On November 4, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) and Novartis reported that they agreed on a repurchase by Roche of the 53.3 million Roche shares held by Novartis (Press release, Hoffmann-La Roche, NOV 4, 2021, View Source [SID1234594407]). The aggregate transaction value is approx. CHF 19 billion. The price per share is CHF 356.9341. It corresponds to the volume weighted average price of the Roche non-voting equity certificates over the last 20 trading days up to and including 2 November 2021. The Board of Directors of Roche has approved the envisaged repurchase, which will be debt-financed by Roche. All shareholders and holders of non-voting equity certificates of Roche benefit from the earnings accretion resulting from the transaction.

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Christoph Franz, Chairman of the Board of Directors of Roche: "I am convinced that the envisaged transaction is in the best interest of Roche and the holders of Roche equity securities from a strategic and economic perspective. As a result, Roche will be even better positioned strategically in the future to provide life-saving medicines and diagnostics to people around the world."

The transaction does not result in a change of control, as the pool formed by shareholders of the founding families has held the majority of the votes represented at general meetings of Roche previously. The voting power of the family pool will increase to approx. 67.5% upon completion of the transaction without any involvement or participation of the family pool in the transaction. The representatives of the family pool did not participate in the deliberations and the vote of the Board of Directors on this transaction. Based on a request of the family pool, the Swiss Takeover Board has exempted the pool from the obligation to submit a mandatory offer based on the applicable statutory provisions.

The percentage of shares held by the public (so-called "free float") will increase from currently 16.6% to 24.9% with the cancellation of the equity stake held by Novartis. This will allow the shares to be included in the Swiss Performance Index (SPI) and possibly in other indices.

The Extraordinary General Meeting to approve the capital reduction by cancellation of the shares repurchased from Novartis and to approve the interim financial statements prepared for the purpose of this transaction will be held on 26 November 2021. In accordance with the Articles of Association of Roche, the official invitation will be published twice in the Swiss Official Gazette of Commerce (SHAB; View Source!/gazette), for the first time on Friday, 5 November 2021. In addition, the invitation advertisement will be published in the daily and financial press from Monday, 8 November 2021.

Roche confirms the outlook for the full year and expects a mid-single-digit sales growth at constant exchange rates. Core EPS growth at constant exchange rates is targeted to be broadly in line with sales growth. Furthermore, Roche is aiming at increasing the dividend in Swiss francs also for 2021.

On November 4, 2021 Sanofi reported that Six oral and 14 poster presentations will be featured during the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from December 11-14 (Press release, Sanofi, NOV 4, 2021, View Source [SID1234594406]).

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"These upcoming data presentations demonstrate our ongoing commitment to delivering meaningful innovations for patients with significant unmet needs in oncology and hematology," said Dietmar Berger, Global Head of Clinical Development and Chief Medical Officer, Sanofi. "In our efforts to support the transformation of therapeutic landscapes, we look forward to presenting our Phase 3 results on fitusiran’s ability to provide protection from bleeds for people with hemophilia A or B with inhibitors. We’re also pleased to work with GMMG as they present investigational data evaluating Sarclisa in patients with newly diagnosed multiple myeloma, the first Phase 3 trial adding an anti-CD38 monoclonal antibody in combination with bortezomib, lenalidomide and dexamethasone."

Understanding the potential for Sarclisa (isatuximab-irfc) in earlier lines of therapy for multiple myeloma and other blood cancers

New data are from the Phase 3 German-Speaking Myeloma Multicenter Group (GMMG) HD7 study evaluating the effect of isatuximab in combination with bortezomib, lenalidomide and dexamethasone (VRd) on the rate of achieving minimal residual disease (MRD) negativity in transplant-eligible patients with newly diagnosed multiple myeloma (MM) after induction therapy, before transplant. These are the first results from a Phase 3 trial adding an anti-CD38 monoclonal antibody to VRd, a recommended first regimen in transplant-eligible newly diagnosed MM. GMMG-HD7 is also the first trial to evaluate MRD negativity at the end of induction as a co-primary endpoint, along with progression free survival, in transplant-eligible patients with newly diagnosed MM. The results of the study were selected as an oral presentation (abstract #463) and as part of the press program. Sanofi provided financial support to GMMG for this study.

Additionally, data from the Phase 2 ISAKIDS trial evaluating isatuximab in combination with standard salvage chemotherapies in children with relapsed or refractory leukemia in first or second relapse will be shared as an oral presentation (abstract #516).

The uses of Sarclisa in adult patients with newly diagnosed multiple myeloma and children with leukemia are currently under clinical investigation and their safety and efficacy in these settings have not been fully evaluated by any regulatory authority.

Sarclisa is approved in several geographies, in combination with pomalidomide and dexamethasone, for the treatment of certain adult patients with relapsed refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. This anti-CD38 monoclonal antibody medicine is also approved in several geographies in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory MM who have received one to three prior lines of therapy.

Advancing our innovative approaches to find treatments for people with rare blood disorders

Hemophilia: The results of the ATLAS-003 Phase 3 study evaluating fitusiran prophylaxis in patients with hemophilia A or B with inhibitors dosed with the 80 mg monthly treatment will be presented in the plenary scientific session (abstract #150273).

Additionally, the Phase 1/2 study results for long-term health-related quality of life in patients with hemophilia A, with or without inhibitors, treated with fitusiran prophylaxis will be shared in a poster presentation (abstract #3197).

Fitusiran is a novel, subcutaneous small interference (si)RNA therapy in development for people with hemophilia A or B, with or without inhibitors.

