logo

OVERVIEW BY KEY OPINION LEADER DR. JOSEPH MIKHAEL

Dr. Joseph Mikhael 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 | 26:46

    ONSCREEN TEXT:

    [GSK logo]

    GSK ONCOLOGY ON DEMAND

     

     

    ONSCREEN TEXT THAT APPEARS THROUGHOUT REMAINDER OF THE VIDEO:

    [BLENREP logo] [GSK logo]

    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. Joseph Mikhael originally aired in February 2021.

     

    VICKIE MCKINLEY:

    I, along with all of GSK, sincerely appreciate your time and your interest in joining us.

     

     

    ONSCREEN TEXT:

    BLENREP (belantamab mafodotin-blmf)

    Trademarks are property of their respective owners.

    ©2020 GSK or licensor. BLMPPTX190001 December 2020

    Produced in USA.

     

    VICKIE MCKINLEY:

    One of the most satisfying aspects of the role that I am in here at GSK is collaborating with hematologists, specific key opinion leaders like we have with us today, Dr. Joseph Mikhael.

     

     

    ONSCREEN TEXT:

    Speaker Disclaimer

    Dr. Joseph Mikhael

    • Hematologist
    • Professor, Applied Cancer Research and Drug Division at Translational Genomics Research Institute
    • Consulting Hematologist and Director of Myeloma Research, HonorHealth Research Institute in Phoenix, Arizona

    Dr. Mikhael 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.

     

    VICKIE MCKINLEY:

    His primary research is in multiple myeloma and on all of its related conditions. He is a professor in the Applied Cancer Research and Drug Division at Translational Genomics Research Institute. He is also a consulting hematologist and director of the myeloma research at HonorHealth Research Institute in Phoenix, Arizona.

     

    Dr. Mikhael, we are so thrilled to have you with us today and appreciate you sharing your time with us. Thank you.

     

    ONSCREEN TEXT:

    BLENREP (belantamab mafodotin-blmf)

    Trademarks are property of their respective owners.

    ©2020 GSK or licensor. BLMPPTX2190001 December 2020

    Produced in USA.

     

    DR. JOSEPH MIKHAEL:

    Thank you so much, Vickie. Thank you, everybody, for joining us.

     

    We know everybody is busy. We know you have lots to do. We're really thankful that you could join us today to learn about this really important compound, as we go forward.

     

    Just a caveat as we begin. This is really very sort of dense information-wise with respect to this agent. I will do my utmost to present it to you in a clear and helpful manner. But I also want to reassure you that we're not going to go over time today. We're clearly going to be able to keep to the time constraints that we have today.

     

     

    ONSCREEN TEXT:

    Speaker Disclaimer

    Dr. Joseph Mikhael

    • Hematologist
    • Professor, Applied Cancer Research and Drug Division at Translational Genomics Research Institute
    • Consulting Hematologist and Director of Myeloma Research, HonorHealth Research Institute in Phoenix, Arizona

    Dr. Mikhael 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. JOSEPH MIKHAEL:

    We'll get right into it here. You've heard already a little bit of who I am, not that you need to

    know. As I like to say, "My name is Joe. I'm here to give the talk." That's about all you need to

    know.

     

    This is a program, as you can see here, that I'm speaking on the behalf of GSK. I'm being

    Remunerated for my services. This is within the guidelines of the FDA and not a CME event.

     

     

    ONSCREEN TEXT:

    INDICATION AND IMPORTANT SAFETY INFORMATION

     

    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.

     

    DR. JOSEPH MIKHAEL:

    The key point to know about this agent, of course, is its indication. Let's start there.

     

    Joking aside, as I always say, anyone who works with me in my Clinic, I always say safety is paramount. There will be a lot of safety information here as we try and walk through it together. I'm happy, as I mentioned, to get into more detail in questions if there are questions that come.

     

    Belantamab mafodotin, or BLENREP (as its tradename) is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies – I'm going to come back to that notion in a minute – that include:

    • An anti-CD38 monoclonal antibody
    • A proteasome inhibitor
    • And an immunomodulatory agent.

     

    The classic three major classes of drugs right now where, as you know with CD38 antibodies, we have primarily daratumumab and isatuximab, but there are also others in development. Those are the two currently. Proteasome inhibitor is classically bortezomib, carfilzomib, or ixazomib. Then for immunomodulatory agents, classically lenalidomide and pomalidomide, although there still may be some use of thalidomide.

