Inclusion Criteria:
1. Participant must be >18 years of age. 2. Monoclonal plasma cells in the bone marrow (BM) ≥10% or presence of a biopsy proven
plasmacytoma and documented Multiple Myeloma (MM) satisfying at least one of the
calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:
CRAB criteria:
i. 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).
ii. Renal insufficiency: creatinine clearance (CrCI) <40mL/min or serum creatinine
>177 μmol/L (>2 mg/dL).
iii. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10
g/dL.
iv. Bone lesions: one or more osteolytic lesions on skeletal radiography, Computed
tomography (CT), or Positron emission tomography (PET-CT).
Biomarkers of Malignancy:
1. Clonal BM plasma cell percentage ≥60%.
2. Involved: uninvolved serum free light chain (sFLC) ratio ≥100.
3. More than 1 focal lesion on magnetic resonance imaging (MRI) studies.
3. Must have at least ONE aspect of measurable disease, defined as one of the following:
- - Urine M-protein excretion ≥200 mg/24 hrs (≥0.2 g/24 hrs), or.
- - Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or.
- - Serum FLC assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum
FLC ratio (<0.26 or >1.65).
4. Not a candidate for high-dose chemotherapy with autologous stem cell transplantation
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 patients
will be assessed with the IMWG frailty index, a scoring system based on age,
comorbidities, and cognitive and physical conditions, which is recommended by the
European Society for Medical Oncology (ESMO) guidelines. Patients with International
Myeloma Working Group (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).
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.
6. Adequate organ system function as defined by the below laboratory assessments.
Hematologic.
- - Absolute neutrophil count (ANC) ≥1.25 X 10^9/L; granulocyte colony-stimulating
factor (G-CSF) use for the past 14 days is NOT allowed.
- - Hemoglobin ≥8.0 g/dL; transfusions are not permitted in the past 14 days prior to
the assessment.
Erythropoietin use is allowed.
- - Platelet count ≥50 x 10^9/L if the BM is >50% involved in myeloma.
Otherwise, ≥75
x 10^9/L; transfusions or platelet stimulating agents are NOT allowed in the past
14 days prior to the assessment.
Hepatic.
- - Total bilirubin ≤1.5xULN (isolated bilirubin ≥1.5xULN is acceptable if bilirubin
is fractionated and direct bilirubin <35%).
Renal.
- - Estimate glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2; calculated using
the Modified Diet in Renal Disease (MDRD) formula.
- - Spot urine (albumin/creatinine ratio) <500 mg/g (56 mg/mmol) OR.
- - 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).
7. 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:
- ≥ 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.
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.
WOCBP participants must use one method of reliable birth
control that is highly effective for 4 months following discontinuation of
belantamab mafodotin. 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 4 months following
discontinuation of belantamab mafodotin treatment, whichever is longer.
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 relation to the first dose
of the 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.
WOCBP is a female who:
- - has achieved menarche at some time point.
- - has not undergone a hysterectomy or bilateral oophorectomy or.
- - has not been naturally postmenopausal (amenorrhea following cancer therapy does
not rule out childbearing potential) for at least 24 consecutive months (i.e.,
has had menses at any time in the preceding 24 consecutive months).
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 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:
1. Prior systemic therapy for MM or Smoldering MM.
- - NOTE 1: An emergency course of steroids (defined as not greater than 40 mg of
dexamethasone [or equivalent] per day for a maximum of 4 days [i.e., a total of
160 mg]) is permitted.
- - NOTE 2: Focal palliative radiation is permitted before enrollment, provided that:
it occurred at least 2 weeks before the first dose of the study drug; the
participant has recovered from radiation-related toxicities; and the participant
did not require corticosteroid administration (for a longer period than that
specified in NOTE 1 above) for radiation-induced AEs.
2. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
National Cancer Institute Common Toxicity Criteria for AEs version 5.
3. Major surgery within 2 weeks before the first dose of the study drug.
- - NOTE 1: patients who underwent major surgery must be clinically stable to be
enrolled in the study.
- - NOTE 2: major surgery shall be defined based on the Investigator's judgment
according to the extent and complexity of the procedure, its pathophysiological
consequences and consecutive clinical outcomes.
4. Presence of active renal condition (infection, requirement for dialysis or any other
significant condition that could affect the 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, psychiatric disorder, or other
conditions (including laboratory abnormalities) that could interfere with the
participant's safety, obtaining informed consent, or compliance with the study
procedures.
6. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not
explained by reversible coagulopathy.
7. Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic
gallstones, or otherwise stable chronic liver disease 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.
- - 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 electrocardiogram (ECG) abnormalities, 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.
10. Class III or IV heart failure as defined by the New York Heart Association functional
classification system.
11. Uncontrolled hypertension.
12. Active infection requiring treatment.
13. 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.
- - 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.
14. Seropositivity for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]).
- - 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.
15. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at
screening or within 3 months before the first dose of the study treatment unless the
participant can meet the following criteria:
- - Successful anti-viral treatment (usually 8 weeks duration) is required, followed
by a negative hepatitis C virus RNA test after a washout period of at least 4
weeks.
16. Current corneal epithelial disease except for mild punctate keratopathy.
- - NOTE: Participants with mild punctate keratopathy are allowed.
Mild (Grade 1)
punctuate keratopathy is characterized by the appearance of only a few, if any,
microcyst-like epithelial changes (MECs), as identified in the slit-lamp
examination, with a low density (non-confluent), and predominantly (≥80%) located
in the periphery of the cornea. 17. Intolerance or contraindications to anti-viral prophylaxis.
18. Unable to tolerate antithrombotic prophylaxis.
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 known history of meningeal or central nervous
system involvement by MM.
21. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to
drugs chemically related to belantamab mafodotin or any of the components of the study
treatment.
22. Use of an investigational drug within 14 days or 5 half-lives (whichever is shorter)
preceding the first dose of study drug.
23. Plasmapheresis within 7 days before the first dose of the study drug.
24. Participants with active small and/or large intestinal disease which is not adequately
controlled with the appropriate treatment (e.g., uncontrolled diarrheal disease).
25. Participants with uncontrolled skin disease.
26. Participants with any condition causing hypophosphatemia, hypokalemia or
hypomagnesemia which is refractory to electrolyte replacement.
27. Participants with previous administration of a gamma secretase inhibitor.
28. Participants with concomitant administration of a strong or moderate CYP3A4 inhibitor
or inducer.
29. 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.
30. Participant must not have received a live or live-attenuated vaccine within 30 days
prior to first dose of belantamab mafodotin.
31. Participant should not use contact lenses while receiving belantamab mafodotin.
32. Because of the embryo-fetal risk of lenalidomide, all participants must adhere to the
lenalidomide pregnancy prevention program applied in their region.