A post hoc analysis from the Phase 1/2 studies looking at the half-life and clearance of efanesoctocog alfa – previously known as BIVV001 – will be shared in a poster presentation (abstract #1035).

Efanesoctocog alfa is an investigational once-weekly factor therapy for people with hemophilia A that may provide high sustained factor activity and near-normal factor levels for the majority of the week. It represents a potential new class of factor VIII therapy. Efanesoctocog alfa is being developed in collaboration with Sobi.

Fitusiran and efanesoctocog alfa are currently under clinical investigation and their safety and efficacy have not been evaluated by any regulatory authority.

Cold Agglutinin Disease (CAD): An oral presentation (abstract #349) shares new data from the CADENZA study, looking at the safety and efficacy of sutimlimab to inhibit C1- activated hemolysis in people with CAD. Additionally, two poster presentations (abstracts #4057 and #2002) provide an overview of the burden of living with CAD, including patient-reported outcome symptom measures. Also, a new analysis from the Phase 3 CARDINAL and CADENZA studies which evaluated sutimlimab in CAD, will report on physical and mental component summary scores and contribution to fatigue in people living with the disease.

Sutimlimab, a first-in-class investigational C1s inhibitor, has the potential to be the first approved treatment for hemolysis in adults with CAD, a serious and chronic autoimmune hemolytic anemia. Sutimlimab is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.

Immune Thrombocytopenic Purpura (ITP): An oral presentation on rilzabrutinib, an investigational oral Bruton tyrosine kinase inhibitor (BTKi), reports on updated Phase 1/2 safety and efficacy results for the treatment of ITP (abstract #14) and a poster presentation (abstract #1010) on the design of the Phase 3 LUNA3 study. Rilzabrutinib is a potential first-in-class, oral BTKi in development for immune-mediated diseases. It is also being investigated for the autoimmune condition IgG4-related disease, asthma, atopic dermatitis, chronic spontaneous urticaria and warm autoimmune hemolytic anemia.

Rilzabrutinib is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.

Acquired Thrombotic Thrombocytopenic Purpura (aTTP): Two poster presentations will share safety and efficacy results for Cablivi (caplacizumab-yhdp) in aTTP: abstract #2080 will share long-term safety and efficacy from the post-HERCULES study in aTTP; additionally, abstract #1009 will show results from a Phase 2/3 study in Japanese patients with immune-mediated TTP.

Cablivi (caplacizumab-yhdp) is approved in several geographies in combination with plasma exchange and immunosuppression for the treatment of aTTP in adults.

Sickle Cell Disease: Preliminary data from the ongoing Phase 1/2 PRECIZN-1 study evaluating the safety and efficacy of SAR445136, formerly known as BIVV003, for the treatment of patients with severe sickle cell disease will be shared in a poster presentation (abstract #2930). SAR445136, an investigational zinc finger nuclease ex vivo gene-edited cell therapy in development with Sangamo, has the potential to be a one-time treatment for sickle cell disease.

SAR445136 is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.

Oncology Abstracts:

Abstract #463: Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone as Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma: The Phase III GMMG-HD7 Trial​. Oral presentation by GMMG. Sanofi provided financial support for this study.
Abstract #516: Isatuximab in Combination with Chemotherapy in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia (ISAKIDS): Interim Analysis​. Oral presentation.
Abstract #4114: Real-World Multiple Myeloma Treatment Patterns by Patient Characteristics and Outcomes in the United States. Poster.
Abstract #2744: A Multi-Center, Phase 1b Study to Assess the Safety, Pharmacokinetics and Efficacy of Subcutaneous Isatuximab Plus Pomalidomide and Dexamethasone, in Patients with Relapsed/Refractory Multiple Myeloma​. Poster.
Abstract #1962: A Matching-Adjusted Indirect Comparison of lsatuximab Plus Carfilzomib and Dexamethasone Versus Daratumumab Plus Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma​. Poster.
Abstract #1671: Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II IRIL Study of the Australian Myeloma Research Consortium (AMaRC 18-02). Poster.
Abstract #4362: A Phase 1/2, Open-Label, Multicenter Study of Isatuximab in Combination with Cemiplimab in Patients with Lymphoma. Abstract online only.
Abstract #4769: ITHACA, a Randomized Multicenter Phase 3 Study of Isatuximab in Combination with Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma: Safety Run-In Preliminary Results. Abstract online only.
Abstract #4767: Trial in Progress: A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard CyBorD Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma. Abstract online only.

Rare Blood Disorders Abstracts:

Hemophilia

Abstract #150273: Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI). Plenary scientific session.
Abstract #498: Prophylaxis with rFIXFc Reduces the Frequency and Delays Time to First Spontaneous Bleed Event in Previously Untreated Patients with Hemophilia B: A Post Hoc Analysis of the PUPs B-LONG Trial​. Oral presentation joint with Sobi.
Abstract #3197: Sustained Improvement in Health-Related Quality of Life in Patients with Hemophilia A with or without Inhibitors Treated with Fitusiran Prophylaxis​. Poster.
Abstract #1035: Efanesoctocog Alfa Half-life and Clearance Are Independent of von Willebrand Factor in Severe Hemophilia A: A Post Hoc Analysis from Phase 1/2a Studies​. Poster joint with Sobi.
Abstract #3031: A Retrospective Observational Descriptive Study on the Effectiveness and Usage of Emicizumab and Antihemophilic Factor (recombinant), Fc Fusion Protein in Patients with Hemophilia A in the U.S​. Poster.