     

    Having at least one of each of those three classes, obviously, is three. There would have to be a fourth therapy as well. Those are what we frequently call triple class exposed or triple class refractory myeloma.

     

    The approval was based on the response rate that I'll show you in a moment. It was given the accelerated approval that, for continuing approval, would be contingent on verification of a larger confirmatory study that we'll hear about in future programs as they are undergone.

     

    That's the sort of nuts and bolts of when we use this drug. I will, over the next period of time, share with you the evidence for that, the mechanism of this drug, and what we saw in the appropriate trials. But before we do that, the way this is laid out today. We're going to talk a little bit about the safety concerns.

     

    The safety concern that's particularly important is ocular toxicity. We know that this drug can cause changes in the cornea of patients, so the outer part of your eye. I don't want to give you PTSD from medical school or nursing school or PA school, whichever you've trained in – or pharmacy school – for anatomy, but this corneal issue can result in changes in vision, which can be severe. There can be corneal ulceration. Then people can get symptoms classically of blurred vision or dry eyes. We'll talk about some of the specifics later.

     

    There is a program, a REMS Program that I'll describe to you more fully where patients must be seen by either an ophthalmologist or optometrist at baseline and prior to each dose to assess the grade of their ocular findings and, in particular, that corneal issue, which we refer to as keratopathy, as I'll describe shortly. That will involve potentially withholding and delaying treatment of belantamab and potentially even discontinue it based on what's happening with that keratopathy.

     

    Because of that, there is a REMS Program you're familiar with (risk evaluation and mitigation strategy). This agent is only available through that REMS Program. It's not something you can just prescribe simply without.

     

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    WARNINGS AND PRECAUTIONS

    Ocular Toxicity: Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety population. 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 symptoms, 65% had clinically relevant visual acuity changes (decline of 2 or more lines on Snellen Visual Acuity in any eye), and 34% had both ocular symptoms and visual acuity changes.

     

    Keratopathy: Keratopathy was reported as Grade 1 in 7% of patients, Grade 2 in 22%, Grade 3 in 45%, and Grade 4 in 0.5% per the KVA scale. 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, and in 24% the 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).

     

    DR. JOSEPH MIKHAEL:

    So, in terms of the ocular toxicity, I'll get into the clinical trial and the details of the trial.

     

    There were some kind of ocular adverse events in three-quarters of patients. You see here 77% of patients. It's not a remedial reading course, so I do expect you to be able to read some of these slides. I'm not going to say every word that's on it.

     

    In that pooled safety population, I'll tell you why that population is pooled (in a minute) from different dosing strategies.

     

    The keratopathy issue, as I mentioned, where the cornea is affected, happened in about 76% of patients. Now, not all of those patients are symptomatic, as you're going to see, because many patients have this asymptomatically. There was an effect in visual acuity in 55% of the overall population. Look more specifically at the key patients that led to this approval. Blurred vision in 27% and dry eyes in 19%.

     

    You can see those who had keratopathy. About half of them have ocular symptoms here, 49% with the visual changes, as you can see there.
    Keratopathy is really the issue at hand that we think most about. You can see here, it happened about 7% in Grade 1, 22% Grade 2, and 45% Grade 3, and very little Grade 4 of 0.5% (on a specific scale that they use). This keratopathy is something, as I say, that occurs in that cornea that can really be visualized by an eye specialist.
    Most keratopathy … to make it clinical now because you're not going to be the one looking formally in the eye, per se, being clinically relevant to us now, the keratopathy typically develops within the first two cycles, so about 65% had it by Cycle 2. As you can see here, of the patients with Grade 2 to 4 keratopathy, 39% recovered to Grade 1 after a median follow-up of 6.2 months.
    In general, it takes time. It is going to often require a dose delay. But you can see here that the median time to resolution was two months. It occurs relatively quickly within the first couple of cycles. Cycles are three weeks, by the way. Typically, if it is going to occur, we see it mostly within those first two months and it takes about two months to resolve. More detail will come with that.

