Study of Belantamab Mafodotin, Cevostamab, Pomalidomide for RRMM Patients (MAPLE)

Inclusion Criteria:

1. Must be able to understand and voluntarily sign an informed consent form (ICF).
2. Must be ≥ 18 years of age at the time of signing the ICF.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Documented diagnosis of MM and must have:

   (Part 1) relapsed and refractory disease having previously received 2 or more prior lines and having previously received lenalidomide, a proteosome inhibitor and/or anti-CD38 mAb (triple class exposed) and must be refractory to the last line of therapy.

   (Part 2) relapsed disease having previously received 1-3 prior line of therapy including lenalidomide, a proteosome inhibitor, and/or an anti-CD38 mAb .
   * Lines of therapy are defined as per the consensus panel of the International Myeloma Workshop and include induction therapy followed by ASCT and consolidation/maintenance as one line.
   * Relapse is defined as documented evidence of progressive disease (PD) after achieving at least stable disease (SD) for ≥ 1 cycle during a previous MM treatment (i.e., relapsed MM). and refractory is defined as disease progression during or within 60 days from the end of the most recent MM treatment.
5. Subjects with measurable disease defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 28 days prior to start of study drug):

   1. Serum M-protein ≥ 5 g/l
   2. Urine M-protein ≥ 200 mg/24 h
   3. Serum free light chains (FLC) assay: Involved FLC level ≥ 100 mg/l and an abnormal serum free light chain ratio (\< 0.26 or \> 1.65).
6. Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:

   \- Transplant was \> 100 days prior to study enrollment
7. Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
8. Adequate organ system function defined as:

   1. Absolute neutrophil count (ANC) \> 1.0 x 109/L. Granulocyte colony-stimulating factor (G-CSF) cannot be given within 7 days prior to first study drug administration.
   2. Hemoglobin ≥ 8.0 g/dL.
   3. Platelet count \>75 x 109/L.
   4. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN).
   5. Total bilirubin ≤ 1.5 x ULN, unless known to have Gilbert's disease. If Gilberts, isolated bilirubin \>1.5 and \<3xULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35%.
   6. Estimated glomerular filtration rate (eGFR) (MDRD) ≥ 30 mL/min.
   7. Albumin/creatinine ratios (spot urine) \<500mg/g (56 mg/mmol).
   8. Albumin ≥ 2.0 g/dL (20 g/L).
   9. Left ventricular ejection fraction (LVEF) \>50%.
   10. Serum calcium (corrected for albumin) level ≤11.5 mg/dL (treatment of hypercalcemia is allowed and patient may enroll if hypercalcemia returns to Grade ≤1 with standard treatment).
9. All prior treatment-related toxicities must be Grade \<1 at the time of screening except for alopecia (any grade), neuropathy (Grade \<2), cataracts or endocrinopathy managed with replacement therapy (any grade).
10. For women of childbearing potential and males: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception.

Male Participants:

Male participants are eligible to participate if they agree to the following during the intervention period and for at 6 months after the last dose of study intervention to allow for clearance of any altered sperm:

1. Refrain from donating sperm.

   PLUS, either:
2. 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 c. Must agree to use contraception/barrier as detailed below: d. 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 when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.

Female Participants:

A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

a. 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 and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the intervention period and for at least 5 months after the last dose of study intervention.

A WOCBP must have a negative highly sensitive pregnancy test \[serum\] as required by local regulations) within 72 hours before the first dose of study intervention and agree to use effective contraception during the study and for 5 months after the last dose of cevostamab, 3 months after the last dose of tocilizumab and 4 months after the last dose of belamaf.

