Belantamab Mafodotin in Combination with Carfilzomib, Pomalidomide, and Dexamethasone for Treatment of Relapsed or Recurrent Multiple Myeloma

Inclusion Criteria

• Subject must be >= 18 years of age
• Life expectancy of more than three months
• Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (>= 0.75 x 10^9/L if attributed to Fy[A-/B-] immunophenotype, also known as [aka] benign ethnic neutropenia)
• Hemoglobin >= 8.0 g/dL
• Platelets >= 75 x 10^9/L
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (Isolated bilirubin >= 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2.5 x ULN
• Estimated glomerular filtration rate (eGFR) >= 30 mL/min/ 1.73 m^2 * As calculated by Modified Diet in Renal Disease (MDRD) formula
• Spot urine (albumin/creatinine ratios [spot urine]) < 500 mg/g (56 mg/mmol) OR Urine dipstick negative/trace (if >= 1+ only eligible if confirmed < 500 mg/g [56 mg/mmol] by albumin/creatinine ratio [spot urine from first void])
• Female subjects: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a woman of childbearing potential (WOCBP) Or * Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, during the intervention period and for at least 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy
• Nonchildbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure
• Male subjects: contraceptive should be used consistently with local regulations regarding the methods of contraception for those subjects in clinical studies. Male subjects are eligible to participate if they agree to the following during the intervention period and for six months after the last dose of study treatment to allow for clearance of any altered sperm: * Refrain from donating sperm PLUS EITHER ** Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR ** Must agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of < 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)
• All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events [NCI-CTCAE], version 5.0) must be =< grade 1 at the time of enrollment except for alopecia and grade 2 peripheral neuropathy
• Subject must be able to understand the study procedures and agree to participate in the study by providing written informed consent
• Subject must be willing to comply with the requirements consistent with the belantamab mafodotin and pomalidomide Risk Evaluation and Mitigation Strategy (REMS) programs
• Subjects with relapsed or refractory multiple myeloma requiring systemic therapy, who have progressed after 2+ prior lines of anti-myeloma treatments. A line of therapy consists of >= 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens
• Subjects may be exposed to lenalidomide, bortezomib, daratumumab, elotuzumab, pomalidomide and/or carfilzomib
• If NO prior chimeric antigen receptor (CAR) T-cell therapy (conventional cohort): * Subjects with only one prior line of therapy must have been exposed to an immunomodulatory imide drug (IMiD) AND either an anti-CD38 monoclonal antibody or a proteasome inhibitor. * Subjects with two or more prior lines of therapy are permitted regardless of prior exposure. * Subjects who have been deemed refractory to EITHER carfilzomib or pomalidomide are permitted but subjects cannot be refractory to both carfilzomib and pomalidomide
• If prior BCMA-directed CAR T-cell therapy: Subjects with prior exposure to BCMA-directed CAR-T cell therapy are permitted to enroll, regardless of carfilzomib/pomalidomide refractory status, if they meet criteria for progression
• Measurable disease, as indicated by one or more of the following: * Serum M-protein of 0.5 g/dL of greater. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement (i.e. M-spike in the beta region), then quantitative immunoglobulin levels are acceptable (IgA, IgM, or IgD >= 600 mg/dL or IgG >= 1100 mg/dL) * Urine M-protein >= 200 mg/24 hours * Involved serum free light chains >= 10 mg/dL provided that free light chain ratio is abnormal
• Subjects must receive insurance approval for pomalidomide and dexamethasone

Exclusion Criteria

• Waldenstrom’s macroglobulinemia, systemic amyloidosis, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, or plasma cell leukemia at the time of screening
• Radiotherapy to multiple sites within 3 weeks before start of protocol treatment (localized radiotherapy to a single site 1 week before start is permissible)
• Subject must not have used an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days preceding the first dose of study drug
• Prior refractory status to belantamab mafodotin
• Current corneal epithelial disease except mild changes in corneal epithelium and mild punctate keratopathy
• Subject must not have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria
• Subject must not have presence of active renal condition (infection, requirement for dialysis or any other condition that could affect Subject’s safety). Subjects with isolated proteinuria resulting from MM are eligible, provided they fulfil the inclusion criteria
• Subject must not use contact lenses while participating in this study unless instructed by an ophthalmologist
• Subject must not be simultaneously enrolled in any interventional clinical trial
• Subject must not have had major surgery =< 2 weeks prior to initiating study treatment
• Subject must not have any evidence of active mucosal or internal bleeding
• Significant neuropathy (grades 3-4, or grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
• Subject must not have evidence of cardiovascular risk including any of the following: * Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant electrocardiography (ECG) abnormalities such as 2nd degree (Mobitz type II) or 3rd degree atrioventricular (AV) block. Controlled atrial fibrillation is not an exclusion * History of myocardial infarction, acute coronary syndromes (including unstable angina, prolonged Fridericia's correction formula [QTcF]), coronary angioplasty, or stenting or bypass grafting within three (3) months of screening * Class III or IV heart failure as defined by the New York Heart Association functional classification system [NYHA, 1994] * Uncontrolled hypertension
• Subject must not have known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment
• Subject must not have an active infection requiring treatment
• Subject with human immunodeficiency virus (HIV) infection will be excluded unless all of the following criteria can be met: (1) CD4+ T-cell count >= 350 cells/uL, (2) No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months, and (3) receiving anti-retroviral therapy for at least 4 weeks, (4) and HIV viral load < 200 copies/mL Note: consideration must be given to anti-retroviral and prophylactic antimicrobials that may have a drug:drug interaction and/or overlapping toxicities with belantamab mafodotin or other combination products as relevant
• Patients will hepatitis B will be excluded unless the following criteria can be met: * Serology: Hepatitis B virus core antibody positive (HbcAb+), hepatitis B virus surface antigen negative (HbsAg-): ** Screening: *** Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) undetectable ** During study treatment: *** Monitoring per protocol *** Antiviral treatment instituted if HBV DNA becomes detectable * Serology: HBsAg+ at screen or within 3 months prior to first dose: ** Screening: *** HBV DNA undetectable *** Highly effective antiviral treatment started at least 4 weeks prior to first dose of study treatment *** Baseline imaging per protocol *** Participants with cirrhosis are excluded ** During study treatment: *** Antiviral treatment maintained throughout study treatment *** Monitoring and management per protocol Note: Presence of isolated hepatitis (Hep) B surface antibody (HBsAb) indicating previous vaccination will not exclude a participant
• Subject must not have positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment unless the subject can meet the following criteria: * Hepatitis C RNA test is negative * Receives successful anti-viral treatment (typically 8 weeks) followed by a negative hepatitis C virus (HCV) RNA test after a washout period of at least 4 weeks Note: Subjects with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained
• Subject must not have invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Subjects with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction
• Subject must not have any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures
• Subjects must not be pregnant or lactating