Overview

This is a phase 1/2, open label, study designed to assess the safety and clinical activity of different belantamab mafodotin doses in combination with daratumumab, lenalidomide and dexamethasone.

The study will evaluate different doses of belantamab mafodotin in combination with daratumumab, lenalidomide and dexamethasone in 2 cohorts and will determine the recommended phase 2 dose (RP2D) to be further evaluated for safety and clinical activity in the dose expansion cohort. The RP2D dose will be used for future studies in the transplant ineligible newly diagnosed multiple myeloma setting.

Overall, approximately 36 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is randomized. The estimated accrual period will be 12 months corresponding to an approximate total study duration of 4 years.

Eligibility

Inclusion Criteria:

1. Participant must be ≥ 18 years or older.
2. Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented MM satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:

   CRAB criteria:

3. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL).

   vi. Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL).

   vii. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL.

   viii. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT.

   Biomarkers of Malignancy:

4. Clonal bone marrow plasma cell percentage ≥60%. e. Involved: uninvolved serum free light chain (FLC) ratio ≥100. f. More than 1 focal lesion on magnetic resonance imaging (MRI) studies.
5. Must have at least ONE aspect of measurable disease, defined as one of the following:
   1. Urine M-protein excretion ≥200 mg/24 hrs (≥0.2 g/24 hrs), or
   2. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
   3. Serum FLC assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
6. Not a candidate for high-dose chemotherapy with ASCT due to presence of significant

   comorbid condition(s), such as cardiac, pulmonary or other major organ dysfunction that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. The participants will be assessed by the IMWG frailty index, a scoring system based on age, comorbidities and cognitive and physical conditions, which is recommended by the ESMO guidelines. Participants with IMWG frailty index score 1 or 2 will be considered transplant ineligible. The reason(s) for transplant ineligibility will be collected in the case report forms (CRFs).

7. ECOG performance status of 0-2 (see Appendix 1).
8. Adequate organ system function as defined by the below laboratory assessments. Hematologic
   1. Absolute neutrophil count (ANC) ≥1.25 X 109/L; GCSF use within the past 14 days are NOT permitted.
   2. Hemoglobin ≥ 8.0 g/dL; transfusions within the past 14 days are NOT permitted.
   3. Platelet count ≥ 50 x 109/L if bone marrow is >50% involved in myeloma. Otherwise ≥75 x 109/L; transfusions within the past 14 days are NOT allowed to reach this level.

      Hepatic

   4. Total bilirubin ≤1.5xULN (isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
   5. ALT ≤ 2.5xULN. Renal
   6. eGFR ≥30 mL/min/1.73 m2; calculated using the Modified Diet in Renal Disease (MDRD) formula.
   7. Spot urine (albumin/creatinine ratio) <500 mg/g (56 mg/mmol) OR
   8. 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).
9. Female participants: contraceptive use should be consistent with local regulations

   regarding the methods of contraception for those participating in clinical studies:

   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) defined as follows:
     1. ≥ 45 years of age and has not had menses for > 1 year
     2. Participants 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
     3. 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.

        OR

   • Is a WOCBP and using two methods of reliable birth control (one method that is

     highly effective and one additional effective [barrier] method), beginning 4 weeks before initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of lenalidomide treatment. Thereafter, WOCBP participants must use one method of reliable birth control that is highly effective for a further 4 months following discontinuation of belantamab mafodotin or 3 months following the discontinuation of daratumumab. WOCBP must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during treatment, during dose interruptions and for 28-days following the last dose of lenalidomide or 3 months following discontinuation of daratumumab treatment or 4 months following discontinuation of belantamab mafodotin treatment whichever is longer. For contraception guidance please refer to Appendix 2.

