A Study Of TAK-981 Given With Monoclonal Antibodies (mAbs) In Adults With Relapsed or Refractory Multiple Myeloma (RRMM)

Phase 1b, Part 1: Observed Plasma Concentration of TAK-981

Observed plasma concentration of TAK-981 was reported.

Time frame: Cycle 1 Day 1: Pre-dose, at end of infusion (EOI), 2, 4, 6, and 24 hours post-dose; Cycle 1 Days 8 and 15: Pre-dose and EOI; Cycle 2 Days 1 and 15: Pre-dose and EOI (Cycle length = 28 days)

Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981

Cmax for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981

Tmax for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981

AUC0-t for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981

AUC0-inf for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981

t1/2z for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, CL: Total Clearance for TAK-981

CL for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981

Vss for TAK-981 was reported.

Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer

ADA positive was defined as participants who had confirmed positive ADA status in at least 1 post-baseline assessments. \>=5-fold in ADA titer was defined as increase in the ADA titer value post-baseline of at least 5-fold from the positive ADA titer value at baseline.

Time frame: Baseline up to 12 months

Phase 1b, Part 1: Serum Concentration of Mezagitamab

Observed serum concentrations of mezagitumab was reported.

Time frame: Cycles 1, 2, 3, 4, 6, 7 and 12: Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)

Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria

ORR: percentage of participants who achieve complete response (CR) or partial response (PR) or better per investigator assessment by IMWG.CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow (BM). PR: \>50 percent (%) reduction of serum M-protein and reduction in 24 hours (h) urinary M-protein by \>90% or to less than (\<) 200 milligrams per 24 hour (mg/24 h); If the serum and urine M-protein were unmeasurable, \>50% decrease in the difference between involved and uninvolved free light chain (FLC) levels was required in place of M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required.

Time frame: From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 12 months)

Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria

CBR: % of participants with response of at least stable disease (SD) for \>=3 months or better (stringent CR \[sCR\], immunophenotypic CR \[iCR\], molecular CR \[mCR\], CR, very good partial response \[VGPR\], PR, minimal response \[MR\] or SD) per investigator assessment by IMWG. sCR: CR plus normal FLC ratio, absence of clonal cells in BM. iCR: sCR plus absence of phenotypical aberrant plasma in BM with minimum of 1 million total BM cells. mCR: CR plus negative allele-specific oligonucleotide polymerase chain reaction. CR: Negative immunofixation on serum, urine, disappearance soft tissue plasmacytomas, \<5% plasma cells in BM. VGPR: Serum, urine M-protein detectable by immunofixation but not on electrophoresis or \>90% reduction in serum M-protein+urine M-protein level \<100mg/24h. PR: \>50% reduction of serum M-protein and in 24h urinary M-protein by \>90% or to \<200mg/24h. MR: \>=25% but \<=49% reduction in serum M-protein, reduction in 24h urine M-protein by 50 to 89%. SD: No CR, VGPR, PR or PD.

Time frame: From first dose of study drug until PD or death, whichever occurred first (up to 12 months)

Phase 1b, Part 1: Duration of Response (DOR) Based on IMWG Criteria

DOR was defined as a time from date of first documentation of a PR or better to the date of first documentation of PD based on IMWG criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in BM. PR: \>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \<200 mg/24 h; If the serum and urine M-protein were unmeasurable, a \>50% decrease in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required. DOR was calculated for those participants with a confirmed PR or CR.

Time frame: From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (up to 12 months)

Phases 1b, Part 1: Time to Progression (TTP) Based on IMWG Criteria

TTP: time from date of first dose to date of first documentation of PD as defined by standard disease criteria. PD was defined as increase of \>25% from lowest response value in any one or more of following: a) Serum M-component and/or (the absolute increase must be \>0.5 grams per deciliter \[g/dL\]). b) Urine M-component and/or (the absolute increase must be \>200 mg/24 h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 milligrams per deciliter (mg/dL). d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimoles per liter \[mmol/L\]) that can be attributed solely to the plasma cell proliferative disorder.

Time frame: From first dose of study drug to the date of the first documentation of PD or death, whichever occurred first (up to 12 months)

Phases 1b, Part 1: Time to Next Treatment (TTNT)

TTNT was defined as the time from the date of first dose to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason.