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    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%. Of the patients with decreased visual acuity of worse than 20/40, 88% resolved and the median time to resolution was 22 days (range: 7 days to 4.2 months). Of the patients with decreased visual acuity of 20/200 or worse, all resolved and the median duration was 22 days (range: 15 to 22 days).

     

    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.

     

    DR. JOSEPH MIKHAEL:

    Now, in terms of visual acuity changes, I'm not going to walk you through eye charts today. I promise. I do enough of that when I get my glasses.

     

    It's important to see that there was a clinically significant decrease in visual acuity of more (defined here as 20/40) in 19% of patients. Those who had more significant 20/200 was in 1.4% of patients.

     

    Again, the median time to resolution of the visual acuity was considerably faster in the keratopathy at 22 days, as you can see here. In terms of the way patients are monitored, we'll show you a bit more detail in the REMS Program, people require (at baseline and prior to every dose) to be seen by an eye specialist, as I noted before.

     

    There are a couple of extra details here that we'll see as we go through. 

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    WARNINGS AND PRECAUTIONS (cont’d)

    BLENREP REMS: 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 only distribute BLENREP to certified healthcare facilities.

    Further information is available at www.BLENREPREMS.com and 1-855-209-9188.

     

    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.

     

    DR. JOSEPH MIKHAEL:

    In terms then specifically of the BLENREP REMS Program, there are multiple levels that have to be established before we can treat a patient. Prescribers, if you're a potential prescriber, you have to be certified through the program, as we would with any other REMS Program, completing the training.

     

    I've had the joy of going through it. Thankfully, it's not particularly challenging, but it just takes a little bit of time to get registered. The prescribers have to be registered.

     

    Then the onus is on us that we talk to our patients about this. It's critical. It's important that we have this discussion about how they could develop these symptoms and how they have to seek ophthalmologic exams before, because you're going to need to see that result before you can prescribe the next dose. That's the role of the prescriber.

     

    There's the role of the patient. They also have to be enrolled and agree to comply with the monitoring program, as established.

     

    The healthcare facilities that you work in—with your pharmacist and the pharmacy—they also have to be certified within the program.

     

    It's ultimately like a three-point check. They see the eye specialist. Then they see you. Then once all those checks and balances are appropriately noted, then the pharmacy that is also certified—can release it. And, of course, wholesalers and distributors, we would hope, who are going to be able to distribute those, must be certified as well because, as I mentioned, everything has to go through this REMS Program. You can see a phone number there if you want a bit more.

     

    All right. Moving from the eye to a couple more safety features before we dive into the data.

     

    Thrombocytopenia: You've got to remember these are heavily pretreated refractory myeloma patients. I'm not for a moment making light of any of these things, but this is typically what we see in that group of patients where 69% of patients had some degree of it, albeit really only 27% had Grade 3 and 4. We'll see more specifics in the trial in a moment. Typically seen within that first month and, actually, ultimately, only led to discontinuation in half a percent of patients. More details to be seen there.

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    WARNINGS AND PRECAUTIONS (cont’d)

    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.

     

    Embryo-Fetal Toxicity: Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman because it contains a genotoxic compound (the microtubule inhibitor, monomethyl auristatin F [MMAF]) and it targets actively dividing cells. 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.

     

    ADVERSE REACTIONS

    The pooled safety population described in Warnings and Precautions 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. Among the 218 patients, 24% were exposed for 6 months or longer.

    The safety of BLENREP as a single agent was evaluated in DREAMM-2. Patients received BLENREP at the recommended dosage of 2.5 mg/kg administered intravenously once every 3 weeks (n = 95). Among these patients, 22% were exposed for 6 months or longer.

     

    DR. JOSEPH MIKHAEL:

    From infusion-related reactions, thankfully, this is not a major phenomenon with this agent where the majority are Grade 1. There was only 1.8% Grade 3 where patients have an infusional reaction from the drug, thankfully, sharing also from my experience. Although, I want to stick very clearly to what's listed here.

     

    Sometimes, I joke that I have to pre-med our team more than I pre-med patients because everyone is nervous about it. Thankfully, this is really quite easily administered. That being said, obviously, if people do experience life-threatening reactions then the appropriate emergency care is necessary and discontinuation of the drug.

