Overview

This is a phase I-II open-label, multicenter, non-randomized study aiming to evaluate the efficacy and safety of belantamab mafodotin in combination with carfilzomib (Kyprolis®) and dexamethasone (Kd). Since this is the first time that this combination is being evaluated in a clinical trial, a first dose escalation part will be developed following the classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase will be open to recruit up to 60 patients.

Patients will receive treatment with belantamab-mafodotin + Kd, until unacceptable toxicity, disease progression, patient withdrawal, loss to follow-up, end of study, or death.

Eligibility

Inclusion Criteria:

Participant must be able to understand the study procedures

1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
2. Patient has given voluntary written informed consent before performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
3. Relapse multiple myeloma patients that have received at least 1 and no more than 3 prior lines of therapy. Induction, intensification with high-dose melphalan and stem cell transplant and maintenance is considered one line of treatment.
4. Patients must be refractory to lenalidomide. Refractoriness is defined as progression while receiving lenalidomide or in the first 60 days after the last dose of lenalidomide.

   Refractoriness would be defined regardless of the dose of lenalidomide received, and the schedule or whether it was given alone or in combination.

5. Patients can have received prior treatment with proteasome inhibitors. Patients with prior bortezomib treatment are eligible regardless of refractory status. Prior carfilzomib treatment is allowed, provided that the patients achieve at least a partial response to prior carfilzomib, and that there is a treatment free interval of at least 6 months.
6. Participant must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24
7. For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/L (100 mg/dl), with an abnormal serum FLC ratio.
8. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
9. Participant must be ≥ 18 years of age
10. Participant must have adequate organ function. Laboratory values that define adequate organ function for inclusion in study are as follow:

    HEMATOLOGIC Absolute neutrophil count (ANC) ≥1.5 X 109/L Hemoglobin ≥8.0 g/dL (prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted) Platelets ≥75 x 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50 × 10*9/L (prior platelet transfusion is permitted up to 7 days before the screening phase) Calcium corrected serum calcium <14 mg/dL (<3.5 mmol/L); or free ionized calcium <6.5 mg/dL (<1.6 mmol/L); HEPATIC Total bilirubin ≤1.5X ULN (Isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) ALT ≤2.5 X ULN AST ≤2.5 X ULN

    RENAL eGFRa ≥40 mL/min/ 1.73 m2 Spot urine (albumin/creatinine ratios) <500 mg/g (56 mg/mmol) OR Negative/trace (if ≥1+ only eligible if confirmed ≥ 500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void) Urine Dipstick

    CARDIAC LVEF (echo) ≥ 40%

11. 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) 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.
         11. 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 from the
             time of first dose of study until 6 months after the last dose of belantamab mafodotin
             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 when having sexual
                       intercourse with a WOCBP (including pregnant females).
         12. All prior treatment-related toxicities (defined by National Cancer Institute- Common
             Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 must be ≤ Grade 1 at the
             time of enrolment except for alopecia
         13. Participant must be able to understand the study procedures and agree to participate
             in the study by providing written informed consent
        Exclusion Criteria:
          1. Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of
             undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell
             leukemia or active POEMS syndrome at the time of screening.
          2. Participant has 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. Participants with
             curatively treated non-melanoma skin cancer may be enrolled without a 2-year
             restriction.
          3. Participant has meningeal involvement of multiple myeloma.
          4. Pregnant or breastfeeding females.
          5. Participant is simultaneously enrolled in other interventional clinical trial.
          6. Participant has used a systemic anti-myeloma drug within 14 days or five half-lives,
             whichever is shorter, preceding the first dose of study drug.
          7. Participant has used an investigational drug within 14 days or five half-lives,
             whichever is shorter, preceding the first dose of study drug.
          8. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose
             of study drug.
          9. Participant has received prior treatment with anti-BCMA agents.
         10. Received plasmapheresis within 7 days prior to the first dose of study drug.
         11. Participant has received prior radiotherapy within 2 weeks of start of study therapy.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease.
         12. Participant has a 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.
         13. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy
             to other molecular antibodies.
         14. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
         15. Participant has current corneal epithelial disease except mild changes in corneal
             epithelium
         16. Participant has peripheral neuropathy or neuropathic pain grade ≥2, as defined by the
             National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version
             4.0.
         17. Participant evidence of cardiovascular risk including any of the following:
               -  QTcF interval QTcF > 480 msec (the QT interval values must be corrected for heart
                  rate by Fridericia's formula [QTcF])
               -  Evidence of current clinically significant uncontrolled arrhythmias, including
                  clinically significant ECG abnormalities such as 2nd degree (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 six months
                  of Screening.
               -  Class III or IV heart failure as defined by the New York Heart Association
                  functional classification system [NYHA, 1994]
               -  Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160
                  mmHg or diastolic ≥ 100 mmHg despite optimal treatment.
         18. Participant has 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 otherwise meets entry criteria.
         19. Presence of active renal condition (infection, requirement for dialysis or any other
             condition that could affect patient's safety). Participants with isolated proteinuria
             resulting from MM are eligible, provided they fulfil inclusion criteria.
         20. Evidence of active mucosal or internal bleeding.
         21. Use of contact lenses while participating in this study.
         22. Any serious medical condition or psychiatric illness that would interfere in
             understanding of the informed consent form.
         23. Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism or
             hyperthyroidism) (i.e. requiring relevant changes in medication within the last month,
             or hospital admission within the last 3 months).
         24. Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
         25. Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with
             forced expiratory volume in the first minute (FEV1) less than 50%.
         26. History of interstitial lung disease or ongoing interstitial lung disease. aa.
             Participant has an active infection requiring antibiotic, antiviral, or antifungal
             treatment bb. Participant has known HIV infection cc. Participant has 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.
        dd. Participant has positive hepatitis C 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.
        Note: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody
        test are not required to also undergo Hepatitis C RNA testing.