Cold Agglutinin Disease

Abstract #349: Inhibition of Complement C1s by Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Efficacy and Safety Results from the Randomized, Placebo-Controlled Phase 3 CADENZA Study. Oral presentation.
Abstract #4057: Development of a Cold Agglutinin Disease-Specific Patient-Reported Outcome Symptom Measure. Poster.
Abstract #2002: Clinically Important Change in SF-12v2 Physical (PCS) and Mental (MCS) Component Summary Scores for Patients with Cold Agglutinin Disease: An Analysis Using the Phase 3 CARDINAL and CADENZA Studies. Poster.

Immune Thrombocytopenic Purpura

Abstract #14: Updated Phase I/II Safety and Efficacy Results for Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed/Refractory Immune Thrombocytopenia​. Oral presentation.
Abstract #1010: LUNA3 Phase III Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial of the Oral BTK Inhibitor Rilzabrutinib in Adults and Adolescents with Persistent or Chronic Immune Thrombocytopenia​. Poster.
Acquired Thrombotic Thrombocytopenic Purpura

Abstract #2080: Long-Term Safety and Efficacy of Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura (aTTP): The Post-HERCULES Study. Poster.
Abstract #1009: The Efficacy and Safety of Caplacizumab in Japanese Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): An Open-Label, Phase 2/3 Study. Poster.
Sickle Cell Disease

Abstract #2930: Preliminary Safety and Efficacy Results from PRECIZN-1: An Ongoing Phase 1/2 Study on Zinc Finger Nuclease-Modified Autologous CD34+ HSPCs for Sickle Cell Disease (SCD). Poster.
Abstract #1860: Quantitative Systems Pharmacology Model of Sickle Cell Disease and Response to Gene Editing Therapy to Support Clinical Development of SAR445136 (BIVV003)​. Poster.

On November 4, 2021 Biomea Fusion, Inc. ("Biomea") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel irreversible small molecules to treat and improve the lives of patients with genetically defined cancers, reported that an abstract containing preclinical data for BMF-219 has been published in Blood, the journal of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Biomea Fusion, NOV 4, 2021, View Source [SID1234594405]).

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The study, as published in Blood, analyzed how Biomea’s irreversible menin inhibitor, BMF-219, is impacting acute myeloid leukemia cells against the background of transcription factors in the GEO dataset. Menin is involved in many protein-protein interactions as part of a larger complex, with Menin and MLL/KMT2A being an example of one of those interactions. Here we investigated how ‘219 disrupts menin globally (selective disruption of global menin co-factors in addition to KMT2A).

Figure 1: Menin and various co-factors

A photo accompanying this announcement is available at View Source

The study demonstrates further the ability of BMF-219 to modulate MYC expression in leukemia cells, offering the foundation for exploring its activity in DLBCL cells. Transcription factor (TF) activity inference was calculated by analysis of TF-binding sites established by chromatin immunoprecipitation sequencing (ChIP-seq) GEO datasets that overlap with BMF-219 mediated differentially expressed genes in MOLM-13 cells using a published statistical framework and algorithm. This analysis revealed MYC, and its co-factor MAX, as top TFs regulating this subset of differentially expressed genes by BMF-219, as TF activity inference was highly enriched for both proteins. Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset. These results strongly point toward altered MYC-activity mediated by BMF-219 in leukemia cells, prompting additional exploration in MYC-dependent lymphoid malignancies.

Figure 2: Transcription factor (TF) activity inference using ChIP-seq of differentially expressed genes in MOLM-13 cells incubated with 500 nM BMF-219 at 24 hours. Each bar represents a study in the GEO repository using the specified TF antibody. TFs with more than one bar represent multiple study sets in GEO that overlap with BMF-219 mediated differentially expressed genes. MYC and MAX are top TFs regulating this subset of differentially expressed genes (p=10-49.5). Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset.

A photo accompanying this announcement is available at View Source

Using these results as the basis for further investigation, we explored BMF-219 and menin reversible inhibitors’ impact on cell viability in two different DLBCL double hit lymphoma (DHL) cell lines (DB and Toledo). Single-agent BMF-219 reduced >90% of cell viability in DB and Toledo cells, at 1.0μM and 0.36 μM, respectively. The IC50 values of BMF-219 were calculated near 0.3 mM for both DB and Toledo cells; however, the two reversible menin inhibitors tested were significantly less effective. One of the reversible inhibitors exhibited IC50 values at multi-fold higher drug concentrations than BMF-219 in both cell lines tested and the other reversible compound tested did not show sensitivity to either cell line.

"With this study, we gained valuable understanding and expanded our knowledge into the mechanism of action of our irreversible menin inhibitor, BMF-219. Besides its targeted selectivity profile, we also recognize the broad impact BMF-219 has on the complexes surrounding menin," said Alex Cacovean, M.D., Biomea Fusion’s Executive Medical Director. "At low dosage levels, by targeting menin, we were able to inhibit MYC gene expression and demonstrated potent cell killing in two very aggressive cell lines, representative of underserved DLBCL subpopulations. We are very excited about these preclinical findings and we are hopeful to now clinically validate the effects of our irreversible menin inhibitor in MYC-positive, double expressor, and double hit DLBCL patients."