     

    Thankfully, we don't have a lot of patients that are pregnant or potentially pregnant. But based on mechanism of action, we expect that this can cause fetal harm, especially because of the toxin that's associated with this monoclonal antibody as I'll describe to you in a moment. This is not recommended, as you can see here, in patients who may be pregnant. We want to take very special precautions around that.

     

    When we look at the pool data, what I mean by that is that there were two arms, as I'll show in the study, at two different dosing levels. Ultimately, we've gone ahead with the 2.5 milligrams per kilogram, but there was also a 3.4. If we look at that pooled number, we can look at various adverse reactions. I'm not going to spend a lot of time on this for number's sake, but I do want us to recognize that when we drill down into the DREAMM-2 study, and specifically for the 2.5 group, we'll understand this a little bit more as to the total numbers that we're looking at. Of course, the drug is given every three weeks.

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    ADVERSE REACTIONS (cont’d)

    Serious adverse reactions occurred in 40% of patients who received BLENREP. Serious adverse reactions in >3% of patients included pneumonia (7%), pyrexia (6%), renal impairment (4.2%), sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Fatal adverse reactions occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung infection (1%).

    Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received BLENREP; keratopathy (2.1%) was the most frequent adverse reaction resulting in permanent discontinuation.

    Dosage interruptions due to an adverse reaction occurred in 54% of patients who received BLENREP. Adverse reactions which required a dosage interruption in >3% of patients included keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%).

    Dose reductions due to an adverse reaction occurred in 29% of patients. Adverse reactions which required a dose reduction in >3% of patients included keratopathy (23%) and thrombocytopenia (5%).

    The most common adverse reactions (≥20%) were keratopathy (71%), decreased visual acuity (53%), nausea (24%), blurred vision (22%), pyrexia (22%), infusion-related reactions (21%), and fatigue (20%). The most common Grade 3 or 4 (≥5%) laboratory abnormalities were lymphocytes decreased (22%), platelets decreased (21%), hemoglobin decreased (18%), neutrophils decreased (9%), creatinine increased (5%), and gamma-glutamyl transferase increased (5%).

     

    DR. JOSEPH MIKHAEL:

    So, serious adverse reactions did occur in 40% of patients. Those included, frankly, the things that we see in multiple myeloma: pneumonia, fever, renal impairment, sepsis, hypercalcemia. As you can see, 3.2% infusional reactions. There were fatal adverse reactions, as tragically we see in refractory patients, that included sepsis, cardiac arrest, and lung infection – as you see here.

     

    Ultimately, though, frankly, permanent discontinuation due to an adverse reaction only occurred in 8% of patients of which the most common cause was keratopathy at 2%. That being contrasted by a higher proportion of patients that had the dose interruptions because, as we mentioned with the keratopathy, there has to be a drug hold. And so, 54% of patients had a dose interruption, as you can see here.

     

    When we look at the adverse events, reactions at large, the most common – keratopathy, decreased visual acuity, nausea, blurred vision, fever, infusion-related reactions, and fatigue – as you see there.

     

    With respect to those that were of a significant Grade 3 or 4, the lab abnormalities that we'll show you in more detail that you can see here with each of the three cell lines, along with a small percentage of patients who had renal insufficiency.

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    USE IN SPECIFIC POPULATIONS

    Lactation: There is no data on the presence of belantamab mafodotin-blmf 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 BLENREP and for 3 months after the last dose.

     

    Females and Males of Reproductive Potential: BLENREP can cause fetal harm when administered to pregnant women. There are no available data on the use of BLENREP in pregnant women to evaluate for drug-associated risk. No animal reproduction studies were conducted with BLENREP.

    Pregnancy Testing: Pregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.

    Infertility: Based on findings in animal studies, BLENREP may impair fertility in females and males. The effects were not reversible in male rats but were reversible in female rats.

     

    DR. JOSEPH MIKHAEL:

    We don't have any data for belantamab in lactation. It's not something, again, that is typically seen in myeloma patients, although not unheard of. Because we know that this could cause fetal harm when administered to pregnant women and we have no data on this, we recommend the pregnancy testing of potentially pregnant or women of reproductive age prior to the initiation of BLENREP.

     

    ONSCREEN TEXT:

    IMPORTANT SAFETY INFORMATION (cont’d)

     

    USE IN SPECIFIC POPULATIONS (cont’d)

    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 patients who received BLENREP at the 2.5-mg/kg dose in DREAMM-2 (n = 95), keratopathy occurred in 67% of patients aged less than 65 years and 73% of patients aged 65 years and older.

