Inclusion Criteria:

• Male or female patients aged 18 years or older.
• Be willing and able to provide written informed consent for the study.
• For patients with MM (for Phase 1b and Phase 2):
  • A prior diagnosis of MM as defined by the IMWG criteria with documented disease progression;
  • 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 patients 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.
  • Has undergone stem cell transplant or is considered transplant ineligible; and
  • Patients with a history of autologous stem cell transplant are eligible if the transplant was > 100 days prior to study consent;
  • Has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (eg, daratumumab, daratumumab and hyaluronidase-fihj, isatuximab) alone or in combination; and
  • Is either refractory, or intolerant to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (i.e., bortezomib, ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease progression with the last therapy;
  • Refractory myeloma is defined as disease that is nonresponsive while on therapy or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve at least minimal response or development of PD while on therapy;
  • A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (e.g., 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by a stem cell transplantation, consolidation, and maintenance is considered 1 line).
• Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Have suitable venous access for safe drug administration and the study-required blood sampling, including PK and pharmacodynamic sampling.
• Have adequate organ function as specified below at screening:
  • Platelet count ≥ 75, 000 mm^3 (≥ 75 × 10^9 /L); value of ≥ 50,000 mm^3 (≥ 50 × 10^9 /L) may be acceptable for patients with ≥ 50% bone marrow burden following discussion with the sponsor (platelet transfusion will be allowed > 3 days before assessment);
  • Hemoglobin must be ≥ 8 g/dL. (RBC transfusion allowed ≥14 days before assessment);
  • Absolute neutrophil count (ANC) ≥ 1000 mm^3 (≥ 1.0 × 10^9 /L); value of ≥ 750 mm^3 (≥ 0.75 × 10^9 /L) may be acceptable for patients with ≥ 50% bone marrow burden following discussion with the sponsor;
  • Estimated creatinine clearance using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with serum creatinine concentrations above the upper limit of normal range (ULN).
• AST (glutamic oxaloacetic transaminase [GOT]) and ALT (GPT) ≤ 3.0 × ULN; bilirubin ≤ 1.5 × ULN. Patients with Gilbert’s syndrome may have a bilirubin level > 1.5 × ULN, per discussion between the investigator and the medical monitor.
• Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela.
  • Note: except Neuropathy Grade ≤ 2, any grade alopecia, or bone marrow parameters [any of Grade 1 or 2 permitted if directly related to bone marrow involvement].
• Female patients who:
  • Are postmenopausal for at least 1 year before the screening visit; OR
  • Are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 6 months after the last dose of drug in the combination; OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
• Male patients, even if surgically sterilized (ie, status postvasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of drug in the combination; OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).
• Must be willing and able to comply with clinic visits and procedures outlined in the study protocol.

Exclusion Criteria:

• Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug or any investigational products (IPs) within 5 half-lives of the first dose of study drug, whichever is appropriate to last therapy received. (e.g., non-IP IMiD, proteasome inhibitor, anti-CD38 mAb could be considered to be eligible if there is at least 14 days after last dose before first dose of study drug).
  • Note: Treatment with a single course of glucocorticoids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg [for example, 40 mg/d for 4 days] of dexamethasone), hormonal therapy for prostate cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors are allowed.
• 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.
• Prior radiation therapy within 14 days of the first dose of TAK-981.
  • Note: Prophylactic localized (“spot”) radiation for areas of pain is allowed.
• Major surgery within 4 weeks before C1D1. Patients should be fully recovered from any surgically related complications.
  • Note: Kyphoplasty is not considered major surgery.
• Plasmapheresis within 28 days of randomization.
• Diagnosis of primary amyloidosis, Waldenström’s disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM) per IMWG criteria or standard diagnostic criteria, plasma cell leukemia (according to the World Health Organization [WHO] criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 10^9 /L), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative syndrome.
• With disease where the only measurable parameter is plasmacytoma.
• 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 patient is not on active anticancer therapy.
• Evidence of central nervous system involvement and/or meningeal involvement of MM exhibited during screening.
• Known severe allergic or anaphylactic reactions to human recombinant proteins or excipients used in the TAK-981 formulation or the mAbs (such as daratumumab or daratumumab and hyaluronidase-fihj as per the prescribing information and for mezagitamab as outlined in the Mezagitamab IB).
• History of treatment discontinuation due to treatment-related toxicity to the combination partner (daratumumab or daratumumab and hyaluronidase-fihj).
• Prior treatment with more than 1 anti-CD38 antibody.
• Chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) 10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered an excluded form of systemic treatment of an autoimmune disease.
• Active or history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
• History of allogeneic tissue or solid organ transplant.
• Receipt of any live vaccine (e.g., varicella, pneumococcus) within 4 weeks of initiation of study treatment.
• Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P450 (CYP) 3A4/5 or are strong P-glycoprotein (Pgp) inhibitors at screening. To participate in this study, such patients should discontinue use of such agents for at least 2 weeks or 5 times the half-life (whichever is shorter) before receiving a dose of TAK-981.
• Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only).
• History of any of the following ≤ 6 months before first dose: congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias > Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
• Baseline prolongation of the QT interval with Fridericia’s correction method (QTcF) (e.g., repeated demonstration of QTcF interval > 480 ms, history of congenital long QT syndrome, or torsades de pointes). If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
• Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
• Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
• Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a on Day 1 before first dose of TAK-981 study drug.

Eligibility last updated 12/10/21. Questions regarding updates should be directed to the study team contact.