A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma

Percentage of participants with TEAEs meeting DLT definition were reported. Toxicity was evaluated as per the NCI CTCAE, Version 5.0. The hematologic TEAEs of Grade ≥3 clearly unrelated to the underlying disease and occur during the first cycle that are considered DLTs: Grade ≥3 hemolysis; Grade 4 neutropenia for >7 consecutive days; Grade 4 thrombocytopenia for >14 consecutive days; Grade 3 thrombocytopenia with clinically significant bleeding; Any other Grade ≥4 hematologic toxicity except for Grade 4 lymphopenia. An incomplete recovery from treatment-related toxicity causing >2-week delay in the next scheduled infusion before the initiation of Cycle 2 were considered a DLT. Percentages were rounded off to the nearest decimal.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as "Not Calculated" - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as "Not Calculated" - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards.

As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)*MRT, where MRT is mean residence time. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.

ADA samples scoring equal to or above the cut-point (titer of 75) were defined as ADA positive. Percentages were rounded off to the nearest decimal.

ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. Percentages were rounded off to the nearest decimal.

The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal.

The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal.

DOR was defined as the time from the date of first documentation of response PR or better (sCR + CR + VGPR + PR) to the time of disease progression or death, whichever occurs first. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours.

Time to response was defined as the time from first dose to the date of first documentation of response (PR or better [sCR + CR + VGPR + PR]) PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours.

PFS was defined as the time from the date of enrollment until the date of progressive disease (PD) or death due to any cause, whichever occurs first as defined by IMWG Criteria. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

The OS was defined as the time from the date of first dose to the date of death due to any cause.

Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)*MRT, where MRT is mean residence time.

ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR :≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR:negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. Percentages were rounded off to the nearest decimal.

The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal.

Duration of clinical benefit was defined as the time from first documented evidence of confirmed MR or better until the earliest date of a confirmed PD per IMWG, or death among participants who achieve a confirmed MR or better. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal.

Duration of disease control was defined as the time from first documented evidence of SD or better until the earliest date of a confirmed PD per IMWG, or death among participants who achieved a SD or better. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

TTP was defined as the time from the date of the first dose until the earliest date of confirmed PD per IMWG, or death due to PD. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

MRD negativity rate at a sensitivity of 10^-5 was defined as participants who were MRD negative at a sensitivity of 10^-5 in participants achieving suspected complete response (CR). CR was defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria was required.

Duration of MRD negativity (10^-5) was defined as the time from the first MRD negative status (10^-5) to the earliest date of the MRD positive status (10^-5), confirmed PD per IMWG or death.

An AE is defined as any untoward medical occurrence in a participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. A TEAE is defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug. Percentages were rounded off to the nearest decimal.

AE: any untoward medical occurrence in participants administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. AE can therefore be any unfavorable \& unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for first time or worsening of pre-existing event after first dose of study drug \& within 30 days of last administration of study drug. Serious TEAEs: any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is a medically important event. Percentages were rounded off to the nearest decimal.

Laboratory values included hematology, chemistry, and urinalysis as interpreted by the investigator.

ECOG performance status was measured at baseline and over time. ECOG performance status was measured on a 6 point scale: Grade 0: Normal activity, Grade 1: Symptoms but ambulatory, Grade 2: In bed <50% of the time, Grade 3: In bed >50% of the time, Grade 4: 100% bedridden, Grade 5: Dead. Reported here is the baseline status and the worst post-baseline status measured. A decrease in grade from baseline indicates an improvement. Only categories for which there was at least 1 participant are reported.

Percentages were rounded off to the nearest decimal.

Medical encounters included hospitalizations, emergency room stays, or outpatient visits.

EORTC QLQ-MY20 is a myeloma-specific module developed by the EORTC group specifically to assess quality of life in participants with multiple myeloma. It contains 20 items which can be grouped into a disease symptom subscale (6 items), side effects of treatment subscale (10 items), body image (1 item) and future perspective subscale (3 items). All transformed scale scores range from 0 to 100 with higher scores indicating worse symptoms (Disease Symptoms and Side Effects of Treatment) or better support/functioning (Future Perspective and Body Image).