     

    Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73m2 as estimated by the Modification of Diet in Renal Disease [MDRD] equation). 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.

     

    Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤upper limit of normal [ULN] and aspartate aminotransferase (AST) >ULN or total bilirubin 1 to ≤1.5 × ULN and any AST). The recommended dosage of BLENREP has not been established in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST).

     

    DR. JOSEPH MIKHAEL:

    When it comes to geriatric use—because we're always going to have to look at specific population—in fact, as we're going to see, there really wasn't a significant difference in distribution of adverse events. Particularly keratopathy, by the way, was not seen more so in the older population, those over 65 versus under 65, frankly.

    We don't dose adjust here for renal impairment. As I'll show you in the clinical trial, patients with creatinine clearance all the way down to 30 were included in the study and there's also no dose adjustment for hepatic impairment.

     

    ONSCREEN TEXT:

    Mechanism of action: antibody-drug conjugate1,2

    [Representational image of BLENREP molecule]

    Monoclonal antibody

    MMAF

    • The antibody component of belantamab mafodotin-blmf is an afucosylated IgG1 directed against BCMA
    • BCMA is a protein expressed on normal B lymphocytes and multiple myeloma cells
    • The small molecule component is MMAF, a microtubule inhibitor
    • Upon binding to BCMA, BLENREP is internalized followed by release of MMAF via proteolytic cleavage
    • The released MMAF intracellularly disrupts the microtubule network, leading to cell cycle arrest and apoptosis
    • BLENREP had antitumor activity in multiple myeloma cells and mediated killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP)

     

    1. BLENREP Prescribing Information. 2. Tai Y-T, et al. Blood. 2014;123(20):3128-3138.

     

    DR. JOSEPH MIKHAEL:

    Let me tell you about the drug. What is this drug and why do I geek out about things like this, being the myeloma geek that I am?

     

    This is a monoclonal antibody that's directed against BCMA. You might be familiar with BCMA or B-cell maturation antigen. This is a prolifically expressed antigen on the surface of myeloma cells and has really now been an interesting target for multiple different agents. Although, of course, belantamab is the first BCMA targeted agent in myeloma.

     

    It's not only a monoclonal antibody that adheres to BCMA. It also has a, if you will, toxin associated with it, this sort of green leafy thing that you see there that's called the MMAF. That's why it's called belantamab mafodotin.

     

    I describe it to patients saying, like, this is like the soldier that's got a backpack. The soldier not only finds the enemy and hooks onto the enemy. It opens up its backpack and drops this toxin into it.

     

    This is what an antibody drug conjugate is all about, of course, where the antibody is able to bind BCMA and is actually being brought into the cell to release that MMAF so that it can cause damage, both through the mechanism that you would expect through a monoclonal antibody, triggering the usual antibody-dependent cellular toxicity, ADCC, ADCP, all those things that we classically see in the immune reaction but in addition is specifically targeted by dropping this toxin in. That's what makes this drug a little bit unique in its mechanism of action and one of the reasons why we'll see the efficacy that we see here shortly.

     

    ONSCREEN TEXT:

    DREAMM-2 Clinical Study

     

    DR. JOSEPH MIKHAEL:

    This was demonstrated in the DREAMM-2 clinical study.

     

    ONSCREEN TEXT:

    The efficacy of BLENREP was evaluated in DREAMM-2, an open-label, multicenter study
    (NCT 03525678)1

    Eligible patients had relapsed or refractory multiple myeloma, had previously received 3 or more prior therapies, including an anti-CD38 monoclonal antibody, and were refractory to an immunomodulatory agent and a proteasome inhibitor.

     

    Patients had measurable disease by International Myeloma Working Group (IMWG) criteria. Patients with corneal epithelial disease at baseline, except mild punctate keratopathy, were excluded from the study.

     

    Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) at baseline were also eligible for the study. Patients received either BLENREP 2.5 mg/kg or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity.

     

    The major efficacy outcome measure was overall response rate as evaluated by an Independent Review Committee (IRC) based on the IMWG Uniform Response Criteria for Multiple Myeloma.