Abstract Details

Title: Novel Irreversible Menin Inhibitor, BMF-219, Shows Potent Single Agent Activity in Clinically Relevant DLBCL Cells
Abstract Number: 148045

About Diffuse Large B Cell Lymphoma (DLBCL)

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma. DLBCL starts in white blood cells called lymphocytes and grows in lymph nodes. Every year, there are ~18,000 people in the United States that are diagnosed with DLBCL. Following initial treatment with standard chemotherapy, ~70% of people have a complete response and ~50% of patients are cured. For patients with relapsed or refractory DLBCL, median overall survival is between 6-7 months. Double Hit Lymphomas (DHL) and Double Expressor Lymphomas (DEL) are high grade B cell lymphomas (HGBLs) that have high MYC and BCL2 dependency.

About BMF-219

BMF-219 is an irreversibly binding inhibitor of menin, a protein that is known to play an essential role in oncogenic signaling in genetically defined leukemias. Preclinically, BMF-219 has demonstrated robust downregulation of key leukemogenic genes in addition to menin itself (via MEN1) in well-established MLLr AML cell lines. Additionally, BMF-219 has shown efficacy in multiple in vivo and in vitro models of acute leukemias. BMF-219 will be evaluated in a first-in-human trial in patients with relapsed or refractory acute leukemia with MLL/KMT2A gene rearrangement or NPM1 mutation.

On November 4, 2021 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported that an abstract detailing new data from a Phase 2 study evaluating selinexor, a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with myelofibrosis (MF) previously treated with JAK inhibition has been selected for an oral presentation at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting and Exposition in Atlanta, GA on December 11-14, 2021 (Press release, Karyopharm, NOV 4, 2021, View Source [SID1234594404]).

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"JAK inhibition is the current standard of care for patients with myelofibrosis; however, patients whose disease fails treatment with ruxolitinib have a poor prognosis, with an expected survival of approximately 14 months, and there are no approved treatment options other than JAK inhibitors," said Srinivas Tantravahi, MBBS, MRCP, University of Utah Hospital and principal investigator of the Phase 2 study. "Interim results from this Phase 2 study demonstrated that once weekly single agent oral selinexor resulted in compelling spleen volume reduction rates in myelofibrosis patients who received at least 24 weeks of treatment, with 33% of those patients achieving a response, defined as ≥35% SVR. In addition to spleen responses, there was improvement in anemia status and symptom scores in these patients. The responses were durable with the first patient on treatment for more than two years. The sustained responses and well-tolerated safety profile highlight selinexor’s potential in patients with myelofibrosis who have either progressed following ruxolitinib or cannot tolerate JAK inhibition. We look forward to sharing these exciting results with the broader medical and scientific community at ASH (Free ASH Whitepaper) this year."

"Once weekly, low-dose selinexor is an oral agent with a unique mechanism of action that has demonstrated strong single-agent activity in myelofibrosis patients with disease refractory to ruxolitinib," said Jatin Shah, MD, Chief Medical Officer of Karyopharm. "Importantly, there are no other classes of drug approved other than JAK inhibitors and a new class of effective drugs is a critical need for patients. Based on these encouraging data, we look forward to dosing the first patient in a new, company-sponsored Phase 2 study evaluating single-agent selinexor versus physician’s choice in patients with previously treated myelofibrosis during the fourth quarter of 2021."

Results from the Phase 2 Study Evaluating Selinexor in Patients with MF Refractory or Intolerant to JAK Inhibitors

The results were based on the open label, prospective, investigator-initiated single center study in adult patients with primary or secondary MF with resistance or intolerance to JAK inhibitor therapy (NCT03627403). Selinexor was administered orally at a dose of 80mg or 60mg once weekly to 12 patients. The primary endpoint of the study is to assess the efficacy of selinexor on SVR. Median duration of prior JAK inhibitor therapy was 22 months and 11 out of 12 patients had MF refractory to ruxolitinib.

As of the data cutoff, the median duration of treatment was 36 weeks. In the nine patients who were on treatment for over 24 weeks, SVR of ≥25% and 35% occurred in four (44%) and three (33%) patients, respectively. The most common treatment related adverse event was weight loss (grade 2 in four patients and grade 3 in one patient). This was manageable with treatment interruption and dose reduction, except in one patient who discontinued treatment. Overall, selinexor demonstrated single-agent activity with sustained spleen responses in patients with JAK inhibitor refractory MF and long-term administration of selinexor was well tolerated. Updated data will be presented at the meeting.

Company to Host Investor Day Event

Karyopharm will host an Investor Day event on Wednesday, December 8, 2021 from 10:00 a.m. to 12:30 p.m. ET to outline its commercial and pipeline priorities and objectives. The event will feature presentations from Karyopharm management and recognized thought leaders in multiple myeloma, gynecological malignancies, and other core focus indications. The event will take place virtually and will be accessible via conference call and webcast. Full details will be made available closer to the Investor Day.

Details for the ASH (Free ASH Whitepaper) 2021 abstracts are as follows:

In total, 17 abstracts were selected for presentation at the meeting, including five oral presentations and 12 posters.

