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

A Phase 1b/2 Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of TAK-981 in Combination With Monoclonal Antibodies in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies (mAbs) to treat participants who have relapsed or refractory multiple myeloma (RRMM).

The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination with anti-CD38 (mAbs) and to determine the recommended Phase 2 dose (RP2D).

Participants will be on this combination treatment for 28-day cycles. They will continue with this treatment until disease progression or unacceptable toxicity.

Study Overview

• Status: Terminated
• Conditions: Relapsed and/or Refractory Multiple Myeloma (RRMM)
• Intervention / Treatment: Drug: TAK-981; Drug: Mezagitamab; Drug: Daratumumab and Hyaluronidase-fihj

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona - PPDS
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville - PPDS
  • Georgia
    • Atlanta, Georgia, United States, 30322-1013
      • Winship Cancer Institute, Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Cancer Center - Rochester - PPDS
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Oncology Hematology West (Omaha) - USOR
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • TriHealth Cancer Institute
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Sammons Cancer Center
    • Tyler, Texas, United States, 75702
      • Northeast Texas Cancer and Research Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Mezagitamab; Mezagitamab SC injection.
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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Mezagitamab; Mezagitamab SC injection.
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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Daratumumab and Hyaluronidase-fihj; Daratumumab and Hyaluronidase-fihj SC injection.
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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Mezagitamab; Mezagitamab SC injection.; Drug: Daratumumab and Hyaluronidase-fihj; Daratumumab and Hyaluronidase-fihj SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	TEAEs were adverse events (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. Adverse event (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.	From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs	The severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (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 activities of daily living (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.	From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0	DLTs were evaluated according to NCI CTCAE version 5.0. Grade 5 AE. Hematologic toxicity: Nonfebrile Grade 4 neutropenia/Grade greater than or equal to (>=) 3 febrile neutropenia; Significant Grade 3 thrombocytopenia; Grade 4 anemia or thrombocytopenia. Nonhematologic Grade 3 or higher toxicities; Grade 2 nonhematologic toxicities leading to dose reduction/discontinuation. Delay in Cycle 2 by greater than (>) 14 days or missed >1 planned doses of TAK-981/monoclonal antibody (mAb) in Cycle 1 due to TEAEs.	Cycle 1 (Cycle length = 28 Days)
Phase 2: Overall Response Rate (ORR)	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 percent (%) 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 serum and urine M-protein were unmeasurable, >50% decrease in 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.	From date of treatment start to until date of first PD or death (whichever occurred first), up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b, Part 1: Observed Plasma Concentration of TAK-981	Observed plasma concentration of TAK-981 was reported.	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.	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.	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.	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.	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.	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.	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.	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.	Baseline up to 12 months
Phase 1b, Part 1: Serum Concentration of Mezagitamab	Observed serum concentrations of mezagitumab was reported.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	Up to 24 months
Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)		Up to 24 months
Phase 2: Minimal Residual Disease (MRD) Negative Rate		Up to 12 months
Phase 2: Durable MRD Negative Rate		Up to 12 months

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

General Publications

• Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, Huszar D. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022 May 5;139(18):2770-2781. doi: 10.1182/blood.2021014267.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Actual): August 2, 2023
• Study Completion (Actual): November 9, 2023

Study Registration Dates

• First Submitted: February 25, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (Actual): March 1, 2021

Study Record Updates

• Last Update Posted (Actual): October 2, 2024
• Last Update Submitted That Met QC Criteria: September 9, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Antineoplastic Agents; Daratumumab
• Other Study ID Numbers: TAK-981-1503

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes