Testing the Combination of Two Approved Drugs and One Experimental Drug in Patients With Relapsed or Refractory Multiple Myeloma

Inclusion criteria

• 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 patients must agree to use an adequate method of contraception for the duration of the study and for 6 months afterwards.
• 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 as detailed below:
• 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).
• Archival tissue must be available for submission for the mandatory correlative studies.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. \
• Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression.
• No patients with uncontrolled human immunodeficiency virus (HIV), hepatitis C and B. Testing for HIV and hepatitis C and B are not required prior to registration. \
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• No positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to registration unless the participant can meet the following criteria:
• RNA test negative.
• Successful anti-viral treatment (usually 8 weeks duration) is required, followed by a negative hepatitis C virus (HCV) RNA test after a washout period of at least 4 weeks.
• Patients with hepatitis B will be excluded unless the following criteria can be met.
• Serology: Hepatitis B core antibody positive (HbcAb)+, hepatitis B surface antigen (HbsAg)-.
• Screening: Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) undetectable.
• During study treatment: Monitoring per protocol.
• During study treatment: Antiviral treatment instituted if HBV DNA becomes detectable.
• Serology: HBsAg+ at screen or within 3 months prior to registration.
• Screening: HBV DNA undetectable.
• Screening: Highly effective antiviral treatment started at least 4 weeks prior to first registration.
• Screening: Baseline imaging per protocol.
• Screening: Participants with cirrhosis are excluded.
• During study treatment: Antiviral treatment maintained throughout study treatment.
• During 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.
• No patients with unacceptable cardiac risk factors defined by any of the following criteria:
• Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block.
• History of myocardial infarction, acute coronary syndromes (including unstable angina), 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 \[Error! Reference source not found., 1994\].
• Uncontrolled hypertension.
• Patients with congenital long QT syndrome, QTcF interval QTcF \> 480 msec (the QT interval values must be corrected for heart rate by Fridericia's formula \[QTcF\]).
• Any history of ventricular fibrillation or torsade de pointes.
• Symptomatic bradycardia defined as heart rate (HR) \< 50 bpm with associated dizziness/syncope.
• Left ventricular ejection fraction \< 30%.
• No patients who have received targeted (non-monoclonal antibodies \[mAb\]) or investigational agents within 2 weeks prior to rgistration and who have not recovered from side effects of those therapies.
• No patients who have undergone major surgery ≤ 2 weeks prior to registration or who have not recovered from the side-effects of surgery.
• No known medical condition causing an inability to swallow oral formulations of agents.
• No active bacterial, viral or fungal infection (s) present.
• Patients cannot have a Child-Pugh score greater than 1 (absent ascites, total bilirubin \< 2, international normalized ratio (INR) \<1.7 (unless on anticoagulation), and no encephalopathy; esophageal or gastric varices, and 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.
• No 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 they fulfill inclusion criteria.
• No evidence of active mucosal or internal bleeding.
• No known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to belamaf or drugs chemically related to belamaf, or any of the components of the study treatment.
• Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening.
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. Participant must not have current corneal epithelial disease except mild changes in corneal epithelium. For belantamab mafodotin, concomitant administration with strong inhibitors of OATP should be avoided.
• RE-REGISTRATION ELIGIBILITY CRITERIA: Patients must meet criteria for progression of myeloma as defined by IMWG criteria indicated as any of the following:
• ≥ 25% increase in M-protein (must be at least 0.5 g/dl above nadir from last treatment regimen).
• 25% difference between involved and uninvolved serum free light chains from its nadir or
• The development of new plasmacytomas or hypercalcemia not due to other causes. In the absence of progression by serum M protein or free light chain, biopsy of new plasmacytoma of extramedullary disease is warranted.
• If refractory myeloma, it should be defined by IMWG criteria as disease which has become non-responsive or progressive on belamaf/dexamethasone.
• RE-REGISTRATION ELIGIBILITY CRITERIA: Measurable disease defined by IMWG criteria as:
• Serum M-protein ≥ 0.5 g/dL.
• Urine monoclonal protein ≥ 200 mg/24h.
• Serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) and serum free light chain ratio is abnormal.
• PET/CT or MRI findings consistent with (c/w) disease progression.
• RE-REGISTRATION ELIGIBILITY CRITERIA: Absolute neutrophil count (ANC) ≥ 1,000/mm\^3.
• RE-REGISTRATION ELIGIBILITY CRITERIA: Platelet Count ≥ 75,000/mm\^3 (or ≥ 50,000/mm\^3 if BM plasma cells \> 50%).
• RE-REGISTRATION ELIGIBILITY CRITERIA: Calc. creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation.
• RE-REGISTRATION ELIGIBILITY CRITERIA: Total bilirubin ≤ 2 mg/dL.
• RE-REGISTRATION ELIGIBILITY CRITERIA: AST/ALT ≤ 2.5 x upper limit of normal (ULN).
• RE-REGISTRATION ELIGIBILITY CRITERIA: Alkaline phosphatase ≤ 3 x ULN.