Sponsor: Takeda

Key Inclusion Criteria:

1. Documented multiple myeloma (MM) diagnosis per IMWG criteria.
2. Measurable disease, defined as at least 1 of the following:
3. Serum M protein ≥0.5 grams per deciliter [g/dL] (≥5 g/L) on serum protein electrophoresis (SPEP).
4. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).
5. Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
6. For participants in the Phase 1 Dose Escalation only: Must have received at least 3 prior lines of therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory imide drug (IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug; or who are triple refractory to a PI, an IMiD, and an anti-CD38 mAb drug, regardless of the number of prior line(s) or therapy.
7. For participants in Phase 2a Dose Finding only:
8. Received 1 to 3 prior line(s) of antimyeloma therapy.
9. Must be refractory to prior lenalidomide treatment.
10. Participants must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment.
11. Documented progressive disease on or after the last regimen.
12. Participants must have PR or better to at least 1 line of prior therapy.
13. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening.

Key Exclusion Criteria:

1. Prior exposure to modakafusp alfa.
2. Participant has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma.
3. Participant has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or baseline, except for alopecia.
4. Previous allogeneic stem cell transplant at any time or autologous stem cell transplant (ASCT) within 12 weeks of planned start of dosing.
5. Seropositive for hepatitis B, or known history of seropositivity for hepatitis C or of seropositivity for human immunodeficiency virus (HIV).
6. Participant has congestive heart failure (New York Heart Association Grade ≥II), cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or clinically significant uncontrolled hypertension.
7. Participant has QT interval corrected by the Fridericia method >480 milliseconds [msec] (Grade ≥2).
8. Participant has a chronic condition that will require the chronic use of systemic corticosteroids >10 milligrams per day (mg/d) of prednisone or equivalent on top of any required corticosteroids for multiple myeloma (MM).

Primary Outcome Measures:

1. Phase 1: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Cycle 1 (cycle length=28 days) ]

DLT will be defined as any of the TEAEs that occur during Cycle 1 and are considered by the investigator to be at least possibly related to modakafusp alfa. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

1. Phase 1: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Per Severity [ Time Frame: Up to 60 months ]

An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Severity grades for TEAEs will be evaluated as per the NCI CTCAE Version 5.0.

1. Phase 2a: Overall Response Rate (ORR) [ Time Frame: Up to 60 months ]

ORR is defined as the percentage of participants who achieve a confirmed partial response (PR) or better during the study in the safety population. ORR will be assessed by the investigator per International Myeloma Working Group (IMWG) criteria.

Secondary Outcome Measures:

1. Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
2. Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
3. Phase 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
4. Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
5. Phase 1: Apparent Serum Terminal Disposition Rate Constant for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
6. Phase 1: Apparent Serum Terminal Disposition Phase Half-life for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
7. Phase 1: Total Clearance After Intravenous Administration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
8. Phase 1: Volume of Distribution at Steady State After Intravenous Administration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
9. Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
10. Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
11. Phase 1: Ctrough: Single-Dose and Multiple-dose Observed Concentration at the End of a Dosing Interval for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
12. Phase 1: AUC∞: Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
13. Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]