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OVERVIEW BY KEY OPINION LEADER DR. RAFAT ABONOUR

Dr. Rafat Abonour provides an in-depth review of BLENREP. The presentation addresses important prescribing information, mechanism of action, clinical data and safety information.

Dr. Joseph Mikhael provides an in-depth review of BLENREP. The presentation addresses important prescribing information, mechanism of action, clinical data and safety information.

  • VIDEO TRANSCRIPT | 34:47

    ONSCREEN TEXT:

    [GSK logo]

    GSK ONCOLOGY ON DEMAND

     

     

    ONSCREEN TEXT THAT APPEARS THROUGHOUT REMAINDER OF THE VIDEO:

    [BLENREP logo] [GSK logo]

    BLENREP belantamab mafodotin-blmf for injection 100 mg

    Please see IMPORTANT SAFETY INFORMATION in this video and full Prescribing Information, including BOXED WARNING.

     

     

    ONSCREEN TEXT:

    The following video is edited from a pre-recorded presentation by Dr. Rafat Abonour originally aired in April 2021.

     

    SARA HUFF:

    Good morning, everybody, this is Sara Huff from GSK.  Thank you for joining us today…

     

     

    ONSCREEN TEXT:

    BLENREP

    belantamab mafodotin-blmf for injection 100 mg

    Trademarks are property of their respective owners.

    ©2021 GSK or licensor.
    BLMPPTX200004 January 2021

    Produced in USA.

     

    SARA HUFF:

    …for our BLENREP product theater.  I'm very pleased to announce Dr. Rafat Abonour.

     

     

    ONSCREEN TEXT:

    SPEAKER DISCLOSURE

    Rafat Abonour, MD

    Director of Multiple Myeloma and Waldenstrom's Disease

    Harry and Edith Gladestein Professor of Cancer Research and Professor of Medicine

    Department of Hematology and Oncology

    Professor of Pathology and Laboratory Medicine

    Indiana University School of Medicine

     

    Dr. Abonour is presenting this program on behalf of GSK, the sponsor of this program, and is contracted with GSK for this service. The information being presented is consistent with FDA guidelines.

     

    SARA HUFF:

    Dr. Abonour is the Director of Multiple Myeloma and Waldenstrom's Disease at the Indiana University School of Medicine.  He is a Harry and Edith Gladestein Professor of Cancer Research, a Professor of Medicine for the Department of Hematology and Oncology, and a Professor of Pathology and Laboratory Medicine. 

     

    He pursued his medical degree at the University of Damascus in Syria, and completed his post-doc in immunology, his internal medicine residency, and his hematology fellowship at the University of Wisconsin in Madison.  His current clinical activities include directing the multiple myeloma and plasma cell program, bone marrow transplanting, and he is a hematology consultant. 

     

    He's been active in clinical research since 1995 and aims at preventing myeloma and improving the treatment of those suffering with the disease.  He also focuses on a disease registry to help understand the course of the disease outside of trials and serves on the executive committee of the Indiana Clinical Translational Science Institute.  He's also chaired a steering committee for the Connect Myeloma Disease Registry.  So, very involved in the management of myeloma and serving his patients. 

     

    And with that, I'd like to turn it over to Dr. Abonour.

     

    ONSCREEN TEXT:

    BLENREP

    belantamab mafodotin-blmf for injection 100 mg

    Trademarks are property of their respective owners.

    ©2021 GSK or licensor.
    BLMPPTX200004 January 2021

    Produced in USA.

     

    DR. RAFAT ABONOUR:

    Thank you, Sara, and good morning, everybody.  It's my pleasure to present to you on BLENREP, which is belantamab mafodotin. 

     

     

    ONSCREEN TEXT:

    SPEAKER DISCLOSURE

    Rafat Abonour, MD

    Director of Multiple Myeloma and Waldenstrom's Disease

    Harry and Edith Gladestein Professor of Cancer Research and Professor of Medicine

    Department of Hematology and Oncology

    Professor of Pathology and Laboratory Medicine

    Indiana University School of Medicine

    Dr. Abonour is presenting this program on behalf of GSK, the sponsor of this program, and is contracted with GSK for this service. The information being presented is consistent with FDA guidelines.

     

    DR. RAFAT ABONOUR:

    So, as you heard, I'm speaking on behalf of GSK, the sponsor of this program, and I'm contracted with them to do this service.  This information is consistent with FDA guidelines.

     

     

    ONSCREEN TEXT:

    BLENREP (belantamab mafodotin-blmf)

    BLENREP is the first and only BCMA-targeting antibody-drug conjugate monotherapy for appropriate patients with relapsed/refractory multiple myeloma1-3

     

    INDICATION

    BLENREP is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

     

    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 a confirmatory trial(s).

     

    IMPORTANT SAFETY INFORMATION

     

    WARNING: OCULAR TOXICITY

    BLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes.

     

    Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity.

     

    Because of the risk of ocular toxicity, BLENREP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS.

     

    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Trudel S, et al. Lancet Oncol. 2018;19(12):1641-1653.

     

    DR. RAFAT ABONOUR:

    So, what is BLENREP?  It is the first and only BCMA-targeting antibody-drug conjugate monotherapy for appropriate patient with relapsed and refractory multiple myeloma.  It's indicated for patients who have received at least 4 lines of therapy, that include a CD38 monoclonal antibody, a proteasome inhibitor, and immunomodulatory drugs. 

     

    The indication is approved under accelerated approval based on the response rate.  Continued approval for this indication may be contingent upon validation verification and description of clinical benefit in subsequent trials. 

     

    The important safety information about this drug is the ocular toxicity where there is some corneal epithelial damage that may result in change in vision, and also some keratopathy, so the patient may develop some corneal ulcer and blurred vision, and dry eyes.  It's very important that we conduct a ophthalmologic exam at baseline and prior to each dose of this drug, promptly report worsening symptoms, and adjust the treatment accordingly, and for that reason, this drug needs to be administered under a REMS program.

     

     

    ONSCREEN TEXT:

    Relapse Is a Reality Despite Currently Available Therapies1

    The RRMM population varies based on the type of relapse and the number and types of treatment regimens used1

    RRMM Patient Population

    • Response, time to progression, or resistance can vary between patients. It may also be dependent on the actual therapies the patient received and how they responded3-5
    • Following relapse or becoming refractory to treatment, patients may respond to later-line therapies with mechanisms of action they have not been previously exposed to6,7

     

    [Graph showing how asymptomatic and symptomatic patients with multiple myeloma respond to treatment over time.]

     

    BLENREP is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.2

     

    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 a confirmatory trial(s).2

     

    RRMM=relapsed or refractory multiple myeloma.

    References: 1. Kurtin SE. J Adv Pract Oncol. 2013;4(suppl 1):5-14. 2. BLENREP Prescribing Information. 3. Richardson PG, et al. J Blood Med. 2017;8:107-121. 4. Yong K, et al. Br J Haematol. 2016;175(2):252-264. 5. Verelst SGR, et al. HemaSphere. 2018;2(4):e45. 6. Cho SF, et al. Front Immunol. 2018;9:1821. 7. Laubach JP, et al. Exp Rev Hematol. 2014;7(1):97-111.

