The purpose of this research study is to determine if two drugs approved for treating
multiple myeloma, belantamab mafodotin and elotuzumab, are safe and more effective when used
together.
Patients with RR MM beyond two-three lines of therapy have inferior outcomes. They have to
cycle through the available lines of treatment options and ultimately succumb to progressive
disease. Despite improvements in modern treatments this subset of MM patients has a grim
prognosis and thus represent a population with unmet need. Hence, further advances in
combination therapies are required. MM is associated with both qualitative and quantitative T
cell dysfunction owing to variety of mechanisms including increased expression of inhibitory
immune checkpoint molecules. Elotuzumab enhances NK cell cytotoxicity via SLAMF7 ligation and
has an established role in therapy of RR MM in combination with immunomodulatory agents
(iMIDs). On the other hand, BCMA has emerged as one of the best therapeutic targets to
eradicate plasma cells in MM. Therapeutic success with anti-BCMA ADC belantamab mafodotin is
readily evident based on the results of recent trials DREAMM 1 and DREAMM2 in
relapsed/refractory MM, leading to its Breakthrough Therapy Designation awarded by US FDA in
2017. Bela has demonstrated the potential to induce immunogenic cell death (ICD) in a
BCMA-expressing MM cells. Tumor cells undergoing ICD induced an antigen-specific T cell
response, enhancing anti-tumor effects. Generally, in myeloma, success in therapy has always
been achieved by multifaceted treatment approach, targeting several pathways concurrently. To
combat antigen loss and resistance, combining monoclonal antibodies with different targets is
proposed. In this study, we propose immune-stimulatory therapy with anti-SLAMF7 antibody
elotuzumab in combination with belantamab mafodotin in subjects with RR MM. Administration of
elotuzumab would enrich NK cells and together with belantamab mafodotin would further
intensify anti-tumor immunity against MM. This combination would provide a novel all-immune
targeted therapy with potentially increased efficacy.
The investigators expect that this unique combination of an antibody drug conjugate and an
immune-stimulatory monoclonal antibody, targeting two very relevant pathways in MM will
result in significant clinical benefit for patients with RR MM. From the standpoint of
safety, each one of these immune-pharmaceutical drugs separately is well-tolerated, and in
combination are not expected to display overlapping toxicity. Thus, the investigators
believe, the adverse event profile of this combination would be favorable.
Inclusion Criteria:
1. Participant must have MM that has relapsed after or is refractory to at least 3 prior
lines of therapy. Relapsed/refractory disease as defined by IMWG criteria.
2. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status
of ≤ 2
3. Participant must be ≥ 18 years of age
4. Prior line of therapy must include iMID and proteasome inhibitor. Prior treatment with
anti-CD38 monoclonal antibody is allowed but not required.
5. Participant must have adequate organ function, defined as:
- ANC ≥1 X 109/L
- Hemoglobin ≥8.0 g/dL
- Platelets ≥75 X 109/L
- Total bilirubin ≤1.5X ULN (Isolated bilirubin ≥1.5xULN is acceptable if bilirubin
is fractionated and direct bilirubin <35%)
- ALT ≤2.5 X ULN
- eGRF ≥40 mL/min/ 1.73 m2
- Spot urine (albumin/creatinine ratios) <500 mg/g (56 mg/mmol) OR
- Urien dipstick Negative/trace (if ≥1+ only eligible if confirmed <500 mg/g (56
mg/mmol) by albumin/creatinine ratio (spot urine from first void)
6. 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 (as described
in Appendix 3), 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.
7. 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)
8. All prior treatment-related toxicities (defined by National Cancer Institute- Common
Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.035.0) must be ≤ Grade 2
at the time of enrolment except for alopecia.
9. 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 must not have current corneal epithelial disease except mild changes in
corneal epithelium
2. Participant must not have current unstable liver or biliary disease defined by the
presence of ascites, encephalopathy, esophageal or gastric varices, persistent
jaundice, or 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
3. Participant must not have 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 and stable chronic kidney
disease are eligible, provided they fulfil inclusion criteria
4. Participant must not use contact lenses while participating in this study
5. Participant must not be simultaneously enrolled in any other interventional clinical
trial
6. Participant must not have used an investigational drug or approved systemic
anti-myeloma therapy (including systemic steroids) within 14 days preceding the first
dose of study drug
7. Participant must not have had plasmapheresis within 7 days prior to first dose of
study treatment
8. Participant must not have received prior treatment with a monoclonal antibody within
30 days of receiving the first dose of study drugs
9. Participant must not have had major surgery ≤ 4 weeks prior to initiating study
treatment
10. Participant must not have any evidence of active mucosal or internal bleeding
11. Participant must not have evidence of cardiovascular risk including any of the
following:
- Evidence of current clinically significant uncontrolled arrhythmias, including
clinically significant 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 [NYHA, 1994]
- Uncontrolled hypertension
12. Participant must not have 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 must not have an active infection requiring IV antimicrobial treatment
14. Participant must not have known HIV infection
15. Participant must not have 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
16. Participant must not have 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.
17. Participant must not have 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.
18. Participant must not have 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
19. Participants must not be pregnant or lactating