     

    • Only the results of the recommended dosage of 2.5 mg/kg are described

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    These were patients that had relapsed refractory myeloma that had had three or more prior therapies that included, as you'd expect from the three classes, a monoclonal antibody, a refractory to an immunomodulatory agent, and a proteasome inhibitor. These people had quite heavily pretreated multiple myeloma. They had measurable disease by virtue of the International Myeloma Working Group.

     

    There weren't a lot of exclusion criteria, thankfully, unless people had quite significant keratopathy in advance, which thankfully is a rare phenomenon. Patients, as I mentioned, even with a creatinine clearance down to 30 were included. The drug is given intravenously, as you heard, over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. That's the plan for it. It's every three-week dosing.

     

    Understandably, the outcome of response rate was evaluated, as it should be, by an independent review committee that followed our IMWG (International Myeloma Working Group) criteria.

     

    ONSCREEN TEXT:

    A total of 97 patients received BLENREP at a dose of 2.5 mg/kg administered intravenously once every 3 weeks1

    • The median number of prior lines of therapy was 7 (range: 3 to 21)

    [Table: Patient characteristics; N=97]

    Median age (yr) (range); 65 (39-85)

    Gender; 53% Male

    Race; White: 74% Black: 16%

    ISS disease Stage II or III; 77%

    Prior autologous stem cell transplantation; 87%

    ECOG performance status of 2; 16%

    Median previous lines of therapy; 7 (range: 3 to 21)

    Patients with high-risk cytogenetics (any of the following: t[4;14], t[14;16], and 17p13del); 27%

     

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

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So, ninety-seven patients received this dose of 2.5. As I mentioned, there were two dosing strategies: 2.5 and 3.4. Because the ultimate approval and moving ahead was with 2.5, we'll focus on that arm. This was given, as I mentioned, IV every three weeks.

     

    When you look at the patient characteristics, it pretty well matches what you'd expect in a myeloma patient portfolio. The median age of 65 with a range up to 85. Slight predominance in men.

     

    Importantly, 16% of patients were black. Myeloma, as you know, is twice as common in the African-American population as it is in the Caucasian population. Blacks – which is good to discuss in Black History Month, in particular – comprise about 17% to 18% of all myeloma patients. Historically, in trials, are very (sadly) underrepresented. Here, 16%.

     

    About three-quarters were Stage 2 or 3. Most patients had a previous autologous stem cell transplant. There was a not-insignificant fraction of them that had an ECOG performance status of two.

     

    The average or median prior therapies were seven, so it tells you how heavily pretreated these patients were. This is not just a mild group. There was the minimum 3, but you could see up to 21. Not surprisingly, a little over a quarter of them had high-risk myeloma, as defined by the cytogenetic abnormality.

     

    ONSCREEN TEXT:

    DREAMM-2: Efficacy results1

    • The median time to first response was 1.4 months (95% CI: 1.0, 1.6)
    • Seventy-three percent of responders had a duration of response ≥6 months

    [Table]Efficacy in DREAMM-2; BLENREP N=97

    Overall response rate (ORR), n (%) (97.5% CI); 30 (31%) (21%, 43%)

    Stringent complete response (sCR), n (%); 2 (2%)

    Complete response (CR), n (%); 1 (1%)

    Very good partial response (VGPR), n (%); 15 (15%)

    Partial response (PR), n (%); 12 (12%)

    Median duration of response in monthsa (range); NR [NR to NR]

    aNR=not reached.

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So if you've been napping, this is the time to wake up because this is what we talk about from the efficacy standpoint that, ultimately, obviously, is important for our patients.

     

    The median time to response was 1.4 months. We see it really after those first couple of doses. The majority of people who are going to respond, respond quite quickly, which is interesting. You can see here that about three-quarters or 73% of responders had a duration that lasted over 6 months. The response rate was in 30 patients or 31%.

     

    The stringent complete response was seen in a few as a complete response, 15% very good partial response, and, as you can see, 12% achieving a partial response. A nice distribution there where it wasn't just partial responses. We saw a considerable fraction of them getting a very good partial remission (which is important), often very much correlating to the duration of response in myeloma, in general.