     

    RAFAT ABONOUR, MD:

    So, first of all, I mean, I think it's very important that we recognize that this graph here, as you can see, and we've probably seen it several times, multiple myeloma does respond to treatment and we're getting some lasting responses.  However, eventually, patients will be relapsed.

     

    Following relapse or becoming refractory to treatment, patient may respond to a later line of therapy that has a different mechanism of action that has not been previously explored.

     

     

    ONSCREEN TEXT:

    BCMA as Multiple Myeloma Target

    BCMA is a cell-surface protein expressed on myeloma cells, late-stage B cells, and plasma cells1-3

    B-cell Maturation Antigen (BCMA)

    • Cell-surface protein expressed on normal B lymphocytes and myeloma cells2,4-6
    • Little or no expression on naïve and memory B cells2,4-6
    • BCMA expression is virtually absent elsewhere2,4-6
    • In all patients, BCMA expression is elevated on myeloma cells vs healthy cells6,7
    • BCMA has also been shown to drive cell proliferation and survival7

     

    [Image showing a representation of BCMA on a Myeloma Cell]

     

    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Trudel S, et al. Lancet Oncol. 2018;19(12):1641-1653. 4. Cohen AD. Am Soc Clin Oncol Educ Book. 2018;38:e6-e15. 5. Lee L, et al. Br J Haematol. 2016;174(6):911-922. 6. Seckinger A, et al. Cancer Cell. 2017;31(3):396-410. 7. Cho SF, et al. Front Immunol. 2018;9:1821.

     

    DR. RAFAT ABONOUR:

    So, for that reason, I think, people have been working on BCMA antigen as a target for treating multiple myeloma.  And BCMA is expressed on myeloma cells and late-stage B cells. 

     

    Basically, it has a little expression on naïve or memory B cells, and BCMA expression is virtually absent elsewhere.  And, in all patients, BCMA expression is elevated on myeloma cells versus healthy cells.  And BCMA has also shown to drive cell proliferation and survival, making it a very important target in treating multiple myeloma.

     

    ONSCREEN TEXT:

    BLENREP Is a BCMA-Targeting Antibody-Drug Conjugate

    Composed of a humanized anti-BCMA monoclonal antibody conjugated to the cytotoxic agent mafodotin by a protease-resistant linker1,2

    BLENREP Structure

    • BLENREP is a BCMA-targeting antibody-drug conjugate1,2
    • Mafodotin, a potent microtubule disruptor, prevents multiple myeloma cells from dividing, leading to apoptosis1,3

    BLENREP is the first and only BCMA-targeting antibody-drug conjugate monotherapy for appropriate patients with relapsed/refractory multiple myeloma1-3

     

    [Image showing a representation of a BLENREP molecule including BCMA-Targeting Antibody and Mafodotin]

     

    BCMA=B-cell maturation antigen.

    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Chen H, et al. Molecules. 2017;22(8):1281.

     

    DR. RAFAT ABONOUR:

    So, what is BLENREP?  It's a BCMA-targeting antibody-drug conjugate.  So, basically, what you do is you have the BCMA antibody and then you have a conjugate which is mafodotin, a potent microtubular disruptor that prevents myeloma cells from dividing, leading to apoptosis.  So, it is really the first and only BCMA-targeting antibody-drug conjugate monotherapy for appropriate patients with relapsed and refractory multiple myeloma.

     

    ONSCREEN TEXT:

    BLENREP Exerts a Multimodal Mechanism of Action

    Delivering a cytotoxic payload and enhancing effector cell-mediated actions1-4

    [image of video]

    BLENREP may have an effect on normal cells.1,2

     

    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Trudel S, et al. Lancet Oncol. 2018;19(12):1641-1653. 4. Chen H, et al. Molecules. 2017;22(8):1281.

     

    DR. RAFAT ABONOUR:

    So, I'm gonna show you a little video about the mechanism of action of BLENREP.

     

    ONSCREEN TEXT:

    BLENREP belantamab mafodotin-blmf for injection 100 mg

    MECHANISM OF ACTION

    (Video plays)

     

    MOA Video Narrator:

    BLENREP - mechanism of action.  B-cell maturation antigen - BCMA - is a cell surface protein present on myeloma cells, late-stage B cells, and plasma cells, but has little or no expression on naïve and memory B cells.  BCMA expression is virtually absent elsewhere.  In all patients, BCMA expression is elevated on myeloma cells versus healthy cells.  BCMA has also been shown to drive cell proliferation and survival. 

     

    BLENREP is the first and only BCMA-targeting antibody-drug conjugate and is composed of a humanized anti-BCMA monoclonal antibody conjugated to the cytotoxic agent mafodotin by a protease-resistant linker.  BLENREP exerts anti-tumor activity via a multi-modal mechanism of action delivering a cytotoxic payload and mediating tumor cell lysis through ADCC and ADCP.  BLENREP may also have an effect on normal cells. 

     

    The rest of this video will focus on the potential effect of BLENREP on malignant cells.  Upon binding to BCMA, BLENREP is internalized.  Once inside the tumor cell, the free cytotoxic drug cys-mcMMAF, also known as mafodotin, is released. 

     

    Mafodotin is a potent microtubule network disruptor that binds to tubelin which disrupts cellular function, leading to cell cycle arrest and apoptosis.  BLENREP also has an afucosylated antibody that enhances the potency and efficacy of effector cell-mediated antibody-dependent cellular cytotoxicity - ADCC – and antibody-dependent cellular phagocytosis - ADCP.

     

    BLENREP, the first and only FDA-approved antibody-drug conjugate to leverage the specificity of BCMA on malignant plasma cells while exerting anti-tumor activity via a multimodal mechanism of action.

     

     

    ONSCREEN TEXT:

    BLENREP Exerts a Multimodal Mechanism of Action

    Delivering a cytotoxic payload and enhancing effector cell-mediated actions1-3

    Specifically Binds to BCMA

    • Upon binding to BCMA on the cell surface, BLENREP is internalized and then releases a cytotoxin, mafodotin1,2

    Delivers a Cytotoxic Payload

    • Mafodotin, a potent microtubule disruptor, prevents multiple myeloma cells from dividing, leading to apoptosis1,4

    Enhances Immune-Mediated Actions

    • BLENREP has an afucosylated antibody that enhances recruitment and activation of immune effector cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP)1-3

     

    [Image showing representation of BLENREP, Mafodotin, Tubulin, and Microtubule]

    [Image showing representation of Myeloma Cell, BLENREP, and Immune Effector Cell]

     

    BLENREP may have an effect on normal cells.1,2

     

    BCMA=B-cell maturation antigen.
    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Trudel S, et al. Lancet Oncol. 2018;19(12):1641-1653. 4. Chen H, et al. Molecules. 2017;22(8):1281.