Oral Presentations

Title: A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor in Patients with Myelofibrosis Refractory or Intolerant to JAK Inhibitors
Presenter: Srinivas Tantravahi, University of Utah
Abstract #: 143
Session Type: Oral Presentation
Session: Myeloproliferative Syndromes: Clinical and Epidemiological: Non-JAK Inhibitor Therapies for Myelofibrosis
Date and Time: Saturday, December 11, 2021 at 1:00 p.m. ET

Title: Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature
Presenter: Paula Restrepo, Icahn School of Medicine at Mount Sinai
Abstract #: 457
Session Type: Oral Presentation
Session: Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Multiple Myeloma and Waldenstrom Macroglobulinemia: Exploring Biomarkers in the Era of Personalized Medicine
Date and Time: Sunday, December 12, 2021 at 12:00 p.m. ET

Title: Enhanced p53 Activation by Dual Inhibition of MDM2 and XPO1 Disrupts MYC Transcriptional Program and Restores Sensitivity to BCL-2 Inhibition in Ven/HMA Resistant AML
Presenter: Yuki Nishida, Saga University
Abstract #: 505
Session Type: Oral Presentation
Session: Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Novel Strategies to Overcome Resistance to BCL-2 Inhibition
Date and Time: Sunday, December 12, 2021 at 4:30 p.m. ET

Title: Rationale for Selinexor Treatment in Daratumumab-Refractory MM Patients Identified by Paired Ex Vivo Drug Sensitivity and RNA-Seq
Presenter: Suresh Kumar Balasubramanian, Wayne State University
Abstract #: 683
Session Type: Oral Presentation
Session: Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Targeting
Mitochondrial Survival Pathways
Date and Time: Monday, December 13, 2021 at 3:45 p.m. ET

Title: Comparison of Salvage Autologous Hematopoietic Cell Transplantation with Outcomes Following Selinexor Combinations Among Double/Triple Refractory Myeloma Patients
Presenter: Praneeth Sudalagunta, H Lee Moffitt Cancer Ctr
Abstract #: 893
Session Type: Oral Presentation
Session: Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Myeloma Pathogenesis and Novel Targets
Date and Time: Monday, December 13, 2021 at 7:15 p.m. ET

Poster Presentations

Title: Efficacy and Safety of Selinexor-Containing Regimens in Patients with Multiple Myeloma Previously Treated with Anti-CD38 Monoclonal Antibodies (αCD38 mAb)
Presenter: Suzanne Lentzsch, Columbia University Irving Medical Center
Abstract #: 1651
Session Type: Poster Presentation
Session: Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster I
Date and Time: Saturday, December 11, 2021 at 5:30 – 7:30 p.m. ET

Title: Effects of Cytogenetic Risk on Outcomes in Multiple Myeloma Treated with Selinexor, Bortezomib, and Dexamethasone (XVd)
Presenter: Nizar Bahlis, University of Calgary
Abstract #: 1634
Session Type: Poster Presentation
Session: Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster I
Date and Time: Saturday, December 11, 2021 at 5:30 – 7:30 p.m. ET

Title: Selinexor in Combination with Daratumumab-Bortezomib and Dexamethasone for the Treatment of Relapse or Refractory Multiple Myeloma: Initial Results of the Phase 2, Open-label, Multicenter GEM-SELIBORDARA Study
Presenter: Paula Rodríguez- Otero, Clínica Universidad de Navarra
Abstract #: 1677
Session Type: Poster Presentation
Session: Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster I
Date and Time: Saturday, December 11, 2021 at 5:30 – 7:30 p.m. ET

Title: Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma
Presenter: Darrell White, QEII Health Sciences Center, Dalhousie University
Abstract #: 2748
Session Type: Poster Presentation
Session: Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Date and Time: Sunday, December 12, 2021 at 6:00 – 8:00 p.m. ET

Title: Selinexor-Based Regimens in Patients with Multiple Myeloma after Prior Anti-B-Cell Maturation Antigen Treatment
Presenter: Muhamed Baljevic, University of Nebraska Medical Center
Abstract #: 2751
Session Type: Poster Presentation
Session: Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Date and Time: Sunday, December 12, 2021 at 6:00 – 8:00 p.m. ET

Title: Single Cell RNA Sequencing of a Selinexor Clinical Trial Reveals Overexpression of Alternative Nuclear Export Pathways Associated with Resistance to Selinexor in RRMM Patients
Presenter: Yael Cohen, Tel Aviv Sourasky Medical Center
Abstract #: 2725
Session Type: Poster Presentation
Session: Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster I
Date and Time: Sunday, December 12, 2021 at 6:00 – 8:00 p.m. ET

Title: Selinexor Enhances NK Cell Activation Against Lymphoma Cells Via Downregulation of HLA
Presenter: Matthew Blunt, University of Southampton
Abstract #: 2411
Session Type: Poster Presentation
Session: Lymphomas: Translational—Non-Genetic: Poster II
Date and Time: Sunday, December 12, 2021 at 6:00 – 8:00 p.m. ET

Title: Molecular Response Patterns in Relapsed/Refractory AML Patients Treated with Selinexor and Chemotherapy
Presenter: Piroska Klement, Hannover Medical School
Abstract #: 2369
Session Type: Poster Presentation
Session: Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Date and Time: Sunday, December 12, 2021 at 6:00 – 8:00 p.m. ET

Title: Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents
Presenter: Sangmin Lee, Weill Cornell Medical College
Abstract #: 3676
Session Type: Poster Presentation
Session: Myelodysplastic Syndromes — Clinical and Epidemiological: Poster III
Date and Time: Monday, December 13, 2021 at 6:00 – 8:00 p.m. ET

Title: Clinical Outcomes in Patients with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the BOSTON Study
Presenter: Sundar Jagannath, Mount Sinai School of Medicine
Abstract #: 3793
Session Type: Poster Presentation
Session: Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster III
Date and Time: Monday, December 13, 2021 at 6:00 – 8:00 p.m. ET

Title: Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: SELINDA Phase Ib LYSA Study
Presenter: Marie Maerevoet, Jules Bordet Institute
Abstract #: 1411
Session Type: Poster Presentation
Session: Aggressive Lymphomas: Prospective Therapeutic Trials: Poster I
Date and Time: Saturday, December 11, 2021 at 5:30 – 7:30 p.m. ET

