A Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as Maintenance Treatment in Participants With Newly Diagnosed Multiple Myeloma Who Are Minimal Residual Disease Positive After Frontline Autologous Stem Cell Transplant

Study Overview
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Brief Summary
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The purpose of this study is to evaluate conversion rate to minimal residual disease (MRD) negativity following the addition of daratumumab to lenalidomide relative to lenalidomide alone, when administered as maintenance treatment to anti-cluster of differentiation 38 (CD38) treatment naive participants with newly diagnosed multiple myeloma who are MRD positive as determined by next generation sequencing (NGS) at screening, following high-dose therapy (HDT) and autologous stem cell transplant (ASCT).

Official Title
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A Randomized Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma Who Are Minimal Residual Disease Positive After Frontline Autologous Stem Cell Transplant

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have newly diagnosed multiple myeloma with a history of a minimum of 4 cycles of induction therapy, have received high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) within 12 months of the start of induction therapy, and be within 6 months of ASCT on the date of randomization Must have a very good partial response (VGPR) or better response assessed per International Myeloma Working Group (IMWG) 2016 criteria at the time of randomization Must have archived bone marrow samples collected before induction treatment (that is, at diagnosis) or before transplant (for example, at the end of induction) or have existing results on the index multiple myeloma clone based on Adaptive Biotechnologies' next generation sequencing (NGS)-based minimal residual disease (MRD) assay. Archived bone marrow samples will be used for calibration of myeloma clonal cells to facilitate assessment of primary end point by NGS. If an existing result on index myeloma clone is available from Adaptive Biotechnologies' NGS-based MRD assay, as part of institutional procedures, an archived bone marrow sample is not required as long as Adaptive Biotechnologies is able to retrieve historical results on the index myeloma clone form the clinical database. Any one of the following archived samples are required: (a) Greater than 1 milliliter (mL) viable frozen bone marrow aspirated aliquot (preferred) collected in an ethylenediaminetetra-acetic acid (EDTA) tube, frozen, and stored at a temperature of -80 centigrade (°C), or; (b) Non-decalcified diagnostic bone marrow aspirate clot sections (block or slides) for MRD assessment: (i) A formalin fixed paraffin embedded (FFPE) block of bone marrow aspirate clot, or slides (preferably 5, if available), 5 micrometer each, of non-decalcified bone marrow, or; (ii) Slides (preferably 5, if available), bone marrow aspirate smear; (iii) Please note, bone marrow core sections are not acceptable samples for analysis; (iv) In exceptional circumstances when index myeloma clone cannot be identified from the archived bone marrow sample, a post-transplant sample can be used to identify myeloma clone with permission from the sponsor Must have residual disease as defined by detectable MRD (Adaptive Biotechnologies' NGS based MRD assay) Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Exclusion Criteria: A history of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the participant has no evidence of disease before the of date of randomization. Exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years Must not have progressed on multiple myeloma (MM) therapy at any time prior to screening Have had prior treatment/therapy with: (a) Daratumumab or any other anti-cluster of differentiation 38 (CD38) therapies, (b) Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management, or (c) Plasmapheresis within 28 days of randomization Be exhibiting clinical signs of meningeal or central nervous system involvement due to multiple myeloma Have known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) less than (<) 50 percent (%) of predicted normal Have known moderate or severe persistent asthma within the past 2 years or current uncontrolled asthma of any classification Have any of the following: (a) Known history of seropositivity for human immunodeficiency virus (HIV); (b) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (that is, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR; (c) Seropositive for hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Daratumumab + Lenalidomide<br>Participants will receive 1800 milligram (mg) daratumumab by subcutaneous (SC) injection in combination with lenalidomide (orally) as maintenance therapy for a maximum of 36 cycles. Each cycle is of 28 days. | Drug: Daratumumab<br>* Daratumumab 1800 mg will be administered by SC injection weekly during Cycles 1 and 2, every 2 weeks during Cycles 3 through 6, and every 4 weeks from Cycle 7 onward until confirmed progressive disease (PD), unacceptable toxicity, or until end of study treatment for a maximum of 36 cycles.<br>* Other names: DARZALEX;Drug: Lenalidomide<br>* Lenalidomide 10 mg will be administered orally from Day 1 to Day 28 (continuously) of each 28-day cycle until confirmed PD, unacceptable toxicity, or until end of study treatment for a maximum of 36 cycles. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily, at the discretion of the investigator.<br>|