     

    DR. RAFAT ABONOUR:

    So basically, just to summarize what you heard in this well-produced video.  So, the mechanism of action is really sort of, you know, like, maybe three steps.

     

    Number one is that you have a specificity against BCMA which we said is highly expressed on myeloma cells.  And then you have the cytotoxic payload mafodotin, which is a potent microtubule disruptor that prevent multiple myeloma cells from dividing.  And then you have this enhanced immune-mediated actions where this antibody will recruit cellular cytotoxic pathways and cellular phagocytosis. 

     

    So, you're getting the activity of the monoclonal antibody, the cytotoxic payload, so, you're getting, you know, two or more for the price of one activity. 

     

     

    ONSCREEN TEXT:

    DREAMM-2 Clinical Study

     

    DR. RAFAT ABONOUR:

    So, so, what happen?  This drug has been studied through this DREAMM-2 clinical study.

     

    ONSCREEN TEXT:

    DREAMM-2 Study Design

    DREAMM-2 was an open-label, randomized study that investigated BLENREP as a single agent in patients whose prior therapy included an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent1

    Study Population1,2,a

    • Relapsed/refractory multiple myeloma patients with measurable disease by IMWG criteria
    • Had undergone autologous stem cell transplant or were considered transplant ineligible
    • Received ≥3 prior therapies, including an anti-CD38 monoclonal antibody, and were refractory to an immunomodulatory agent and a proteasome inhibitor

    Dosing1,2

    • Patients in DREAMM-2 received BLENREP either 2.5 mg/kg or 3.4 mg/kg* intravenously once every 3 weeks until disease progression or unacceptable toxicity
    • Dose was modified in some cases due to adverse reactions

    Efficacy Outcomes1,2

    Primary endpoint:

    • Overall response rate as evaluated by an Independent Review Committee based on the IMWG Uniform Response Criteria for Multiple Myeloma

    Key secondary endpoints included:

    • Duration of response
    • Time to first response

     

    *The efficacy outcome analysis in this presentation is based upon the results obtained with the recommended dosage of 2.5 mg/kg (N=97).1,2

     

    eGFR=estimated glomerular filtration rate; IMWG=International Myeloma Working.

    aPatients with corneal epithelial disease, except mild punctate keratopathy, at baseline were excluded from the study. Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) at baseline were eligible for the study.

    References: 1. BLENREP Prescribing Information. 2. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    And then, in this study, the population of patients were relapsed, refractory multiple myeloma according to the International Myeloma Working Group, where they have measurable disease. 

     

    They have had undergone an autologous stem cell transplantation or were considered a transplant ineligible, and they have received three, or more prior line of therapy that included a monoclonal antibody to CD38 and have been refractory to an immunomodulatory agent and a proteasome inhibitor.

     

    The design of the study was simple. Patient received either 2.5 milligram per kilogram, or 3.4 milligram per kilogram intravenously over 30 minutes every three weeks until disease progression or unacceptable toxicity. Dose modifications in some cases were observed due to adverse reactions. 

     

    And the primary end point of this study was overall response rate as evaluated by the independent review committee based on International Myeloma Working Group uniform response criteria for multiple myeloma.  The secondary end points were duration of response and time to first response.

     

     

    ONSCREEN TEXT:

    DREAMM-2: Patient Characteristics

    DREAMM-2 evaluated BLENREP in patients with a median 7 lines of prior therapy1

    [Table]

    Patient Characteristics1,2; BLENREP 2.5 mg/kg (N=97)

    Median age (yr) (range); 65.0 (39-85)

    Gender-Male; 53%

    Gender-Female; 47%

    Race-White; 74%

    Race-Black; 16%

    ISS disease Stage II or III; 77%

    Received prior autologous stem cell transplant; 87%

    ECOG performance status of 2; 16%

    Patients with high-risk cytogenetic factorsa ; 27%

    Median prior lines of therapy, n (range); 7 (3-21)

    Received prior daratumumab; 100%

     

    ECOG=Eastern Cooperative Oncology Group; ISS=International Staging System.

    aAny of the following cytogenetics: t[4;14], t[14;16], or 17p13del.

    References: 1. BLENREP Prescribing Information. 2. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    So, what did we treat, who did we treat in this trial? Basically, in the dose of 2.5 milligram per kilogram, 97 patients were enrolled.  As you can see, a slight male predominance, 53%.  74% of the patient were white, and 16% were black.  77% Of the patient had Stage 2 or 3, and 87% of the patient had a prior autologous stem cell transplant. 

     

    Performance status of 2 was seen in 16%, and 27% of the patient enrolled on this trial had high risk cytogenetic feature, and then, a prior line of therapy, the mean was 7 and the range 3 to 21 line of therapy.  And 100% of the patient obviously, received daratumumab.

     

     

    ONSCREEN TEXT:

    DREAMM-2: Efficacy Results

    Clinically meaningful and durable responses were observed with BLENREP in a patient population with a median 7 lines of prior therapy

     

    Overall Response Rate1

    Nearly one-third of patients responded to BLENREP1

    31% (30/97, 97.5% CI:21%, 43%) N=97

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, what were the efficacy result of this DREAMM-2 clinical trial? 

    So, it was a median of 7 line of prior therapy, 31% of the patient showed a response and obviously, one-third of these patients have responded. 

     

     

    ONSCREEN TEXT:

    DREAMM-2: Efficacy Results

    Clinically meaningful and durable responses were observed with BLENREP in a patient population with a median 7 lines of prior therapy

    [Circle chart]

    Overall Response Rate1; 31% (30/97, 97.5% CI:21%, 43%) N=97

    2% (n=2) sCR

    1% (n=1) CR

    15% (n=15) VGPR

    12% (n=12) PR

    60% of responding patients (n=18/30) had a very good partial response or better1

     

    CR=complete response; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    And if you look at the response, 15% of the patient had very good partial response.  There was one patient in complete remission, and two patient had a stringent complete remission, which means that 60% of the responding patients, 18 out of 30, had a very good partial response or better.

     

     

    ONSCREEN TEXT:

    DREAMM-2: Efficacy Results

    Clinically meaningful and durable responses were observed with BLENREP in a patient population with a median 7 lines of prior therapy

    [Circle chart]

    Overall Response Rate1; 31% (30/97, 97.5% CI:21%, 43%) N=97

    2% (n=2) sCR

    1% (n=1) CR

    15% (n=15) VGPR

    12% (n=12) PR

    The median time to first response was 1.4 months (95% CI: 1.0, 1.6)1

    Median duration of response NOT REACHED at 6 months of follow-up2

    73% of responders had a duration of response ≥6 months at the time of data cutoff1

     

    CR=complete response; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.

    Reference: 1. BLENREP Prescribing Information. 2. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    So, what was the median time to response?  It was 1.4 months, and you can see the 95% confidence interval.

    And the median duration of response in this trial was a median follow-up of 6 months was not reached, and 73% of the responders had a duration of response of more than 6 months at the time of data cutoff.

