Belantamab Mafodotin, Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma

Inclusion Criteria

• Histologically confirmed diagnosis of refractory multiple myeloma (MM). * Has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (e.g., daratumumab) alone or in combination, and is refractory to an immunomodulatory imide drug (IMiD) (i.e., lenalidomide or pomalidomide), and to a proteasome inhibitor (e.g., bortezomib, ixazomib or carfilzomib). (Refractory myeloma is defined as disease that is nonresponsive while on primary or salvage therapy or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve at least minimal response or development of progressive disease (PD) while on therapy).
• Has measurable disease with at least one of the following: * Serum M-protein >= 0.5 g/dL (>= 5 g/L) * Urine M-protein >= 200 mg/24 hour (h) * Serum free light chain (FLC) assay: Involved FLC level >= 10 mg/dL and an abnormal ratio (< 0.26 or > 1.65).
• Provide signed written informed consent.
• 18 years or older (at the time consent is obtained).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Participants with a history of autologous stem cell transplant or prior B-cell maturation antigen (BCMA) targeted therapy (e.g. CAR-T cells, BiTes) can enroll on the study provided that: * Therapy was > 100 days prior to study enrolment * No active infection(s).
• Absolute neutrophil count (ANC) >= 1.0 X 10 ^ 9/L.
• Hemoglobin >= 8.0 g/dL.
• Platelets >= 50 X 10 ^ 9/L.
• Total bilirubin =< 1.5 X upper limit of normal (ULN).
• Alanine aminotransferase (ALT) =< 2.5 X ULN.
• Renal estimated glomerular filtration rate (eGFR) >= 30 mL/min.
• Urine dipstick- Negative/trace (if >= 1+ only eligible if confirmed =< 500 mg/g by albumin/creatinine ratio (spot urine first void) or albumin/creatinine ratio (from spot urine) =< 500 mg/g (56 mg/mmol).
• Albumin/creatinine ratio (from spot urine) =< 500 mg/g (56 mg/mmol).
• Female participants: Contraceptive use for those participating in clinical studies (men or women) should be consistent with local regulations. A female participant 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 12 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. ** We will review the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a new undetected pregnancy. * Non childbearing 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 participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for 6 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 contraception/barrier and 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.
• All prior treatment-related toxicities must be =< grade 1 at the time of enrollment except for grade 2 peripheral neuropathy.
• 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.

Exclusion Criteria

• Systemic anti-myeloma therapy within =< 14 days or 5 half-lives, whichever is shorter, or plasmapheresis within 7 days prior to the first dose of study drug.
• Systemic treatment with high dose steroids (equivalent to >= 60 mg prednisone daily for >= 4 days) within the past 14 days if administered to treat MM or non- MM disease.
• Symptomatic amyloidosis, active central nervous system (CNS) disease, active plasma cell leukemia at the time of screening.
• Prior allogeneic stem cell transplant (SCT). NOTE: Participants who have undergone syngeneic transplant may be allowed, if no history of graft versus host disease (GvHD).
• Current corneal epithelial disease except mild punctate keratopathy.
• Evidence of active bleeding.
• Any major surgery within the last four weeks.
• Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided participants fulfill entry criteria.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere participants’ safety, obtaining informed consent or compliance with study procedures.
• Current unstable liver disease per Investigator assessment 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) is acceptable if participant otherwise meets entry criteria.
• Other malignancies are excluded, except for malignancy from which the patients have been disease-free for more than 2 years.
• Evidence of cardiovascular disease including any of the following: * Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block. * History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of screening. * Class III or IV heart failure as defined by the New York Heart Association functional classification system. * Uncontrolled hypertension.
• Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any other components of the study treatment.
• Active infection requiring treatment.
• Known human immunodeficiency virus (HIV) infection.
• Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb), at screening or within 3 months prior to first dose of study treatment. Note: presence of Hep B surface antibody (HBsAb) indicating previous vaccination will not exclude a participant.
• 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. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
• Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening.
• Pregnant or lactating female.
• Concomitant administration of strong P-glycoprotein inhibitors and inhibitors of organic anion transporter protein (OATP) will be avoided.