Title: A Phase 2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) with or without Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR DLBCL)
Presenter: Seung Tae Lee, University of Maryland School of Medicine
Abstract #: 1420
Session Type: Poster Presentation
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster I
Date and Time: Saturday, December 11, 2021, 5:30-7:30PM ET

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. NEXPOVIO (selinexor) has also been granted conditional marketing authorization for adult patients with heavily pretreated multiple myeloma by the European Commission. Karyopharm’s supplemental New Drug Application (sNDA) requesting an expansion of its indication to include the treatment for patients with multiple myeloma after at least one prior therapy was approved by the FDA on December 18, 2020. In June 2020, Karyopharm received accelerated FDA approval of XPOVIO for its second indication in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326
Email: [email protected]

XPOVIO (selinexor) is a prescription medicine approved:

In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (XVd).
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti–CD38 monoclonal antibody (Xd).
For the treatment of adult patients with relapsed or refractory diffuse large B–cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
SELECT IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care.
Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony–stimulating factors.
Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care.
Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care.
Serious Infection: Monitor for infection and treat promptly.
Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes.
Embryo–Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception.
Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract.
Adverse Reactions

The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3–4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%.
The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.
The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3–4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients.
Use In Specific Populations
Lactation: Advise not to breastfeed.

For additional product information, including full prescribing information, please visit www.XPOVIO.com.

On November 4, 2021 Bristol Myers Squibb (NYSE: BMY) reported the presentation of research across a wide range of hematologic diseases at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, which will take place in Atlanta, Georgia, and virtually, from December 11 to 14, 2021 (Press release, Bristol-Myers Squibb, NOV 4, 2021, View Source [SID1234594403]). Data from more than 80 company-sponsored studies will be featured, including 23 oral presentations, highlighting key research and development programs in lymphomas, leukemias, multiple myeloma and myeloid diseases, and showcasing our commitment to delivering transformative medicines across major hematologic diseases.

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Key data being presented by Bristol Myers Squibb and its partners at the 2021 ASH (Free ASH Whitepaper) Annual Meeting and Exposition include:

First presentation of results from pivotal Phase 3 TRANSFORM study evaluating CD19-directed chimeric antigen receptor (CAR) T cell therapy Breyanzi (lisocabtagene maraleucel) head-to-head against the current standard of care treatment approach for second-line relapsed or refractory (R/R) large B-cell lymphoma (LBCL)
Two-year follow-up data from the pivotal TRANSCEND NHL 001 study of Breyanziin third-line and later R/R LBCL
First clinical results for anti-SIRPα antibody CC-95251 plus rituximab, as well as first clinical results for CELMoD CC-99282, both in patients with R/R non-Hodgkin’s lymphoma
First disclosure of safety and efficacy results from dose expansion of the MM-001 study evaluating CELMoD iberdomide in combination with dexamethasone in patients with R/R multiple myeloma
First disclosure of preliminary results from the Phase 1/2 MM-002 study of CELMoD CC-92480 in combination with dexamethasone and bortezomib in patients with R/R multiple myeloma
Further analyses from the pivotal KarMMa trial in R/R multiple myeloma evaluated baseline predictors of complete responses and outcomes for patients treated with subsequent anti-myeloma therapies, including alternative B-cell maturation antigen (BCMA)-directed therapies, after treatment with Abecma (idecabtagene vicleucel),the first-in-class BCMA-directed CAR T cell therapy
Abstracts highlighting multiple Bristol Myers Squibb’s therapies in hard-to-treat myeloid diseases, including longer-term data and analyses of different acute myeloid leukemia subtypes and baseline characteristics with Onureg (azacitidine tablets) from the Phase 3 QUAZAR AML-001 study and safety with Inrebic(fedratinib) from the Phase 3b FREEDOM trial in myelofibrosis
Updated analyses of Reblozyl (luspatercept-aamt) from the Phase 2 BEYOND study in beta thalassemia and from the Phase 3 MEDALIST study in lower-risk myelodysplastic syndromes
"Our presence at ASH (Free ASH Whitepaper) continues our longstanding commitment to hematology and underscores the potential of our innovative research platforms to deliver meaningful, new treatment options for people with unmet needs living with hematologic diseases," said Samit Hirawat, M.D., executive vice president, chief medical officer, global drug development, Bristol Myers Squibb. "These data reinforce our progress in advancing transformative research across a wide range of hematologic malignancies including multiple myeloma, lymphoma, and myeloid diseases."

Selected Bristol Myers Squibb studies at the 63rd ASH (Free ASH Whitepaper) Annual Meeting and Exposition include:

Abstract Title

Author

Presentation Type/#

Session Title

Session Date/Time

Acute Myeloid Leukemia

Prognostic Impact of NPM1 and FLT3 Mutations at Diagnosis and Presence of Measurable Residual Disease (MRD) after Intensive Chemotherapy (IC) for Patients with Acute Myeloid Leukemia (AML) in Remission: Outcomes from the QUAZAR AML-001 Trial of Oral Azacitidine (Oral-AZA) Maintenance

Hartmut Döhner

Oral

Abstract #804

617. Acute Myeloid Leukemia: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: New options of risk assessment and prediction of therapy response in AML

Monday, December 13,

5:45 PM

Long-term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial

Andrew Wei

Oral

Abstract #871

615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Updates in treatment for high-risk AML

Monday, December 13,

6:15 PM

Beta Thalassemia

Luspatercept Redistributes Body Iron to the Liver in Transfusion-Dependent-Thalassemia (TDT) During Erythropoietic Response