     

     

    ONSCREEN TEXT:

    DREAMM-2: Subgroup Analysis

    Patients with high-risk cytogenetics

    27% (26/97) of the patients who received the 2.5 mg/kg dose of BLENREP in the DREAMM-2 study had high-risk cytogenetic factors (presence of t[4;14], t[14;16] or 17p13del)1

    In this subgroup of 26 patients with high-risk cytogenetics, an overall response rate of 38.5%
    (10/26; 97.5% CI: 18.3, 62.1) was observed2

     

    This was a prespecified, exploratory analysis not adjusted for multiplicity and not controlled for type 1 error. No efficacy conclusions can be drawn from this data2

     

    References: 1. BLENREP Prescribing Information. 2. Data on file, GSK.

     

    DR. RAFAT ABONOUR:

    So, in the 27 patient who had high-risk cytogenetic and treated with 2.5 milligram per kilograms, those cytogenetic that were high-risk were translocation 4;14, translocation 14;16, and 17p deletion.  In this subgroup of 26 patient the overall response rate was 38.5%.  This was not a prespecified exploratory analysis and not adjusted for multiplicity and not controlled for type 1 error.  So obviously, no efficacy conclusion can be drawn from these data; however, further analysis may reveal the importance of this drug in high-risk patients awaiting those data.

     

     

    ONSCREEN TEXT:

    BLENREP Safety Profile in DREAMM-21

    Adverse reactions with incidence ≥10%

    [Table: Adverse reactions; (BLENREP 2.5 mg/kg n=95)  All grades (%); Grade 3-4 (%)

    Eye disorders

    Keratopathya;71;44

    Decreased visual acuityb;53;28

    Blurred visionc;22;4

    Dry eyesd;14;1

    Gastrointestinal disorders

    Nausea;24;0

    Constipation;13;0

    Diarrhea;13;1

    General disorders and administration site conditions

    Pyrexia;22;3

    Fatiguee;20;2

    Procedural complications

    Infusion-related reactionsf;21;3

    Musculoskeletal and connective tissue disorders

    Arthralgia;12;0

    Back pain;11;2

    Metabolic and nutritional disorders

    Decreased appetite;12;0

    Infections

    Upper respiratory tract infectiong;11;0

     

    a Keratopathy was based on slit lamp eye examination, characterized as corneal epithelium changes with or without symptoms.

    b Visual acuity changes were determined upon eye examination.

    c Blurred vision included diplopia, vision blurred, visual acuity reduced, and visual impairment.

    d Dry eyes included dry eye, ocular discomfort, and eye pruritus.

    e Fatigue included fatigue and asthenia.

    f Infusion-related reactions included infusion-related reaction, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, lethargy, and tachycardia.

    g Upper respiratory tract infection included upper respiratory tract infection, nasopharyngitis, rhinovirus infections, and sinusitis.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, I think it's very important that we know about the safety profile of this drug, and what we know from DREAMM-2, the adverse reaction that was seen in more than 10%, the eye disorders sort of the main thing.  So, keratopathy was seen in 71% of the patient, and grade 3 and 4 was seen in 44% of the patient.  Decreased visual acuity was seen in 53%, and 28% of the patient had grade 3 and 4. Blurred vision all grades were 22%, and grade 3 and 4 were 4%.  Dry eye were seen in 14% of the patient, 1% had a grade 3 and 4. 

     

    GI toxicity that had been reported were nausea, constipation, and diarrhea, mostly grade 1 and 2, 24% and 13%.  General manifestation, pyrexia and fatigue were seen in about 20% of the patient, grade 3 and 4 were 3 and 2%.  Infusion-related reactions were seen in about 20% of the patient, only 3% had a grade 3 and 4.  Arthralgia was seen in 12% of the patient, and back pain 11% of the patient.  Decreased appetite were reported in 12% of the patient, and 11% of the patient had an upper respiratory tract infection; none of these were grade 3 or 4.

     

     

    ONSCREEN TEXT:

    BLENREP Safety Profile in DREAMM-2 (cont’d)1

    Most common adverse reactions, serious and fatal adverse reactions

    Most common adverse reactions (≥20%), all grades

    • Keratopathy (71%)
    • Decreased visual acuity (53%)
    • Nausea (24%)
    • Blurred vision (22%)
    • Pyrexia (22%)
    • Infusion-related reactions (21%)
    • Fatigue (20%)

     

    Most common Grade 3 or 4 (≥5%) laboratory abnormalities

    • Lymphocytes decreased (22%)
    • Platelets decreased (21%)
    • Hemoglobin decreased (18%)
    • Neutrophils decreased (9%)
    • Creatinine increased (5%)
    • Gamma-glutamyl transferase increased (5%)

     

    Serious Adverse Reactions; BLENREP 2.5 mg/kg (n=95)

    Serious Adverse Reactions; 40%

    Pneumonia; 7%

    Pyrexia; 6%

    Renal impairment; 4.2%

    Sepsis; 4.2%

    Hypercalcemia; 4.2%

    Infusion-related reactions; 3.2%

     

    Fatal Adverse Reactions; BLENREP 2.5 mg/kg (n=95)

    Fatal Adverse Reactions; 3.2%         

      Sepsis; 1%

      Cardiac arrest; 1%

      Lung infection; 1%

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, in term of the most common adverse reaction seen in more than 20%, keratopathy, again, is 71%, decreased visual acuity was in 53%, and you can see nausea, vomiting, and pyrexia in about 20% of the patient.  And infusion-related reaction, again, 21% of the patient, and 20% of the patient had fatigue. 

     

    In term of grade 3 and 4 laboratory abnormalities seen in more than 5% of the patient.  Lymphopenia 22%, thrombocytopenia 21%, anemia 18%, neutropenia 9%, and increased creatinine in 5%, and change in liver enzyme was seen in 5%.

     

    So, in term of other adverse-related reaction, 40% of the patient had those.  Pneumonia was seen in 7%, fever in 6%, renal impairment, sepsis, and hypercalcemia in 4.2% of the patients, and infusion-related reactions in 3.2% of the patient.  There were 3.2% fatal adverse reaction, 1% sepsis, 1 cardiac arrest, and 1 lung infection.

     

     

    ONSCREEN TEXT:

    BLENREP Safety Profile in DREAMM-2 (cont’d)1

    Dose modifications and discontinuations

    [Table: Patients, n (% ); BLENREP 2.5 mg/kg (n=95)]

    ARs leading to permanent treatment discontinuation; 8%

    Permanent discontinuation due to keratopathy; 2.1%

    ARs which required a dosage interruption in >3% of patients; 54%

    Dosage interruptions due to keratopathy; 47%

    Dosage interruptions due to blurred vision; 5%

    Dosage interruptions due to dry eye; 3.2%

    Dosage interruptions due to pneumonia; 3.2%

    ARs which required a dose reduction in >3% of patients; 29%

    Dose reductions due to keratopathy; 23%

    Dose reductions due to thrombocytopenia; 5%

     

    • 8% of patients discontinued treatment due to an adverse reaction
    • 2.1% of patients discontinued treatment due to keratopathy
    • No permanent loss of vision was reported in the DREAMM-2 study2

     

    AR=adverse reaction.

