 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median duration of neurotoxicity was 5 days (range: 1 - 61 days). The median duration of neurotoxicity was 6 days (range: 1 - 578) in all patients including those with ongoing neurotoxicity at the time of death or data cut off. Thirty-four patients with neurotoxicity had CRS. Neurotoxicity had onset in 3 patients before, 29 patients during, and 2 patients after CRS. The rate of Grade 3 neurotoxicity was 8% in the 450 x 106 CAR+ T cell dose cohort and 1.4% in the 300 x 106 CAR+ T cell dose cohort. The most frequently reported (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%). Grade 4 neurotoxicity and cerebral edema in 1 patient has been reported with ABECMA in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have been reported after treatment with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient treated in the 300 x 106 CAR+ T cell dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. The rate of HLH/MAS was 8% in the 450 x 106 CAR+ T cell dose cohort and 1% in the 300 x 106 CAR+ T cell dose cohort. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4-9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, preemptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Viral Reactivation: Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In the KarMMa study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion.

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