Maciej Garbowski

Oral Abstract

#761

102. Iron Homeostasis and Biology: Disorders of Iron and Heme and Novel Treatments

Monday, December 13,

5:30 PM

Luspatercept Improves Health-Related Quality of Life (HRQoL) Symptoms and RBC Transfusion Burden in Patients with Non-Transfusion-Dependent β-thalassemia (NTDT) in the BEYOND Trial

Antonis Kattamis

Poster Abstract #3081

112. Thalassemia and Globin Gene Regulation: Poster III

Monday, December 13,

6:00 – 8:00 PM

Graft vs. Host Disease

Overall Survival of Patients Treated with Abatacept in Combination with a Calcineurin Inhibitor and Methotrexate After Allogeneic Hematopoietic Stem Cell Transplantation – Analysis of the Center for International Blood and Marrow Transplant Research Database

Leslie Kean

Poster Abstract #3912

722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III

Monday, December 13, 6:00 – 8:00 PM

Lymphoma

Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed by Autologous Stem Cell Transplantation (ASCT) as Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 TRANSFORM Study

Manali Kamdar

Oral Abstract

#91

704. Cellular Immunotherapies: Cellular Therapies for Lymphomas

Saturday, December 11,

9:30 AM

Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy

Veronika

Bachanova

Oral Abstract

#230

624. Hodgkin Lymphomas and T/NK cell Lymphomas: Hodgkin Lymphoma Clinical Trials

Hematology Disease Topics & Pathways:

Clinical Trials

Saturday, December 11, 2:15 PM

Nivolumab First-Line Therapy for Elderly Hodgkin Lymphoma Patients: a LYSA Phase II Study

Julien Lazarovici

Oral Abstract

#232

624. Hodgkin Lymphomas and T/NK cell Lymphomas: Hodgkin Lymphoma Clinical Trials

Saturday, December 11, 2:45 PM

OUTREACH: Results from a Phase 2 Study of Lisocabtagene Maraleucel (liso-cel) Administered as Inpatient (Inpt) or Outpatient (Outpt) Treatment in the Nonuniversity Setting in Patients (Pts) with R/R Large B-Cell Lymphoma (LBCL)

John Godwin

Poster Abstract

#1762

704. Cellular Immunotherapies: Clinical: Poster I

Saturday, December 11,

5:30 – 7:30 PM

Six-Year Results from the Phase 3 Randomized Study Relevance Show Similar Outcomes for Previously Untreated Follicular Lymphoma Patients Receiving Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed By Rituximab Maintenance

Franck Morschhauser

Poster Abstract

#2417

623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II

Sunday, December 12,

6:00 – 8:00 PM

Differential Effects of Iberdomide Versus Revlimid on Leukocyte Trafficking, Immune Activation and DLBCL Tumor Cell Killing

Yumi Nakayama

Oral Abstract

#718

622. Lymphomas: Translational-Non-Genetic: Lymphoma biology

Monday, December 13,

3:30 PM

Completed Induction Phase Analysis of MAGNIFY: Phase 3b Study of Lenalidomide + Rituximab (R2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Frederick

Lansigan

Oral Abstract

#812

623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Follicular Lymphoma: Advances in Treatment Approaches

Monday, December 13,

4:45 PM

Discovery and Preclinical Characterization of CC-95251, an Anti-SIRPa Antibody that Enhances Macrophage-Mediated Phagocytosis of Non-Hodgkin Lymphoma (NHL) Cells when Combined with Rituximab

Henry Chan

Poster Abstract

#2271

605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II

Monday, December 13,

6:00 – 8:00 PM

Characteristics of Post-Infusion Chimeric Antigen Receptor (CAR) T Cells and Endogenous T Cells Associated with Early and Long-term Response in Lisocabtagene Maraleucel (liso-cel)–Treated Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Jerill Thorpe

Poster Abstract

#2417

704. Cellular Immunotherapies: Clinical: Poster III

Monday, December 13,

6:00 – 8:00 PM

Two-Year Follow-up of TRANSCEND NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed or Refractory (R/R) Large B-Cell Lymphomas (LBCL)

Jeremy Abramson

Poster Abstract

#2840

704. Cellular Immunotherapies: Clinical: Poster III

Monday, December 13,

6:00 – 8:00 PM

Cost-effectiveness of Liso-cel versus Axi-cel for Treatment of Relapsed or Refractory Large B-Cell Lymphoma

Christopher Parker

Poster Abstract

#3003

902. Health Services Research—Lymphoid Malignancies: Poster II

Monday, December 13,

6:00 – 8:00 PM

Clinical Activity of CC-99282, a Novel, Oral Small Molecule Cereblon E3 Ligase Modulator (CELMoD) Agent, in Patients (Pts) with Relapsed or Refractory Non-Hodgkin Lymphoma (R/R NHL) – First Results from a Phase 1, Open-Label Study

Jean-Marie Michot

Poster Abstract

#3574

626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster III

Monday, December 13,

6:00 – 8:00 PM

Multiple Myeloma

Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Dose-Expansion Phase of the CC-220-MM-001 Trial

Sagar Lonial

Oral Abstract #162

653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Novel Targets and Amyloid

Saturday, December 11, 1:15 PM

Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the CONNECT Multiple Myeloma (MM) Disease Registry​