    References: 1. BLENREP Prescribing Information. 2. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    So, dose modification and discontinuation, what happened in this trial? 

    Adverse reaction that led to permanent treatment discontinuation was seen in 8% of the patient.  And permanent discontinuation due to keratopathy was seen in 2.1% of the patient in the 95 patient treated with 2.5 milligram per kilogram. 

     

    Adverse reaction that required dose interruption in more than 3% of the patient was seen in 54% of the patient.  Due to keratopathy in 47% of the patient, due to blurred vision in 5% of the patient, due to dry eye in 3.2% of the patient, and due to pneumonia in 3.2% of the patient.  Adverse reaction required dose reduction in more than 3% of the patient, noted in 29% of the patient, were keratopathy in 23% of the patient and thrombocytopenia in 5% of the patient.  8% of patient discontinue treatment were due to adverse reaction, and 2.1% were due to keratopathy.  There was no permanent loss of vision reported in the DREAMM-2 study. 

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS

    Ocular Toxicity

    Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety populationa

    • Ocular adverse reactions included keratopathy (76%), changes in visual acuity (55%), blurred vision (27%), and dry eye (19%)

     

    Among patients with keratopathy (n=165):

    • 49% had ocular symptomsb
    • 65% had clinically relevant visual acuity changes (decline of 2 or more lines on Snellen Visual Acuity in any eye)
    • 34% had both ocular symptoms and visual acuity changes

     

    Patients With Keratopathy (n=165)

    65% - Clinically Relevant Visual Acuity Changes

    49% - Ocular Symptomsb

    34% - Both Ocular Symptoms and Visual Acuity Changes

     

    aThe pooled safety population reflects exposure to BLENREP at a dosage of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose) administered intravenously once every 3 weeks in 218 patients in DREAMM-2. Of these patients, 194 received a liquid formulation (not the approved dosage form) rather than the lyophilized powder.

    bSuch as blurred vision and dry eyes.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, let's dig into the ocular toxicity.  So, ocular adverse reaction occurred, again, in 77% of the patient.  This is pooled safety analysis of 218 patients. Ocular adverse reaction included keratopathy in 76% of the patient, visual acuity in 55% of the patient, blurred vision 27% of the patient, and dry eye in 19% of the patient.

     

    So, among the patient with keratopathy, which was 165 patient, 49% had ocular symptoms, 65% had the clinically relevant visual acuity changes; that's a decline 2 or more lines on the visual acuity scale.  And 34% of the patient had both ocular symptoms and visual acuity changes.  So, this is just on the right, you can see here the visual clinically relevant visual acuity changes 65%, ocular symptoms 49%, and both 34%.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS

    Ocular Toxicity (cont’d)

    Keratopathy

    Keratopathy Grade per the Keratopathy and Visual Acuity (KVA) Scale

    Grade 1; 7% 

    Grade 2; 22% 

    Grade 3; 45%  

    Grade 4; 0.5%

    Cases of corneal ulcer (ulcerative and infective keratitis) have been reported

    Most keratopathy events developed within the first 2 treatment cycles (cumulative incidence of 65% by Cycle 2)

     

    Of the patients with Grade 2 to 4 keratopathy (n=149)

    39% recovered to Grade 1 or lower after median follow-up of 6.2 months

    Of the 61% who had ongoing keratopathy:

    • 28% were still on treatment
    • 9% were in follow-up
    • 24% of follow-up ended due to death, study withdrawal, or lost to follow-up

    For patients in whom events resolved, the median time to resolution was 2 months (range: 11 days to 8.3 months)

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, what were the grade of the keratopathy that's seen in the pooled safety analysis? 

     

    Grade 1, 7%, grade 2, 22%, grade 3 was the majority, 45%, and grade 4, 0.5%.  Cases of ocular ulcers, or ulcerative and infective keratitis has been reported in this pooled analysis, and most keratopathy events developed within the first 2 treatment cycles with cumulative incidence of 65% by cycle 2. 

     

    So, of the patient with grade 2 to 4 keratopathy, which is 149 patients, 39% recovered to grade 1 or lower after a median of 6.2 months.  Of the 61% with ongoing keratopathy, 28% of the patients are still on treatment, 9% were in follow-up, and 24% of the patient ended due to either death, study withdrawal, or lost to follow-up.  So, for the patient in whom the event resolved, the median time to resolution was 2 months and ranged from 11 days to 8.3 months.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS (CONT’D)

    Ocular Toxicity (cont’d)

    Visual Acuity Changes

    A clinically significant decrease in visual acuity of worse than 20/40 in the better-seeing eye was observed in 19% of the 218 patients and of 20/200 or worse in the better-seeing eye in 1.4%

    Worse than 20/40

    • 19% of patients
    • 88% resolved
    • Median time to resolution: 22 days (range: 7 days to 4.2 months)

    20/200 or worse

    • 1.4% of patients
    • All resolved
    • Median duration: 22 days (range: 15 to 22 days)

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    Let's go to visual acuity changes.  Again, clinically significant decrease in visual acuity of worse than 20/40 in the better seeing eye was developed in 19% of the 218 patient, and 20/200 or worse in the better seeing eye was happen in 1.4%.  So, what happened to the 19% who had worse than 20/40?  88% resolved, and the median time to resolution was 22 days, with a range of 7 days to 4.2 months.  For those who had 20/200 or worse, which is only 1.4% of the patient, they all resolved with median duration of, again, 22 days, ranging from 15 to 22 days.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS (CONT’D)

    Ocular Toxicity (cont’d)

    Monitoring and Patient Instruction

    • Conduct ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose, and promptly for worsening symptoms
    • Perform baseline examinations within 3 weeks prior to the first dose
    • Perform each follow-up examination at least 1 week after the previous dose and within 2 weeks prior to the next dose
    • Withhold BLENREP until improvement and resume at same or reduced dose, or consider permanently discontinuing based on severity
    • Advise patients to use preservative-free lubricant eye drops at least 4 times a day starting with the first infusion and continuing until end of treatment. Avoid use of contact lenses unless directed by an ophthalmologist
    • Changes in visual acuity may be associated with difficulty for driving and reading
    • Advise patients to use caution when driving or operating machinery
    • BLENREP is only available through a restricted program under a REMS

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, because of that, we need to monitor the patient carefully.  So, we need to conduct an ophthalmologic examinations, visual acuity and a slit lamp at baseline and prior to each dosing of BLENREP, and promptly for worsening symptoms.  So, the baseline examination need to be done within 3 weeks, prior to the first dose, and then perform each follow-up examination at least 2 weeks prior to the next dose.

