Clinical Trial Finder

Inclusion Criteria:

1. Participants must have RRMM with measurable disease: a) Has measurable disease defined as one of the following:

• - Serum M-protein ≥0.5 g/dL (≥5 g/L).

• - Urine M-protein ≥200 mg/24 hours.

• - In participants without measurable M-protein in serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.

2. Has undergone stem cell transplant or is considered transplant ineligible. 3. Has failed at least 3 prior lines of anti-myeloma treatments and is either refractory, or intolerant to at least 1 immunomodulatory drug ( IMiD); (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib, ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease progression with the last therapy. 5.Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 6.Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela.

Exclusion Criteria:

1. Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug. 2. Current participation in another interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) within 4 weeks of the first dose of TAK-981 and throughout the duration of this trial. 3. Prior radiation therapy within 14 days of the first dose of TAK-981. 4. Major surgery within 4 weeks before C1D1. participants should be fully recovered from any surgically related complications. 5. Plasmapheresis within 28 days of randomization. 6. Diagnosis of primary amyloidosis, Waldenström's disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM), plasma cell leukemia POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative syndrome. 7. With disease where the only measurable parameter is plasmacytoma. 8. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy. 9. Prior treatment with more than 1 anti-CD38 antibody. 10. Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only). 11. History of QT interval with Fridericia's correction (QTcF) >480 ms. 12. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C infection. 13. Systemic infection requiring systemic antibiotic therapy. 14. Active or history pneumonitis. 15. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study drug. 16. Receiving strong or moderate Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers. 17. History of unstable cardiac comorbidities in the following 6 months.

The drug being tested in this study is called TAK-981. TAK-981 in combination with an anti-CD38 monoclonal antibody (mAbs) is being tested to treat people who have RRMM. The study will include a dose escalation phase and a dose expansion phase. The study will enroll approximately 81 participants; approximately 30 participants in the dose escalation phase (Part 1) approximately 15 participants in (Part 2) and up to 36 participants in dose expansion phase (Part 2). Participants will receive escalating doses of TAK-981 in combination with fixed doses as follows:

• - Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab.

• - Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab.

• - Phase 1b, Part 2 - Dose Escalation: TAK-981 + Daratumumab and Hyaluronidase-fihj.

Once RP2D is determined in Phase 1, participants with RRMM will be enrolled in Phase 2. • Phase 2

• - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab.

This multi-center trial will be conducted in North America. The overall time to participate in this study is 2 years. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.

Arms

Experimental: Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab

Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks in Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: Escalating doses of TAK-981 BIW intravenous (IV) infusion on Days 1, 4, 8, 11 and 15 in Cycle 1 and 2 (each Cycle is of 28 days) followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

Experimental: Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab

Mezagitamab: A fixed dose of 600 mg SC injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks from Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: Escalating doses of TAK-981 QW IV infusion on Days 1, 8, 15, and 22 in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks. up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

Experimental: Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj

Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly in Cycles 1 and 2 , (each cycle is of 28 days) followed by every 2 weeks in Cycle 3 through 6 , followed by every 4 weeks up to Cycle 24 until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: As per dose and schedule of TAK-981 defined in Phase 1b Part 1.

Experimental: Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab

TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.

Interventions

Drug: - TAK-981

TAK-981 IV infusion.

Drug: - Mezagitamab

Mezagitamab SC injection.

Drug: - Daratumumab and Hyaluronidase-fihj

Daratumumab and Hyaluronidase-fihj SC injection.