Time frame: From the date of first dose of study drug to the date of the first dose initiation of the next line of antineoplastic therapy (up to 12 months)

Phases 1b, Part 1: Progression-free Survival (PFS) Based on IMWG Criteria

PFS was defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first. PD was defined as increase of \>25% from lowest response value in any one or more of the following: a) Serum M-component and/or (the absolute increase must be \>0.5 g/dL). b) Urine M-component and/or (the absolute increase must be \>200 mg/24h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

Time frame: From the first dose of study drug to date of PD or death, whichever occurred first (up to 12 months)

Phases 1b, Part 1: Overall Survival (OS)

OS was defined as the time from the date of first dose to the date of death. OS was analyzed using Kaplan-Meier (KM) method. Participants were followed for survival after the last dose of study drug.

Time frame: From date of first dose of study drug up to death from any cause (up to 27 months)

Phases 1b, Part 1: Fold Change From Baseline in Level of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Peripheral Blood Lymphocytes

Blood samples were collected to assess TAK-981-SUMO adduct formation. TAK-981-SUMO adduct formation in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formation during the inhibition of the SUMO-activating enzyme by TAK-981.

Time frame: Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days)

Phases 1b, Part 1: Fold Change From Baseline in SUMO Pathway Inhibition in Peripheral Blood Lymphocytes

Blood samples were collected to assess SUMO inhibition. SUMO pathway inhibition in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing SUMO-2/3 chains.

Time frame: Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days)

Phase 2: Number of Participants With TEAEs and TEAEs by Severity

TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product. The severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT consensus grading. Where Grade 3 was severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4 was 4 Life-threatening consequences; urgent intervention indicated. and Grade 5 was death related to AE. TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.

Time frame: Up to 24 months

Phase 2: CBR Based on IMWG Criteria

CBR: percentage of participants with response of at least (SD for \>=3 months or better sCR, iCR, mCR, CR, very good partial response \[VGPR\], PR, minimal response \[MR\] or SD) per investigator assessment by IMWG. sCR: CR plus normal FLC ratio, absence of clonal cells in BM. iCR: sCR plus absence of phenotypical aberrant plasma in BM with minimum of 1 million total BM cells. mCR: CR plus negative allele-specific oligonucleotide polymerase chain reaction. CR: Negative immunofixation on serum, urine, disappearance soft tissue plasmacytomas, \<5% plasma cells in BM. VGPR: Serum, urine M-protein detectable by immunofixation but not on electrophoresis or \>90% reduction in serum M-protein+urine M-protein level \<100mg/24h. PR: \>50% reduction of serum M-protein and in 24h urinary M-protein by \>90% or to \<200mg/24h. MR:\>=25% but \<=49% reduction in serum M-protein, reduction in 24h urine M-protein by 50 to 89%. SD: No CR, VGPR, PR or PD.

Time frame: Up to 24 months

Phase 2: DOR Based on IMWG Criteria

DOR was defined as a time from date of first documentation of a PR or better to the date of first documentation of PD based on IMWG criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in BM. PR: \>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \<200 mg/24 h; If the serum and urine M-protein were unmeasurable, a \>50% decrease in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required.

Time frame: Up to 24 months

Phase 2: TTP Based on IMWG Criteria

TTP: time from date of first dose to date of first documentation of PD as defined by standard disease criteria. PD was defined as increase of \>25% from lowest response value in any one or more of following: a) Serum M-component and/or (the absolute increase must be \>0.5 grams per deciliter \[g/dL\]). b) Urine M-component and/or (the absolute increase must be \>200 mg/24 h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 milligrams per deciliter (mg/dL). d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

Time frame: Up to 24 months

Phase 2: Time to Next Treatment (TTNT)

TTNT was defined as the time from the date of first dose to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason.

Time frame: Up to 24 months

Phase 2: PFS Based on IMWG Criteria

PFS was defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first. PD was defined as increase of \>25% from lowest response value in any one or more of the following: a) Serum M-component and/or (the absolute increase must be \>0.5 g/dL). b) Urine M-component and/or (the absolute increase must be \>200 mg/24h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

Time frame: Up to 24 months

Phase 2: Overall Survival (OS)

OS was defined as the time from the date of first dose to the date of death.

Time frame: Up to 24 months

Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)

Time frame: Up to 24 months

Phase 2: Minimal Residual Disease (MRD) Negative Rate

Time frame: Up to 12 months

Phase 2: Durable MRD Negative Rate

Time frame: Up to 12 months