     

    ONSCREEN TEXT:

    DREAMM-2: Summary of Adverse Reactions1

    • The most common adverse reactions (≥20%) were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue. The most common Grade 3 or 4 (≥5%) laboratory abnormalities were lymphocytes decreased, platelets decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased
    • Serious adverse reactions occurred in 40% of patients who received BLENREP. Serious adverse reactions in >3% of patients included pneumonia (7%), pyrexia (6%), renal impairment (4.2%), sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Fatal adverse reactions occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung infection (1%)
    • Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received BLENREP; keratopathy (2.1%) was the most frequent adverse reaction resulting in permanent discontinuation
    • Dosage interruptions due to an adverse reaction occurred in 54% of patients who received BLENREP. Adverse reactions which required a dosage interruption in >3% of patients included keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%)
    • Dose reductions due to an adverse reaction occurred in 29% of patients. Adverse reactions which required a dose reduction in >3% of patients included keratopathy (23%) and thrombocytopenia (5%)

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So,  just a quick summary of the adverse reactions, so most common adverse reactions in this subgroup kind of reflected what we saw in the pool data earlier:

     

    The most common ones, understandably, were:

    • Keratopathy
    • Decreased visual acuity
    • Nausea
    • Blurred vision
    • Pyrexia (fever)
    • Infusion-related reactions
    • Fatigue

     

    What I had previously described, so I'm not going to repeat all of these things again. We'll see them a little bit more in context in just a minute.

     

    The serious adverse reactions, as you can see here, included pneumonia in 7% (perhaps the most important), with a permanent discontinuation due to those adverse reactions of 8% whereas the dose interruptions were 54%.

     

    ONSCREEN TEXT:

    Adverse reactions reported in ≥10% of patients (N=95)1

    [Table: Adverse reactions; (BLENREP N=95) All Grade (%); 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.

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So we look at those reported out of those 95 patients that were given that dose level that we've just discussed. A key point here is that 71% of patients had some degree of keratopathy, which is one of the reasons why obviously we need to monitor them as carefully as we do.

     

    About half of them had decreased visual acuity. When we look at Grade 3 to 4, that's about a quarter of patients or 28% of patients have that, if you will, significant decreased visual acuity. A smaller fraction of patients experienced blurred vision and dry eyes, but not insignificant.

     

    Thankfully, from a Grade 3/4 standpoint, we don't see a lot of nausea, constipation, diarrhea, or fever, or infusion reactions, as I've described before. The majority of those subsequent adverse reactions, as you see here, are very much of Grade 1 and 2.

     

    ONSCREEN TEXT:

    Laboratory abnormalities (≥20%) worsening from baseline in patients who received BLENREP in DREAMM-2

    [Table: Laboratory abnormality; (BLENREP N=95) All Grade (%); Grade 3-4 (%)

    Hematology

    Platelets decreased;62;21

    Lymphocytes decreased;49;22

    Hemoglobin decreased;32;18

    Neutrophils decreased;28;9

    Chemistry

    Aspartate aminotransferase increased;57;2

    Albumin decreased;43;4

    Glucose increased;38;3

    Creatinine increased;28;5

    Alkaline phosphatase increased;26;1

    Gamma-glutamyl transferase increased;25;5

    Creatinine phosphokinase increased;22;1

    Sodium decreased;21;2

    Potassium decreased;20;2

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    When it comes to lab abnormalities, again, remind you these are triple class refractory patients with a median prior seven lines of therapy. These are the numbers that we expect to see with about 20% of the patients having Grade 3 to 4 thrombocytopenia and lymphopenia, not so much on the neutrophil side with only 9% in Grade 3 neutropenia.

     

    We saw some patients experience some liver abnormalities and chemistry abnormalities, as you see here. Albeit, again, less than 5% in Grade 3 to 4.

     

    ONSCREEN TEXT:

    BLENREP dosing and administration1

    Important Safety Information (as seen in the PI)

    • Perform an ophthalmic exam prior to initiation of BLENREP and during treatment
    • Advise patients to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist

    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:

    • BLENREP 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.

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So, a reminder, as a safety feature that these patients are being seen by an eye specialist before each dose. But patients are also going to be provided with eye drops. That's important for them to be using those to both prevent any complications and reduce the nature of them. We generally recommend people not taking contact lenses throughout this period of time, although that can be discussed obviously with their ophthalmologist.