    So, withhold BLENREP until improvement and resume the same dose, or reduce based on a table I'm going to show you here in a minute.  Consider permanently discontinuing based on the severity of the side effect.  So, we need to advise the patient to use a preservative-free lubricant eye drop at least 4 times a day starting with the first infusion and continuing until the end of the treatment.  Avoid the use of contact lenses unless it's really indicated by the ophthalmologist.  Changes in visual acuity may be associated with difficulty driving, so we need to advise the patients about that because it's a safety consideration.  Similarly, using/ operating machinery and the like, we need to tell the patient about that and avoid it when there's visual acuity changes.  And because of all these considerations, right now we have to administer BLENREP through the REMS program that I told you about earlier.

     

     

    ONSCREEN TEXT:

    BLENREP Risk Evaluation and Mitigation Strategy (REMS)1

    BLENREP is available only through a restricted program under a REMS called the BLENREP REMS because of the risks of ocular toxicity

     

    Notable requirements of the BLENREP REMS include the following:

    • Prescribers must be certified with the program by enrolling and completing training in the BLENREP REMS
    • Prescribers must counsel patients receiving BLENREP about the risk of ocular toxicity and the need for ophthalmic examinations prior to each dose
    • Patients must be enrolled in the BLENREP REMS and comply with monitoring
    • Healthcare facilities must be certified with the program and verify that patients are authorized to receive BLENREP
    • Wholesalers and distributors must distribute BLENREP only to certified healthcare facilities

     

    Further information is available at:

    BLENREPREMS.com

    1-855-209-9188

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, basically, who's involved in the REMS program?  Basically, the prescriber must be certified with the program by enrolling and completing the training in the BLENREP REMS program.  Prescriber must counsel the patient receiving the BLENREP about the risk of ocular toxicity and the need for ophthalmologic examination prior to each dose.  Patient must be enrolled in the BLENREP REMS and comply with monitoring.  Healthcare facility must be certified with the program and verify that the patient are authorized to receive BLENREP.

     

    And also, the wholesale distributor must only distribute BLENREP to certified facility.  And everybody will probably have access to these websites and phone numbers.

     

     

    ONSCREEN TEXT:

    Administration and Adverse Reaction Management

     

    DR. RAFAT ABONOUR:

    Alright.  So, how will we administration and adverse reaction management, how do we deal with that? 

     

     

    ONSCREEN TEXT:

    BLENREP Is Approved as a Single-Agent Monotherapy1

    BLENREP is administered as an outpatient, in-office infusion over approximately 30 minutes1,2

     

    OUTPATIENT, IN-OFFICE ADMINISTRATION

    Approximately 30-MINUTE intravenous infusion

    2.5 mg/kg administered once every 3 weeks until disease progression or unacceptable toxicity

    • Perform an ophthalmic examination prior to initiation of BLENREP and during treatment
    • Advise patients to use preservative-free lubricant eye drops and to avoid wearing contact lenses unless directed by an ophthalmologist
    • Modify dosage as needed for adverse reactions
    • Reconstitute and dilute prior to administration. Please see full Prescribing Information for instructions

    References: 1. BLENREP Prescribing Information. 2. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    So, first of all, the drug is given outpatient in the clinics and it's an infusion over 30 minutes, and the approved FDA dosing is 2.5 milligram per kilogram every 3 weeks until disease progression or unacceptable toxicity.  Again, the patient need to have an eye exam within 3 weeks prior to the first dose and within 2 weeks from subsequent doses. 

     

    The patient need to be using the preservative-free lubricant eye drops and avoid wearing contact lenses.  Dose modification are needed for adverse reactions - I'll show you the table for that.  And there’s the reconstitution of each dose prior to administration; there is clear information in the PI that your pharmacists will obviously know, and will comply with it.

     

     

    ONSCREEN TEXT:

    BLENREP Administration

    Use of systemic steroids and monitoring for infusion-related reactions

    • Systemic steroids are not required in combination with BLENREP for the treatment of relapsed/refractory multiple myeloma1
    • Additionally, premedication with a steroid is not required prior to initial infusion with BLENREP1
    • Patients should be monitored for infusion-related reactions2
    • For Grade 2 or 3 reactions, interrupt the infusion and provide supportive treatment
    • Once symptoms resolve, resume at a lower infusion rate
    • Administer premedication, such as a corticosteroid, for all subsequent infusions
    • Discontinue BLENREP for life-threatening infusion-related reactions and provide appropriate emergency care

     

    References: 1. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221. 2. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, other thing is that this drug was approved as a single agent, systemic steroid are not required in combination for the treatment of relapse of refractory multiple myeloma. 

     

    Additional premedication with a steroid is not required but patients should be monitored for infusion-related reactions and treat like you treat any antibody-based infusions.  So, for a grade 2 and 3 reaction you stop the infusion, provide supportive treatment.  Once the symptoms resolve, you can resume the infusion at the lower rate and administer premedication such as corticosteroid for all subsequent infusion.  Discontinue, obviously, BLENREP for life-threatening infusion-related reaction, and provide appropriate emergency care.

     

     

    ONSCREEN TEXT:

    Ophthalmic Examinations for Patients Receiving BLENREP1

    Patients receiving BLENREP must be monitored for corneal adverse reactions

    An eye care professional should conduct ophthalmic examinations (visual acuity
    and slit lamp) at baseline, prior to each dose, and promptly for worsening symptoms

     

    [Timeline]

    3 WEEKS before 1st Dose of BLENREP; Ophthalmic Examination Before 1st Dose (Baseline);

    Perform baseline examinations within 3 weeks prior to the first dose

     

    2 WEEKS prior to subsequent Doses of BLENREP; Ophthalmic Examination Before Subsequent Doses; Perform each follow-up examination at least 1 week after the previous dose and within 2 weeks prior to the next dose

     

    Withhold BLENREP until improvement and resume at same or reduced dose, or consider permanently discontinuing based on severity

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, again, this is just sort of a visual presentation of the schedule.  Before the first dose, within 3 weeks of the first dose you need to have an eye exam, and then subsequent exam was in 2 weeks prior to subsequent dosing.  And, if there is a grade 2 or higher corneal adverse reaction, or visual acuity changes, you hold the BLENREP until improvement and resume at the same dose or a reduced dose based on the guidelines.

     

     

    ONSCREEN TEXT:

    Adverse Reaction Management for Corneal Reactions1

    Management considerations for corneal reactions before and during treatment

    • Advise patients to use preservative-free lubricant eye drops at least 4 times a day starting with the first infusion and continuing until end of treatment
    • Advise patients to avoid use of contact lenses unless directed by an ophthalmologist
    • Changes in visual acuity may be associated with difficulty for driving and reading. Advise patients to use caution when driving or operating machinery
    • Manage corneal adverse reactions with dose modification or discontinuation, per the REMS requirements (available at BLENREPREMS.com). Additional information on BLENREP REMS is presented on slide 23

     

    REMS=Risk Evaluation and Mitigation Strategy.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, in term of counseling the patient, you need to advise the patient about using the eye drop 4 times a day at least, prior to the start and throughout the treatment period.  Advise the patient not to wear their contact lenses.  Any change in visual acuity or symptoms need to be reported, and advise the patient about not driving or using heavy machinery, operating machinery.  And then comply with the REMS program.

