A Study to Evaluate 3 Dose Schedules of Daratumumab in Participants With Smoldering Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate three daratumumab dose schedules in participants with Smoldering Multiple Myeloma.

Detailed Description
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This is a randomized, open-label (identity of assigned treatment will be known to participants and study staff), 3-arm (3 treatment groups), multicenter study of daratumumab in participants diagnosed with intermediate or high-risk Smoldering Multiple Myeloma (SMM [ie, early disease without any symptoms]). Participants will be randomized (assigned by chance) to one of 3 treatment groups (arm A [long intense], arm B [intermediate] and arm C [short intense]) to receive daratumumab. Each treatment group will investigate 1 of 3 dosing schedules of daratumumab. The study will include a 28-Day Screening Phase, a Treatment Phase of 1 to 20 treatment cycles (each cycle is 8 weeks in duration for total period of 8 to 160 weeks), and a Follow up Phase of 4-weeks from the last dose of study drug. For participants in Arm A (long intense) and Arm B (intermediate), there is a possibility to extend treatment with IV daratumumab (Q8W) after the end of Cycle 20 if, as per investigator discretion, there is a positive benefit/risk ratio, absence of Grade >=3 treatment related toxicity, and at least stable disease has been achieved. For participants participating in treatment extension, the duration of infusion may be shortened to a 90-minute infusion or can switch to daratumumab 1800mg subcutaneous (Q8w). The Follow-up Phase will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. The end of the study will occur approximately 7 years after the last participant enrolled receives a first dose of study drug. 'Disease assessment will be performed locally per Standard of Care.

Official Title
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A Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: daratumumab
* Drug: daratumumab
* Drug: daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of smoldering multiple myeloma (SMM) for less than 5 years Have a confirmed diagnosis of intermediate or high-risk SMM, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Exclusion Criteria: Active multiple myeloma,requiring treatment as defined by the study protocol Primary systemic AL (immunoglobulin light chain) amyloidosis Prior or concurrent exposure to any of the following: approved or investigational treatments for SMM or/and multiple myeloma, daratumumab or other anti CD-38 therapies, treatment with corticosteroids with a dose greater than (>) 10 milligram (mg) prednisone per day or equivalent and bone-protecting agents (eg, bisphosphonates, denosumab) or are only allowed if given in a stable dose and for a nonmalignant condition, or received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1, Day 1 History of malignancy (other than SMM) within 3 years before the date of randomization, except for the following if treated and not active: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of breast, or International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix Known chronic obstructive pulmonary disease (COPD) OR moderate or severe persistent asthma within the past 2 years Any concurrent medical or psychiatric condition or disease (eg, autoimmune disease, active systemic disease, myelodysplasia) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Long Intense)<br> | Drug: daratumumab<br>* 16 mg/kg administered by intravenous (IV) infusion once every week in Cycle 1, every other week in Cycle 2 and Cycle 3, every 4 weeks in Cycle 4 to Cycle 7, and from Cycle 8 to Cycle 20 on Day 1 of each cycle. If, as per investigator discretion, there is a positive benefit/risk ratio, absence of Grade greater than or equal to (>=) 3 treatment related toxicity, and at least stable disease has been achieved, treatment can be extended and given every 8 weeks after Cycle 20. For participants participating in treatment extension, the duration of infusion may be shortened to a 90-minute infusion or can switch to daratumumab 1800mg subcutaneous (Q8w).<br>|
| Experimental: Arm B (Intermediate)<br> | Drug: daratumumab<br>* 16 mg/kg administered by IV infusion once every week in Cycle 1, and then on Day 1 of each cycle from Cycle 2 to Cycle 20, and every 8 weeks after Cycle 20. If, as per investigator discretion, there is a positive benefit/risk ratio, absence of Grade greater than or equal to (>=) 3 treatment related toxicity, and at least stable disease has been achieved, treatment can be extended and given every 8 weeks after Cycle 20. For participants participating in treatment extension, the duration of infusion may be shortened to a 90-minute infusion or can switch to daratumumab 1800mg subcutaneous (Q8w).<br>|
| Experimental: Arm C (Short Intense)<br> | Drug: daratumumab<br>* 16 mg/kg administered by IV infusion once every week in Cycle 1 only. Treatment cycles are 8 weeks in length.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants who achieve a complete response (CR) | CR, defined having negative immunofixation on the serum and urine, and <5% plasma cells (PCs) in bone marrow. | Up to 7 years | 
| The percentage of participants that have an event (disease progression or death) per patient-year |  | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants who are minimal residual disease (MRD) negative |  | Up to 7 years | 
| Time to next treatment (TNT) | TNT, defined as the time from the date of randomization to the date of the first subsequent multiple myeloma treatment. | Up to 7 years | 
| The percentage of participants who achieve a Complete Response (CR) or a Partial Response (PR) | See definition of CR above. PR, defined as >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours. | Up to 7 years | 
| The median time of progression free survival (PFS) | PFS is defined as time from date of randomization to date of initial documented disease progression (PD) according to SLiM-CRAB (S=sixty, Li=light chains, M=MRI, C=calcium [elevated], R=renal failure, A=anemia, B=bone lesions) criteria, myeloma defining events, or date of death, whichever occurs first. As per SLiM-CRAB criteria, clonal bone marrow plasma cell percentage >=60%, Involved : uninvolved serum free Li ratio >= 100, >1 focal lesion on MRI studies, calcium elevation: >0.25 millimole per liter (mmol/L) ( >1 milligram per deciliter [mg/dL]) higher than upper limit of normal or >2.75 mmol/L (>11 mg/dL); creatinine clearance <40 milliliter per minute (mL/min) or serum creatinine >177 micromole per liter (µmol/L) (>2 mg/dL); hemoglobin <10 gram per deciliter (g/dL) (<6.5 mmol/L) or >2 g/dL (>1.25 mmol/L) lower than lower limit of normal; 1 or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT). | Up to 7 years | 
| The percentage of participants with symptomatic multiple myeloma |  | Up to 7 years | 
| Response to first subsequent multiple myeloma treatment |  | Up to 7 years | 
| Overall survival rate |  | Up to 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoldering multiple myeloma (SMM), Daratumumab