             A WOCBP must have two negative pregnancy tests before therapy initiation. The first
             test should be performed within 10-14 days and the second test within 24 hours before
             the start of lenalidomide therapy.
             The participant should not receive lenalidomide until the investigator has verified
             that the results of these pregnancy tests are negative. The investigator should
             evaluate the effectiveness of the contraceptive method in relationship to the first
             dose of study treatment. The investigator is responsible for a review of medical
             history, menstrual history, and recent sexual activity to decrease the risk for
             inclusion of a woman with a nearly undetected pregnancy.
          8. 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 until 28 days after the last dose of lenalidomide or 3
             months following the discontinuation of daratumumab or 6 months after the last dose of
             belantamab mafodotin, whichever is longer, 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).
          9. Participants must be able to understand the study procedures and agree to participate
             in the study by providing written informed consent.
        Exclusion Criteria:
        Participants are excluded from the study if any of the following criteria apply:
          1. Prior systemic therapy for MM, or SMM.
               -  NOTE 1: An emergency course of steroids (defined as no greater than 40 mg of
                  dexamethasone [or equivalent] per day for a maximum of 4 days [that is, a total
                  of 160 mg]) is permitted.
               -  NOTE 2: Focal palliative radiation is permitted prior to enrollment, provided
                  that it occurred at least 2 weeks before the first dose of study drug, that the
                  participant has recovered from radiation-related toxicities, and that the
                  participant did not require corticosteroid administration (for a longer period
                  than that specified in NOTE 1 above) for radiation-induced adverse events
          2. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
             National Cancer Institute, Common Toxicity Criteria for Adverse Events (NCI CTCAE)
             Version 5.
          3. Major surgery within 2 weeks before the first dose of study drug (NOTE: participant
             must be clinically stable following a major surgery to be entered in the study).
          4. Presence of active renal condition (infection, requirement for dialysis, or any other
             significant condition that could affect participant's safety). Participants with
             isolated proteinuria resulting from MM are eligible, provided that they fulfil the
             other inclusion criteria.
          5. Any serious and/or unstable pre-existing medical or psychiatric disorder, or other
             conditions (including laboratory abnormalities) that could interfere with
             participant's safety, obtaining informed consent, or compliance to the study
             procedures.
          6. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not
             explained by reversible coagulopathy.
          7. Current active unstable liver or biliary disease defined by the presence of ascites,
             encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,
             persistent jaundice, or cirrhosis. (except for Gilbert's syndrome or asymptomatic
             gallstones; otherwise stable non-cirrhotic chronic liver disease; or hepatobiliary
             involvement of malignancy as per the Investigator's assessment).
          8. Participants with previous or concurrent malignancies other than MM are excluded.
             Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy
             that has been considered medically stable for at least 2 years. The participant must
             not be receiving active therapy, other than hormonal therapy for this disease.
             o NOTE: Participants with curatively treated non-melanoma skin cancer are allowed
             without a 2-year restriction.
          9. Evidence of cardiovascular risk including any of the following:
               -  Evidence of current clinically significant untreated arrhythmias, including
                  clinically significant ECG abnormalities, second degree (Mobitz Type II), or
                  third degree atrioventricular (AV) block.
               -  Screening 12-lead ECG showing a baseline QT interval >470 msec
               -  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 (Appendix 3).
               -  Uncontrolled hypertension.
         10. Participant has known chronic obstructive pulmonary disease (COPD) (defined as a
             forced expiratory volume in 1 second [FEV1] <50% of predicted normal), persistent
             asthma, or a history of asthma within the last 2 years (controlled intermittent asthma
             or controlled mild persistent asthma is allowed). NOTE: Participants with known or
             suspected COPD must have an FEV1 test at screening.
         11. Active infection requiring treatment.
         12. Known HIV infection, unless the participant can meet all of the following criteria:
               -  Established anti-retroviral therapy (ART) for at least 4 weeks and HIV viral load
                  <400 copies/mL.
               -  CD4+ T-cell (CD4+) count ≥350 cells/uL.
               -  No history of AIDS-defining opportunistic infections within the last 12 months. o
                  NOTE: consideration must be given to ART and prophylactic antimicrobials that may
                  have a drug:drug interaction and/or overlapping toxicities with belantamab
                  mafodotin or other combination products as relevant (See Section 7.2, Drug
                  Interactions)
         13. To be seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]) at screening or within 3 months prior to first dose of study
             treatment.
               -  NOTE 1: Participants with resolved infection (i.e., participants who are positive
                  for antibodies to hepatitis B core antigen [antiHBc] or antibodies to hepatitis B
                  surface antigen [antiHBs]) must be screened using real-time polymerase chain
                  reaction (PCR). Those who are PCR positive will be excluded.
               -  NOTE 2: presence of antiHBs indicating previous vaccination will not constitute
                  an exclusion criterion.
         14. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at
             screening or within 3 months before the first dose of study treatment 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.
         15. Current corneal epithelial disease except for mild punctate keratopathy.
             o NOTE: Participants with mild punctate keratopathy are allowed.
         16. Intolerance or contraindications to anti-viral prophylaxis.
         17. Unable to tolerate antithrombotic prophylaxis.
         18. Active or history of venous thromboembolism within past 3 months.
         19. AL amyloidosis (light chain amyloidosis), active POEMS syndrome (polyneuropathy,
             organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes)
             or active plasma cell leukemia at the time of screening.
         20. Exhibiting clinical signs of or with a known history of meningeal or central nervous
             system involvement by MM.
         21. Known intolerance or immediate or delayed hypersensitivity reaction or idiosyncratic
             reaction to: drugs chemically related to belantamab mafodotin, or any of the
             components of the study treatment; daratumumab subcutaneous (SC) or to any of its
             excipients; or infused protein products, sucrose, histidine, and polysorbate 80.
         22. Use of an investigational drug within 14 days or 5 half-lives (whichever is longer)
             preceding the first dose of study drug.
         23. Plasmapheresis within 7 days before the first dose of study drug.
         24. Participants with uncontrolled skin disease.
         25. Participants with concomitant administration of a strong or moderate CYP3A4 inhibitor
             or inducer
         26. Any serious and/or unstable pre-existing medical, psychiatric disorder or other
             conditions (including lab abnormalities) that could interfere with participant's
             safety, obtaining informed consent or compliance to the study procedures.
         27. Participant must not have received a live or live-attenuated vaccine within 30 days
             prior to first dose of belantamab mafodotin.
         28. Participant should not use contact lenses while receiving belantamab mafodotin.