Sundar Jagannath

Oral Abstract

#117

905. Outcomes Research- Lymphoid Malignancies: Multiple Myeloma and Other Plasma Cell Disorders ​

Saturday, December 11,​

10:00 AM

Baseline Correlates of Complete Response to Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy in Patients with Relapsed and Refractory Multiple Myeloma: Subanalysis of the KarMMa Trial

Nina Shah

Poster Abstract

#1739

704. Cellular Immunotherapies: Clinical: Poster I

Saturday, December 11 5:30 – 7:30 PM

Matching-Adjusted Indirect Comparisons of Efficacy Outcomes in Patients with Relapsed and Refractory Multiple Myeloma for Idecabtagene Vicleucel (KarMMa) vs. Selinexor Plus Dexamethasone (STORM Part 2) and Belantamab Mafodontin (DREAMM-2): Updated Analysis with Longer Follow-up

Paula Rodriguez-Otero

Poster Abstract

#1978

905. Outcomes Research—Lymphoid Malignancies: Poster I

Saturday, December 11,

5:30 – 7:30 PM

Updated Clinical and Correlative Results From the Phase I CRB-402 Study of the BCMA-Targeted CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma

Noopur Raje

Oral Abstract #548

Cellular Immunotherapies: Cellular Therapies for Myeloma

Sunday, December 12

4:45 PM

CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002

Paul Richardson

Poster Abstract

#2731

653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II

Sunday, December 12

6:00 – 8:00 PM

Subsequent Anti-myeloma Therapy after Idecabtagene Vicleucel (Ide-cel, bb2121) Treatment in Patients with Relapsed/Refractory Multiple Myeloma from the KarMMa Study

Paula Rodriguez-Otero

Poster Abstract

#2743

653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II

Sunday, December 12 6:00 – 8:00 PM

Updated Health-Related Quality of Life Results from the KarMMa Clinical Study in Patients with Relapsed and Refractory Multiple Myeloma Treated with the B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Idecabtagene Vicleucel (ide-cel, bb2121)

Michel Delforge

Poster Abstract

#2835

704. Cellular Immunotherapies: Clinical: Poster II

Sunday, December 12, 6:00 – 8:00 PM

Idecabtagene Vicleucel (ide-cel, bb2121), a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy: Qualitative Analyses of Post-Treatment Interviews (Months 6–24) for Patients with Relapsed and Refractory Multiple Myeloma in the KarMMa Clinical Trial

Nina Shah

Poster Abstract

#3041

Session Name: 905. Outcomes Research—Lymphoid Malignancies: Poster II

Sunday, December 12 6:00 – 8:00 PM

Large-Scale Mass Cytometry Reveals Significant Activation of Innate and Adaptive Immunity in Bone Marrow Tumor Microenvironment of Iberdomide-Treated Myeloma Patients

Oliver Van Oekelen

Oral Abstract

#730

651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: The Myeloma Immune Microenvironment

Monday, December 13, 3:30 PM

Myelodysplastic Syndrome

Treatment Duration and Exposure Adjusted Safety Analysis in the MEDALIST Study (luspatercept)

Uwe Platzbecker

Poster Abstract

#1524

637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster I

Saturday, December 11 5:30 – 7:30 PM

Myelofibrosis

Safety and Tolerability of Fedratinib, an Oral Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate- or High-risk Myelofibrosis (MF) Previously Treated with Ruxolitinib: Results from the Phase 3b FREEDOM Trial

Vikas Gupta

Oral Abstract

#389

634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis

Sunday, December 12, 10:30 AM

Spleen and Symptom Responses with Fedratinib (FEDR) Patients with Myelofibrosis (MF) and Substantial Splenomegaly

Jean‐Jacques Kiladjian

Poster Abstract

#2576

634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II

Sunday, December 12 6:00 – 8:00 PM

Bristol Myers Squibb: Creating a Better Future for Cancer Patients

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 scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at 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. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

BREYANZI

Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T cell therapy with a defined composition and 4-1BB costimulatory domain. Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose. The 4-1BB signaling domain enhances the expansion and persistence of the CAR T cells.

Indications

Breyanzi is approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. Breyanzi is also approved in Japan for the treatment of patients with R/R LBCL and follicular lymphoma.

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients.

Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com, or contact Bristol Myers Squibb at 1-888-423-5436.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI 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.

Avoid administration of BREYANZI in patients with clinically significant active systemic infections.

Viral reactivation: 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 B cells. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.
Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

ABECMA Indications

ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

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 availableat www.AbecmaREMS.com or 18884235436.

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. Rate of prolonged neutropenia was 49% in the 450 x 106 CAR+ T cell dose cohort and 34% in the 300 x 106 CAR+ T cell dose cohort. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Median time to cytopenia recovery was similar across the 300 and 450 x 106 dose cohort.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to institutional guidelines.

Hypogammaglobulinemia: Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

ONUREG U.S. Indication

ONUREG (azacitidine tablets)is approved in the U.S. for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.

U.S. Important Safety Information

CONTRAINDICATIONS

ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS

Risks of Substitution with Other Azacitidine Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment with ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG for intravenous or subcutaneous azacitidine.
Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS): In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG or placebo. 107 received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG for MDS have not been established. Treatment of MDS with ONUREG is not recommended outside of controlled trials.
Embryo-Fetal Toxicity: ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose.
ADVERSE REACTIONS

Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG.
Most common (≥10%) adverse reactions with ONUREG vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION

There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose
REBLOZYL Indication

REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions

REBLOZYL is indicated for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/ myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia

Important Safety Information

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta-Thalassemia

Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)
Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%)
Myelodysplastic Syndromes

Grade >3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients
The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection
LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.