Inclusion Criteria:
1. Subjects who are ≥ 18 years of age
2. Participant has a histologically or cytologically confirmed diagnosis of MM as defined by IMWG criteria
3. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of score of 0, 1, or 2
4. Participant is considered transplant ineligible or for participants with a history of autologous stem cell transplant (ASCT), ASCT was \>100 days before initiating study treatment
5. Participant has measurable disease with at least one of the following criteria:
* Serum M protein \>0.5 g/dL (\>5 g/L), or
* Urine M protein \>200 mg/24h, or
* Serum free light chain (FLC) assay: Involved FLC level \>5 mg/dL (\>50 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65)
6. Participant is quadruple-class exposed or refractory (anti-CD38 antibody (e.g., daratumumab, isatuximab) alone or in combination, immunomodulatory agent (e.g., lenalidomide, pomalidomide), a proteasome inhibitor (e.g., bortezomib, ixazomib, carfilzomib) and BCMA-directed CAR-T cells and/or anti-BCMA bispecific antibodies) and has failed at least 3 prior lines of anti-myeloma therapies
7. Documented presence of BCMA.
8. All prior treatment related toxicities (defined by NCI-CTCAE Version 5.0) must be Grade ≤1 at the time of enrollment, except for alopecia and Grade 2 hematological, hepatic and renal laboratory values.
Participant must have adequate organ function at minimum, defined in Table 2 "adequate organ function".
9. Life expectancy of at least 6 months, in the opinion of the investigator
10. Sex and Contraceptive/Barrier Requirements
11. Participants must adhere to contraceptive guidelines on contraception methods in clinical studies to minimize the risk of pregnancy
12. Signed informed consent
13. Participant affiliated to or a beneficiary of a social security category
Exclusion Criteria:
Patients under guardianship or curators 2. Patients with insufficient proficiency in French to understand the study information 3. Prior treatment with an anti-BCMA targeted therapy within 90 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs.
A known intolerance or immediate or delayed hypersensitivity to drugs chemically related to Belantamab mafodontin or Mezigdomide or any of of the components of the study treatment.
5\. Prior treatment with an antibody-drug conjugate. 6. Prior treatment with Mezigdomide. 7. Prior allogeneic stem cell transplant. 8. Any major surgery within 4 weeks before the first dose of study drug (or 2 weeks if clinically stable). Additional exception allowed for bone-stabilizing surgery after consultation with medical monitor.
9\. Has received a live or attenuated vaccine within 30 days before the first dose of study treatment.
10\. Participant has received plasmapheresis ≤ 7 days before the first dose of study treatment.
11\. Presence of active renal condition (infection, requirement for dialysis, or any other condition that could affect participant's safety).
12\. 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 with the study procedures.
13\. Evidence of active mucosal or internal bleeding. 14. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice.
15\. Evidence of cardiovascular risk. 16. Participant has malignancies other than MM are excluded, except for any other malignancy from which the participant has been disease free for \>5 years with the exception of the following noninvasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the tumor, nodes, and metastases clinical staging system), or prostate cancer that is curative.
17\. Active infection requiring antibiotic, antiviral, or antifungal therapy. 18. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening.
19\. Current corneal epithelial disease, except mild punctuate keratopathy. 20. Contact lenses are not allowed for participants while they are receiving Belantamab mafodontin treatment. Contact lens use may be restarted after discontinuation of Belantamab mafondontin treatment, provided the eye-care specialist confirms there are no other contraindications.
21\. Treatment with strong CYP3A4/5 modulators or Potassium-Competitive Acid Blockers or Proton Pump Inhibitors or unable to absorb oral therapies (i.e. gastric surgery).
22.Participant is a pregnant or lactating female. 23. Participant with known HIV infection is excluded, unless the specific criteria (see relative section) are met.
24\. Patient with a presence of hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (HbcAb) at screening or within 3 months before first dose of study treatment should be excluded, unless the criteria described in the relative section are met.
25\. Participant with a positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before first dose of study treatment are excluded, unless the criteria described in the relative section are met.