| Active Comparator: Lenalidomide<br>Participants will receive lenalidomide (orally) alone as maintenance therapy for a maximum of 36 cycles. Each cycle is of 28 days. | Drug: Lenalidomide<br>* Lenalidomide 10 mg will be administered orally from Day 1 to Day 28 (continuously) of each 28-day cycle until confirmed PD, unacceptable toxicity, or until end of study treatment for a maximum of 36 cycles. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily, at the discretion of the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Minimal Residual Disease (MRD) Negative Status as determined by NGS | The percentage of participants with MRD negative status (at 10^[-5]), that is the MRD conversion rate from baseline to 12 months after maintenance treatment, will be determined by next generation sequencing (NGS). | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS: duration from date of randomization to PD/death, whichever occurs first. IMWG criteria for PD: greater than or equal to (>=)25% from lowest response level in serum M-protein (absolute increase >=0.5 gram per deciliter [g/dL]); serum M-protein increase >=1 g/dL, if lowest M component >=5 g/dL; urine M-component: absolute increase >=200 mg/24 hour; only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); only in participants without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow PC%: absolute increase >=10%; appearance of new lesion(s), >=50% increase from nadir in sum of products of maximal perpendicular diameters of measured lesions (SPD) >1 lesion, or >=50% increase in longest diameter of previous lesion >1 centimeter (cm) in short axis; >=50% increase in circulating PCs if this is only measure of disease. | Up to 3 years | 
| Percentage of Participants with Overall Minimal Residual Disease (MRD) Negative Status | Percentage of participants with overall MRD negative status at any time after the date of randomization will be assessed. | Up to 3 years | 
| Durable MRD Negative Rate | Durable MRD negativity rate, defined as the percentage of participants who have achieved MRD negative status (at 10^-5) in 2 bone marrow aspirate examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between assessments. | Up to 3 years | 
| Percentage of Participants Achieving Complete Response (CR) or Stringent Complete Response (sCR) | Complete response is based on serum M-Protein assessments. International Myeloma Working Group (IMWG) criteria for CR: Negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (<) 5 percent (%) (plasma cells [PCs] in bone marrow aspirates. IMWG criteria for sCR: CR plus normal free light chain (FLC) ratio, and absence of clonal cells in bone marrow biopsy by immunohistochemistry. | Up to 3 years | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to date of death due to any cause. If participant is alive, participant's data will be censored at the last date participant was known to be alive. | Up to 4.1 years | 
| Duration of Complete Response (CR) | Duration of CR is the duration from the date of initial documentation of a CR or sCR to the date of first documented evidence of progressive disease (PD) as per IMWG criteria, or death due to PD, whichever occurs first. | Up to 3 years | 
| Change in Health-Related Quality of Life (HRQoL) as Measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ)-C30 | EORTC QLQ-C30 has been widely used among participants with multiple myeloma. It includes 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week (past week item) and responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms. | Baseline up to 3 years | 
| Change in HRQoL as Measured by European Quality of Life Five Dimensions Questionnaire-5-level (EQ-5D-5L) | The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus a visual analog scale rating health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). | Baseline up to 3 years | 
| Change in HRQoL as Measured by EORTC QLQ-Multiple Myeloma Module (MY20) | The EORTC QLQ-MY20 has been designed to be used alongside the EORTC QLQ-C30 to address issues of more relevance to myeloma participants. The EORTC QLQ-MY20 20-items make up 4 scales: disease symptoms, side effects of treatment, future perspective, and body image. Item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms. | Baseline up to 3 years | 
| Number of Participants with Treatment-emergent Adverse Events (TEAEs) as a Measure of Safety and Tolerability | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are AEs with onset during the Treatment Phase or that are a consequence of a pre-existing condition that has worsened since baseline. | Up to 4.1 years |