     

     

    ONSCREEN TEXT:

    Dosage Modifications for Adverse Reactions1

    Recommended dosage and dosage modifications for adverse reactions

    Recommended Dosage

    The recommended dosage of BLENREP is 2.5 mg/kg of actual body weight given as an intravenous infusion over approximately 30 minutes once every 3 weeks until disease progression or unacceptable toxicity

    Dosage Modifications for Adverse Reactions

    The recommended dose reduction for adverse reactions is 1.9 mg/kg intravenously once every 3 weeks. Discontinue BLENREP in patients who are unable to tolerate a dose of 1.9 mg/kg

     

    Dosage Modifications for Corneal Adverse Reactions

    • Recommended dosage modifications for corneal adverse reactions are based on both corneal examination findings and changes in best corrected visual acuity (BCVA)
    • Determine the recommended dosage modification of BLENREP based on the worst finding in the worst affected eye
    • The worst finding should be based on a corneal examination finding or a change in visual acuity per the Keratopathy and Visual Acuity (KVA) scale

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, the recommended doses is 2.5 milligrams of actual body weight, infused over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.  There's one dose level reduction to 1.9 milligram per kilogram; again, you continue that dose as long as there are no toxicities and no progression.

     

    We talked about the need for reporting any ocular toxicity or visual acuity changes.  Determine the recommended dose based on those symptoms and their severity.

     

     

    ONSCREEN TEXT:

    Dosage Modifications for Adverse Reactions (cont’d)1

    Dosage modifications for corneal adverse reactions per the KVA scale

     

    [Table: KVA Grade; Corneal Adverse Reaction; Recommended Dosage Modifications]

    Grade 1; Corneal examination finding(s): Mild superficial keratopathya, Change in BCVAb: Decline from baseline of 1 line on Snellen Visual Acuity; Continue treatment at current dose.

    Grade 2; Corneal examination finding(s): Moderate superficial keratopathyc, Change in BCVAb: Decline from baseline of 2 or 3 lines on Snellen Visual Acuity and not worse than 20/200; Withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade 1 or better and resume at same dose.

    Grade 3; Corneal examination finding(s): Severe superficial keratopathyd, Change in BCVAb: Decline from baseline by more than 3 lines on Snellen Visual Acuity and not worse than 20/200; Withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade 1 or better and resume at reduced dose.

    Grade 4; Corneal examination finding(s): Corneal epithelial defecte, Change in BCVAb: Snellen Visual Acuity worse than 20/200; Consider permanent discontinuation of BLENREP. If continuing treatment, withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade 1 or better and resume at reduced dose.

     

    a Mild superficial keratopathy (documented worsening from baseline), with or without symptoms.

    b Changes in visual acuity due to treatment-related corneal findings.

    c Moderate superficial keratopathy with or without patchy microcyst-like deposits, sub-epithelial haze (peripheral), or a new peripheral stromal opacity.

    d Severe superficial keratopathy with or without diffuse microcyst-like deposits, sub-epithelial haze (central), or a new central stromal opacity.

    e Corneal epithelial defect such as corneal ulcers.

     

    BCVA=best corrected visual acuity; KVA=keratopathy and visual acuity.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, this is a very important table that you really have to have in your office, your nurses, your pharmacist.  You need to be aware of this.  So, when the patient develop grade 1 you continue the treatment.  You get a grade 2 toxicity, you hold until they improve to grade 1 or better, and you resume at the same dose.  If the patient get a grade 3 toxicity, you hold, they improve to grade 1 or better, you go to a lower dose.  So, 1.9 milligram per kilogram.  If they're a grade 4 toxicity, you will consider permanent discontinuation of BLLENREP.  So, what is a grade 1?  Basically, you have mild superficial keratopathy, decline of baseline by 1, then that's grade 1.  But if you have a moderate significant superficial keratopathy, or a decline by 2 to 3 lines, that's consider grade 2; that's when you stop until they get better and then resume at the same dose.  For a grade 3 toxicity, severe superficial keratopathy, or a decline by 3 or more on the visual acuity scales in the worst eye, not worse than 20/200, then you hold, they get better, you restart at 1.9 milligram per kilogram.  So, the severe, you're getting corneal epithelial defect, you're getting severe acuity worse than 20/200, you hold and probably you won't be able to restart it. 

     

     

    ONSCREEN TEXT:

    Dosage Modifications for Adverse Reactions (cont’d)1

    Dosage modifications for other adverse reactions

    [Table: Adverse Reaction; Severity; Recommended dosage modifications]

    Thrombocytopenia; Platelet count 25,000 to less than 50,000/mcL; Consider withholding BLENREP and/or reducing the dose of BLENREP.

    Thrombocytopenia; Platelet count less than 25,000/mcL; Withhold BLENREP until platelet count improves to Grade 3 or better. Consider resuming at a reduced dose.

    Infusion-related reactions; Grade 2 (moderate) or Grade 3 (severe); Interrupt infusion and provide supportive care. Once symptoms resolve, resume at lower infusion rate; reduce the infusion rate by at least 50%.

    Infusion-related reactions; Grade 4 (life-threatening); Permanently discontinue BLENREP and provide emergency care.

    Other adverse reactions; Grade 3; Withhold BLENREP until improvement to Grade 1 or better. Consider resuming at a reduced dose.

    Other adverse reactions; Grade 4; Consider permanent discontinuation of BLENREP. If continuing treatment, withhold BLENREP until improvement to Grade 1 or better and resume and reduced dose.

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    How about for thrombocytopenia?  Well, I mean, I think if you have a platelet count of 25 to 50 you can consider withholding and/or reducing the dose of BLENREP.  When the patient get a platelet count less than 25,000, you will hold, they get better, then you resume at a reduced dose.  For grade 2 infusion-related reactions, you can, you know, lower the rate, reduce the infusion rate by at least 50%.  For obviously grade 4, you know, you probably need to discontinue permanently.  Other adverse reaction grade 3 you hold, they get better, you consider a reduced dose.  For a grade 4 you consider permanent discontinuation.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS (CONT’D)

    Thrombocytopenia

    • Thrombocytopenia occurred in 69% of 218 patients in the pooled safety population, including Grade 2 in 13%, Grade 3 in 10%, and Grade 4 in 17%. The median time to onset of the first thrombocytopenic event was 26.5 days. Thrombocytopenia resulted in dose reduction, dose interruption, or discontinuation in 9%, 2.8%, and 0.5% of patients, respectively
    • Grade 3 to 4 bleeding events occurred in 6% of patients, including Grade 4 in 1 patient. Fatal adverse reactions included cerebral hemorrhage in 2 patients
    • Perform complete blood cell counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity

    Infusion-Related Reactions

    • Infusion-related reactions occurred in 18% of 218 patients in the pooled safety population, including Grade 3 in 1.8%
    • Monitor patients for infusion-related reactions. For Grade 2 or 3 reactions, interrupt the infusion and provide supportive treatment. Once symptoms resolve, resume at a lower infusion rate. Administer premedication for all subsequent infusions
    • Discontinue BLENREP for life-threatening infusion-related reactions and provide appropriate emergency care

