Clinical Article
Belantamab mafodotin-blmf: A Novel Treatment Option for Relapsed/Refractory Multiple Myeloma
Primary Author: Akhilesh Sivakumar, Pharm.D., PGY2 Oncology Pharmacy Resident, Emory Healthcare/Winship Cancer Institute
Reviewing Author: Arpita Gandhi, Pharm.D., BCOP, Hematology/Oncology Clinical Pharmacy Specialist, Emory Healthcare/Winship Cancer Institute
Corresponding Author:
Akhilesh Sivakumar, Pharm.D.
PGY2 Oncology Pharmacy Resident
Emory Healthcare/Winship Cancer Institute
1364 Clifton Road NE
Atlanta, GA 30322
T: (470) 728-8843
Introduction
Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy in the United States, accounting for about 17% of all blood cancers. It is characterized by unchecked production of monoclonal plasma cells in the bone marrow, resulting in high levels of dysfunctional monoclonal immunoglobulins in the blood and urine, ultimately leading to organ dysfunction.1,2
MM is a disease of the elderly population, with a median age of 69 years at diagnosis. A plethora of new and effective drugs have been approved for the treatment of MM in the last 10-15 years. These have significantly improved prognosis and survival of patients and have essentially rendered MM a chronic disease. Now, 5-year relative survival rates are approximately 54% among all MM patients and median overall survival exceeds 10 years in young, transplant-eligible patients.3,4
Diagnosis
Diagnosis of MM requires > 10% plasma cells in the bone marrow plus one or more signs of end-organ damage, known as the CRAB criteria (hypercalcemia, renal insufficiency, anemia, or bone disease). In the absence of CRAB criteria, having MM-defining events (including clonal bone marrow plasma cells > 60%, detection of serum light chains, and/or presence of focal lesions on radiographic imaging) also qualifies for treatment.2,5
Treatment of Newly Diagnosed MM (NDMM)
Treatment of NDMM involves consideration of cytogenetics, transplant eligibility, and numerous patient factors (age, performance status, and comorbidities). Patients are generally started on a multi-agent induction therapy in order to induce remission (i.e. no signs of disease). Induction regimens commonly consist of combination therapy with agents such as an immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib), corticosteroid (dexamethasone), and/or anti-CD38 monoclonal antibody (daratumumab). After 3-4 cycles of induction therapy, transplant-eligible patients proceed to autologous stem cell transplantation (ASCT), followed by single- or multi-agent maintenance therapy. Transplant-ineligible patients receive 8-12 cycles of induction therapy followed by single- or multi-agent maintenance therapy.6
Treatment of Relapsed/Refractory MM (RRMM)
Despite effective treatment strategies for NDMM, MM remains incurable and relapse is inevitable. Among more than 40 treatment options listed by the National Comprehensive Cancer Network (NCCN) Guidelines, choice of therapy depends on numerous factors including but not limited to response to previous therapies, duration of remission, history of ASCT or transplant ineligibility, patient factors (age, performance status, and comorbidities), toxicities to previous therapies, clinical versus biochemical relapse, etc.7,8 The general approach to treating RRMM is to use doublet or triplet regimens that include some combination of a protease inhibitor, an immunomodulatory agent and/or a monoclonal antibody, and usually a steroid backbone. Despite the plethora of effective treatment options available for RRMM, patients ultimately cycle through several lines of therapy due to the incurable nature of the disease, and hence, tend to have a poor prognosis overall.9
B-Cell Maturation Antigen (BCMA) Targeted Therapy
BCMA is a member of the tumor necrosis factor (TNF) receptor superfamily whose expression plays a key role in maturation of B-cells and their differentiation into plasma cells. BCMA overexpression has been associated with MM progression due to activation of signal transduction pathways that lead to enhanced plasma cell growth and survival.10,11 Due to this selective expression of BCMA on malignant plasma cells, new BCMA-targeted therapies are in active development.
Belantamab mafodotin-blmf (Blenrep)
Belantamab mafodotin-blmf is a first-in-class antibody-drug conjugate (ADC) composed of a BCMA-targeted monoclonal antibody (belantamab) linked to the cytotoxic payload monomethylauristatin F (MMAF). Upon binding to BCMA targets on plasma cells, the ADC is internalized and MMAF is released intracellularly, leading to cytotoxic effect via microtubule inhibition (Figure 1).11 This agent was approved by the U.S. Food and Drug Administration (FDA) in August 2020 based on findings from the DREAMM-2 trial (Table 2).9,12
Key Points about Adverse Effects
Keratopathy can be dose-limiting and occurs due to MMAF deposition and associated microtubule disruption in corneal epithelial cells, causing symptoms such as dry eyes and blurry vision that can progress to vision loss (reversible upon discontinuation).13 Due to this concern, belantamab mafodotin-blmf is only available through a restricted program under a risk evaluation and mitigation strategy (REMS) called the BLENREP REMS. The prescriber, patient, and healthcare facility must enroll in the program. Per REMS, ophthalmic exams should be conducted at baseline, prior to each dose, and immediately following worsening symptoms. In addition, patients should be counseled to utilize preservative-free lubricant eye drops at least 4 times daily starting with the first infusion and continued until therapy completion.12
Belantamab mafodotin-blmf can cause thrombocytopenia that may require dose interruption and/or reduction based on severity.12
IRRs have also been reported with belantamab mafodotin-blmf. Management should consist of infusion interruption, supportive care, and resumption of the infusion at a lower rate upon IRR resolution. In addition, patients should receive premedication for all subsequent doses to reduce the risk of recurrence.12 Since belantamab mafodotin-blmf was associated with a high incidence of IRRs in the DREAMM-2 trial, strong consideration should be given to initiate prophylactic premedications prior to all doses (including the first).
Pharmacist’s Role
Pharmacists play a key role in the management of patients receiving treatment with belantamab mafodotin-blmf. Important responsibilities include patient and caregiver counseling (especially regarding the use of lubricant eye drops, need for regular ophthalmic exams throughout treatment, and embryo-fetal toxicity in females of reproductive potential), laboratory monitoring to assess for dose interruptions and/or reductions, and ensuring compliance with BLENREP REMS.
Conclusion
Discovery of BCMA as a therapeutic target in RRMM has provided a unique treatment modality given its exclusive expression on plasma cells, thus minimizing risk of off-target toxicities. As the first FDA-approved BCMA-targeted therapy, belantamab mafodotin-blmf is an effective treatment option with manageable adverse effects. An ideal candidate for belantamab mafodotin-blmf is an MM patient with good performance status and progressive disease after four or more lines of therapy, including a protease inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody.
There are several ongoing clinical trials evaluating use of belantamab mafodotin-blmf in both the newly diagnosed as well as relapsed/refractory MM settings.14 These studies may pave the way for use of multidrug combination regimens containing belantamab mafodotin-blmf in earlier lines of therapy in patients with MM and are exciting new developments on the horizon.
References
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