Inclusion Criteria:

1. Male or Female subjects > 18 years of age

2. Be willing and able to provide written informed consent prior to any protocol-related procedures including screening evaluations.

   • Must meet 2014 International Myeloma Working Group (IMWG) guideline for diagnosis of Multiple Myeloma (and not smouldering myeloma) Dose Escalation: Participants in dose escalation must have measurable disease as defined by IMWG criteria, or have active bone findings on PET/CT or >1 measurable plasmacytoma that can be monitored on other imaging modalities.

     1. Dose Expansion: Participants must have measurable disease by IMWG criteria.

3. Have been previously treated with at least 1 prior line of MM therapy and have previously been exposed to an Immunomodulatory Drug (IMiD), PI, and CD38 either in combination or as single agents and are relapsed/refractory or intolerant of prior therapies.

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

5. Must have adequate organ and hematologic function as defined:

   1. Absolute Neutrophil Count (ANC) > 1000 in the absence of growth factor support (granulocyte colony stimulating factor [GSCF] within 7 days or pegylated granulocyte colony stimulating factor [peg-G-CSF] within 14 days)
   2. Hemoglobin > 8 g/dL.
   3. Platelet Count > 75 x10^9/L in the absence of transfusion support within 7 days.
   4. Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤2.5 × upper limit of normal (ULN); bilirubin ≤1.5 × ULN. Subjects with Gilbert's syndrome may have a bilirubin level <3.0 × ULN

6. Estimated glomerular filtration rate (eGFR) > 30 as calculated by the Modified Diet in Renal Disease (MDRD) formula. All prior treatment-related toxicities (as defined by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v6.0) must be < Grade 1 at the time of enrollment, except for alopecia. Spot urine (albumin/creatinine ratios) < 500 mg/g (56mg/mmol) OR urine dipstick Negative/trace (if > + only eligible if confirmed <500 mg/kg [56mg/mmol] by albumin/creatinine ratio [spot urine from first void])

7. Sex and contraceptive/barrier requirements:

   • Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

   • 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 within 72 hours before dosing on Cycle 1 Day 1 and agree to use a highly effective method of contraception during the study and for 4 months after the last dose of belantamab mafodotin.

   • 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 an early 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
     • Participants who have been amenorrheic 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.

   • 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 WOCBP (including pregnant females).

   • Contraceptive highly recommended during belantamab mafodotin studies*

   • Highly Effective Methods† That Have Low User Dependency

     • Implantable progestogen-only hormone contraception associated with inhibition of ovulation†
     • Intrauterine device (IUD)
     • Intrauterine hormone-releasing system (IUS)†
     • Bilateral tubal occlusion
     • Vasectomized partner

   • Note: Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.

   • Highly Effective Methods† That Are User Dependent

     • Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation‡

       • oral
       • intravaginal
       • transdermal
       • injectable

     • Progestogen-only hormone contraception associated with inhibition of ovulation

       • oral
       • injectable

   • Sexual abstinence

   • Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

   • *Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those participating in clinical studies.

   • †Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly.

   • ‡Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those that inhibit ovulation as the primary mode of action.

   • Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should not be used together (due to risk of failure with friction).

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this trial:

A subject who meets any of the following criteria must not be enrolled on the study:

1. Diagnosis of any of the following:

   1. Amyloidosis
   2. Plasma Cell Leukemia
   3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
   4. Myelodysplastic Syndrome, Myeloproliferative Neoplasia, or any other primary hematologic malignancy concurrent with Multiple Myeloma
   5. Any other history of malignancy other than Multiple Myeloma deemed at high risk of recurrence during study. Indolent cancers (e.g. prostate cancer without radiographic evidence of disease or history of resected local breast cancer on long term hormonal therapy) are acceptable.

2. Treatment with any of the following:

   1. Systemic anticancer therapy < 14 days prior to first dose of study related therapy (Step-Up Dose 1), or <30 days for monoclonal antibodies (e.g. anti-CD38 antibodies). mAb for serious conditions unrelated to MM, such as COVID, may be permitted but need to be discussed with the medical monitor.
   2. Limited field radiotherapy < 7 days or extended field radiotherapy < 8 weeks prior to C1D1
   3. Major surgery < 4 weeks of the first dose of study drug on C1D1
   4. Any live or attenuated vaccines within 30 days of C1D1

3. History of refractoriness to Talquetamab or Belantamab mafodotin

   • Participants who received < 3 cycles of Talquetamab time limited therapy such as for bridging to other therapies without evidence of disease progression on treatment will be considered eligible after discussion with medical monitor.

4. Active central nervous system involvement of disease, unless they are clinically stable for > 4 weeks after completing treatment prior to screening (a brain and/or other anatomic regions with CNS involvement MRI within 1 month of enrollment is required).

   • Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin or any other components of the study treatment.

5. Any of the following cardiovascular events within 6 months prior to C1D1:

   1. Known heart failure with reduced left ventricular ejection fraction < 45%
   2. Congestive heart failure New York Heart Association Class III or IV
   3. Unstable angina pectoris
   4. Unstable symptomatic ischemic heart disease
   5. Myocardial infarction
   6. Uncontrolled hypertension despite appropriate medical therapy
   7. Ongoing symptomatic cardiac arrhythmias > grade 2
   8. Pulmonary embolism or cerebrovascular events
   9. Any other serious cardiac condition (e.g. pericardial effusion or restrictive cardiomyopathy)
   10. Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities such as second degree (Mobitz Type II) or third degree atrioventricular (AV) block.

6. History of autoimmune disease requiring systemic immunosuppressive therapy with daily dose of prednisone > 10mg or equivalent doses, or any other form of immunosuppressive therapy.

7. Any concurrent or uncontrolled medical, comorbid, or psychiatric condition that would, in the opinion of the investigator, limit compliance with study protocols.

   • Female subjects who are actively breastfeeding or pregnant on study start.

   • Presence of active renal condition (infection, requirement for dialysis, or any other condition that could affect participant's safety).

   • Active infection requiring treatment.

   • Evidence of active mucosal or internal bleeding.

   • 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. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.

   • Current corneal epithelial disease except mild punctuate keratopathy.

   • Contact lenses are not allowed for participants while they are receiving belantamab mafodotin treatment. Contact lens use may be restarted after discontinuation of belantamab mafodotin treatment, provided the eye-care specialist confirms there are no other contraindications.

   • HIV considerations:

   • Participants with known HIV infection are excluded, unless the following criteria are met:

     • Established antiretroviral therapy (ART) for at least 4 weeks and HIV viral load <400 copies/mL
     • CD4+ T-cell (CD4+) counts ≥350 cells/µL
     • 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.

   • Hepatitis B considerations:

   • Has documented presence of HBsAg and/or HBcAb at screening or within 3 months prior to the first dose of study intervention. Participants with hepatitis B will be excluded unless the following criteria can be met:

Serology: HBcAb+ HBsAg- Screening: HBV DNA undetectable During study treatment: Monitoring as per protocol • Antiviral prophylaxis must be given; choice of therapy as per local guidance

Serology: HBsAg+ at screening or within 3 months prior to first dose Screening: HBV DNA undetectable • Highly effective antiviral treatment started at least 4 weeks prior to first dose of study treatment • Baseline imaging per protocol • Participants with cirrhosis are excluded During study treatment: • Antiviral treatment maintained throughout study treatment • Monitoring and management as per protocol

• Hepatitis C considerations:
• Participants 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 following conditions are met:
• Participants with a positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained.
• 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 unless the participant can meet the following criteria:
• RNA test negative
• Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks.
• Note: Hepatitis RNA testing is optional and participants with a negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.