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    So, how often does thrombocytopenia happen?  In the pooled safety analysis of 218 patient, grade 2 happened in 13% of the patient.  Grade 3 in 10% of the patient, and grade 4 in 17% of the patient.  The median onset of thrombocytopenia was 26.5 days, and it resulted in dose reduction dose interruption, and discontinuation in 9, 2.8, and 0.5%.  So, discontinuation 0.5%, dose interruption 2.8%, and dose reduction in 9% of the patient.  So, grade 3 and 4 bleeding events happened in 6% of the patient, including grade 4 in 1 patients.  And fatal adverse reaction, including cerebral hemorrhage happened in 2 patient of the 218 patient in the pooled safety analysis.  So, obviously, you know, you need to be getting a CBC and adjust their treatment accordingly.  Infusion-related reactions in the 218 patient in the pooled safety population happened in 18% of the patient.  Grade 3 was 1.8%, and so for grade 2 and 3, interrupt, slow the rate, they get better, you resume at the lower rate.  And, you know, you administer premedication based on your guidelines.  So, obviously, anybody with life-threatening complications you permanently discontinue BLENREP.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    WARNINGS AND PRECAUTIONS (CONT’D)

    Embryo-Fetal Toxicity

    • Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman
    • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with BLENREP and for 4 months after the last dose
    • Advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose
    • Pregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP

     

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    Based on the mechanism of action it can cause embryo fetal toxicity, so it should not be administered to a pregnant woman, and a woman should be advised of the potential risk and use effective reproductive contraception during the treatment and 4 months after the last dose of treatment.  Advise them, male and female, of reproductive potential to use effective contraception again during BLENREP and 6 months after the last dose. Pregnancy test obviously is recommended for females of reproductive potential prior to the initiation of BLENREP.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (CONT’D)1

    USE IN SPECIFIC POPULATIONS

    Lactation

    • Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with BLENREP and for 3 months after the last dose

    Females and Males of Reproductive Potential

    • Based on findings in animal studies, BLENREP may impair fertility in females and males

    Geriatric Use

    • Of the 218 patients who received BLENREP in DREAMM-2, 43% were aged 65 to less than 75 years and 17% were aged 75 years and older. Keratopathy occurred in 80% of patients aged less than 65 years and 73% of patients aged 65 years and older. Among the 95 patients who received BLENREP at the 2.5-mg/kg dose, keratopathy occurred in 67% of patients aged less than 65 years and 73% of patients aged 65 years and older

    Renal or Hepatic Impairment

    • The recommended dosage has not been established in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2 not on dialysis or requiring dialysis. The recommended dosage has not been established in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST)

     

    AST=aspartate aminotransferase; eGFR=estimated glomerular filtration rate; ULN=upper limit of normal.

    Reference: 1. BLENREP Prescribing Information.

     

    DR. RAFAT ABONOUR:

    Lactation. The woman should not be breastfeeding during treatment and at least 3 months after the last dose.  And we talked about the important of avoiding pregnancy earlier.  So, what do we know about geriatric population use of this drug? 

     

    So, of the 218 patient in the pooled safety analysis 43% of the patient were older than 65 and 17% were age 75 and older.  So, we have data on elderly patient.  Keratopathy happened in 80% of those patient who were less than 65, and 73% of the patient age 65 and older.  And among the 95% of the patient receiving the 2.5% milligram per kilogram, keratopathy happened in 67% of the patient aged less than 65, and 73% of the patient aged 65 and older.  In terms of renal insufficiency, the patient who were enrolled on the study had to have a creatinine clearance above 30; so, we have no established safety of the drug in severe renal dysfunction, or those on dialysis.  And similarly, the recommended dose has not been established for a patient who has moderate or severe hepatic impairment.

     

     

    ONSCREEN TEXT:

    BLENREP is the first and only BCMA-targeting antibody-drug conjugate for the treatment of appropriate patients with relapsed/refractory multiple myeloma1-3

    Studied as a single agent

    in a heavily pretreated patient population1

    Clinically meaningful and durable responses

    • The majority of responders (60% [18/30]) achieved a clinically meaningful response, with a VGPR or better1
    • In the total population (97 patients), 2 patients (2%) had a sCR, 1 (1%) had a CR, 15 (15%) had a VGPR, and 12 (12%) had a PR
    • Median duration of response was not reached at 6 months4
    • 73% of responders had a duration of response ≥6 months1

    Outpatient, in-office administration

    2.5 mg/kg infusion over approximately 30 minutes administered once every 3 weeks until disease progression or unacceptable toxicity1

    31% overall response rate

    (30/97; 97.5% CI: 21%, 43%) in a patient population with a median 7 lines of prior therapy1

    Most common adverse reactions (≥20%)

    in patients who received the recommended dose included keratopathy (71%), decreased visual acuity (53%), nausea (24%), blurred vision (22%), pyrexia (22%), infusion-related reactions (21%), and fatigue (20%)1

     

    IMPORTANT SAFETY INFORMATION

    WARNING: OCULAR TOXICITY

    BLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes.

    Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity.

    Because of the risk of ocular toxicity, BLENREP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS.

     

    BCMA=B-cell maturation antigen; CR=complete response; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.
    References: 1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138. 3. Trudel S, et al. Lancet Oncol. 2018;19(12):1641-1653. 4. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

     

    DR. RAFAT ABONOUR:

    So, I think what we know right now about the BLENREP as the BCMA-targeting antibody-drug conjugate for a patient with multiple myeloma, is studied as a single agent in heavily pretreated population of patients.  Clinically meaningful and durable response were seen in the majority of the responder and the median duration of response was not reached with at 6 months, 73% of the patient who had responded had a duration of response of more than 6 months.  It's an outpatient drug, the overall response rate was 31% as a single agent, and the most adverse common reactions were keratopathy, decreased visual acuity, some nausea, and some blurred vision.  So, again, I mean, because of that, we need to be very careful, conduct the eye exam prior to each dose, and advise the patient about that. 

     

    So, with that, I think this is my last slide, Sara.

     

     

    ONSCREEN TEXT:

    [BLENREP logo]

    [GSK logo]

    Trademarks are property of their respective owners.

    ©2021 GSK or licensor.

    BLMPPTX200004 January 2021

    Produced in USA.

     

    SARA HUFF

    Wonderful.  Well, thank you for sharing that and for the presentation today. 

     

     

    ONSCREEN TEXT:

    Thank You for Watching

     

    Trademarks are property of their respective owners.

    ©2021 GSK or licensor.

    BLMVID210008 August 2021

    Produced in USA.

     

     

    SARA HUFF

    We greatly appreciate your time and passion that you input every day caring for your myeloma patients.  We appreciate the time with our audience for joining us on this Saturday morning.  And with that, we'll conclude our product theater and everybody, enjoy the rest of the conference, have a great weekend!

     

    DR. RAFAT ABONOUR

    Thank you.

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