Exclusion Criteria:

1. Prior treatment with bispecific or BCMA targeted antibody drug conjugate. Note prior anti-BCMA CAR T-cell therapy is permitted provided that the subject achieved a response of partial response (PR) or better and did not progress within 12 months of CAR T-cell infusion.
2. Prior exposure to FcRH5 targeted therapy.
3. Life-expectancy less than or equal to 12 weeks.
4. WOCBP who are pregnant or lactating.
5. Known history of amyloidosis, POEMS syndrome, active plasma cell leukemia (defined as circulating plasma cell count exceeding 500/uL or 5% of the peripheral blood white cells) at the time of screening.
6. Inability to comply with protocol-mandated hospitalization and activities restrictions.
7. History of allogeneic stem cell transplant.
8. 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.
9. Evidence of active mucosal or internal bleeding.
10. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety).
11. Subjects with previous or concurrent malignancies are allowed only if the second tumor is not contributing to the subject's illness and deemed to be at negligible risk of metastasis or death (e.g., expected 5-year OS ≥90%). Examples include ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score ≤7) not requiring treatment or appropriately treated Stage I uterine cancer. Subjects must be appropriately observed or managed/controlled are permitted onto study. The subject must not be receiving active therapy, other than hormonal therapy for this disease and the disease must be considered medically stable for at least 2 years.
12. Current corneal epithelial disease except mild punctate keratopathy.
13. History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

    \- Note that patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
14. Patients with history of confirmed progressive multifocal leukoencephalopathy (PML).
15. Prior solid organ transplantation.
16. Treatment with radiotherapy (with the exception of local, palliative radiotherapy for management of pain or for stabilization of an extensive bone lesion at risk of pathologic fracture or damage to surrounding tissue), any chemotherapeutic agent, or treatment with systemic therapy (systemic or biologic agent) 14 days. Prior treatment with a monoclonal antibody within 28 days of receiving the first dose of study drug.

    Prior treatment with a monoclonal antibody, denosumab for hypercalcaemia is allowed.
17. Use of an investigational drug within five half-lives or 28 days if the half-life of the investigational agent is unknown, preceding the first dose of study drug.
18. Any major surgery within the last ≤ 4 weeks prior to initiating study treatment.
19. 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 chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria.
20. Evidence of cardiovascular risk including any of the following:

    1. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobiz Type II) or 3rd degree atrioventricular (AV) block.
    2. QTc interval ≥ 470 msecs. NOTE: The QT interval should be corrected for the heart rate by Fridericia's formula (QTcF)
    3. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within 6 months of Screening.
    4. Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
    5. Uncontrolled hypertension
21. Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM

    * Note that patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed.
    * Note that patients with a history of epilepsy who have had no seizures in the past 2 years while not receiving any anti-epileptic medications are allowed.
22. Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease)
23. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belamaf and/or cevostamab any of the components of the study treatment. History of severe hypersensitivity to other mAbs.
24. Known history of HLH/IEH-HS or macrophage activation syndrome (MAS).
25. Prior treatment with systemic immunotherapeutic agents, including, but not limited to cytokine therapy and anti-CTLA4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first dose of study drugs.
26. Active infection requiring antibiotic, antiviral, or antifungal treatment.
27. Known HIV infection.
28. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
29. Known or suspected chronic active Epstein-Bar Virus (EBV) infection. Guidelines for diagnosing chronic active EBV infection are provided by Okano et al. 2005.
30. Presence of hepatitis B (HBV) surface antigen (HBsAg) or positive HBV PCR test at screening or within 3 months prior to first dose of study treatment. Participants with positive hepatitis B core antibody (HBcAb) can be enrolled, only if confirmatory negative Hepatitis B DNA is obtained AND patient is on hepatitis B prophylaxis (eg tenofovir or entecavir) before first dose of study drugs. Presence of isolated Hep B surface antigen (HBsAb) indicating previous vaccination will not exclude a participant.
31. Positive hepatitis C (HCV) antibody test result or positive hepatitis C 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.
32. History of receiving systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), with the exception of corticosteroid treatment ≤10mg/day prednisone or equivalent within 2 weeks prior to first dose of study drugs.

    1. The use of inhaled corticosteroids is permitted
    2. The use of mineralocorticoids for management of orthostatic hypotension is permitted
    3. The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted however the dose should not exceed 10 mg prednisone a day.
33. Intolerance to prednisone or dexamethasone that would preclude the patient from taking the full starting dose of dexamethasone or prednisone as described in the protocol.