     

    I've talked a little bit about the dosing already. The dose is 2.5 milligrams per kilogram given every 3 weeks over 30 minutes.

     

    If there are adverse reactions that require dose modifications, we mentioned there isn’t the modification for renal insufficiency or hepatic insufficiency. That one dose level reduction is now down to 1.9 as opposed to 2.5.

     

    ONSCREEN TEXT:

    Dosage modifications for corneal adverse reactions1

    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 worse-affected eye. The worst finding should be based on a corneal examination finding or change in visual acuity per the Keratopathy Visual Acuity (KVA) scale.

     

    [Table: 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.

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So, a few things about dose modification, probably the most important is related to the corneal findings where, at Grade 1, we continue with the current dose. If people experience Grade 2 corneal findings, which are a grading that we don't do, thankfully. That's what the eye specialists are there for; to understand the keratopathy and can check their visual acuity. That's what the best-corrected visual acuity or BCVA stands for. They also have a keratopathy visual acuity. You know ophthalmologists. They have to have a short form for everything. (My brother is an ophthalmologist, so I can make fun of them.)

     

    Based on those, they give you a grading. If it's Grade 1, we can continue where we're at. You saw the percentage of patients that have a Grade 1. But if it's Grade 2 or above, then there is important changes that need to be made, namely that we're withholding the belantamab until there is a reduction in that grade to a lower grade.

     

    Once we've reached Grade 4, as you can see here, we consider permanent discontinuation of the belantamab thereafter. 

     

    ONSCREEN TEXT:

    Dosage modifications for other adverse reactions1

    [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.

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    When it comes to other things that you're likely more familiar with, this is what the table tells us to do with thrombocytopenia. I always say, "Look. It's really important to understand why is the patient thrombocytopenic? Is it because their marrow is filled? Is it because their marrow has been beaten down with prior therapy?" This obviously has to be taken in clinical judgment.

     

    The formal recommendation is to consider withholding it when it's between 25 and 50 and holding it when it's below 25. But obviously, you have to use your clinical judgment as to the nature of the potential use of transfusions or co-factors or other interventions.

     

    Similarly, for infusion-related reactions, we interrupt it and provide, generally speaking, more of supportive care and potentially resume it at half the rate. If it's very severe or life-threatening, obviously, we discontinue it.

     

    In general, you can see here what we do for Grade 3 and Grade 4 adverse reactions.

     

    ONSCREEN TEXT:

    Ocular toxicity: Monitoring and patient instruction1

     

    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.

     

    1. BLENREP Prescribing Information.

     

    DR. JOSEPH MIKHAEL:

    So, in case you haven't figured it out yet, the ophthalmologic exams have to be conducted at baseline and prior to each dose. That's part of the REMS Program. It's part of what we're going to have to do for all of our patients on this.

     

    We advise our patients to continue to get those drops that are provided to them. That they continue to take that four times a day to help reduce the risk.

     

    Then, if they…of course, like with anything, we need to have an open and honest conversation with our patients that if they're experiencing anything with respect to visual acuity that's affecting particular things like driving, that they should report it to us. As we mentioned, this is really only available through the REMS Program.

     

    I hope that was helpful in the overview of this medication and what it's all about.

     

    MODERATOR

    Dr. Mikhael, would you like to make any closing comments?

     

    DR. JOSEPH MIKHAEL:

    No, just apart from the fact that there is a learning curve for everything and people are here to help. I know the company is more than happy to talk to you.

     

    I'm kind of disturbingly accessible if it involves helping a myeloma patient. You can find me. I'm not difficult to find. I'm pretty liberal with giving my cell phone out and email, carrier pigeon, whatever way you want to reach me. I tend to be accessible. If it's going to help with your patient, I'm more than happy to try and help.

     

    ONSCREEN TEXT:

    [BLENREP logo]

    Thank You for Watching.

    [GSK logo]

    Trademarks are property of their respective owners.

    ©2021 GSK or licensor. BLMVID210007 July 2021 Produced in USA.

     

    MODERATOR

    On behalf of GSK, I would like to thank you for participating in today's event.

     

EXPLORE A

BOLD APPROACH

TO TREATMENT

Learn more about how BLENREP works and who it can help.

VISIT THE SITE

RELATED VIDEOS