Multiple Myeloma
Conditions
Brief summary
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).
Interventions
DRUGDaratumumab
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.
DRUGLenalidomide
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had Minimal Residual Disease (MRD) Conversion From Baseline to 12 Months After Start of Maintenance Treatment as Determined by Next Generation Sequencing (NGS) | From randomization up to 12 months | Percentage of participants who achieved MRD negative (MRD conversion) status from baseline to 12 months after maintenance treatment was defined as percentage of participants who were MRD positive at baseline (randomization) and achieved MRD negative status (at 10\^-5) during the time period from randomization to 12 months plus 2 months window, but prior to progressive disease (PD) and subsequent anti-myeloma therapy. |
Secondary
| Measure | Time frame |
|---|---|
| Progression-free Survival (PFS) | From randomization to either disease progression or death (up to 7.1 years) |
| Percentage of Participants Who Achieved Overall MRD (at 10^-5) Negativity Conversion From Baseline to End of Study Treatment Period | From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years) |
| Percentage of Participants Who Achieved Durable (Greater Than or Equal to [>=] 12 Months) MRD Negative Status (10^-5) | From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years) |
| Response Rates by International Myeloma Working Group (IMWG) 2016 Criteria | From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years) |
| Overall Survival (OS) | From randomization up to 7.1 years |
| Duration of Complete Response (CR) | From date of initial documentation of CR or sCR up to first documented disease progression or death due to disease progression whichever occurs first (up to 7.1 years) |
| Health-related Quality of Life: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-C30 (EORTC QLQ-C30) | From baseline (Cycle 1 Day 1) up to 7.1 years |
| Health-related Quality of Life: Change From Baseline in European Quality of Life Five Dimensions Questionnaire-5-level (EQ-5D-5L) | From baseline (Cycle 1 Day 1) up to 7.1 years |
| Health-related Quality of Life: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Multiple Myeloma Module (EORTC QLQ-MY20) | From baseline (Cycle 1 Day 1) up to 7.1 years |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From Cycle 1 Day 1 up to 30 days after the last study treatment or day prior to start of subsequent antimyeloma therapy (up to 7.1 years) |
Countries
Canada, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Pre-assignment details
Currently, results posted till interim data cutoff date of 04-April-2024 (primary completion date).
Participants by arm
| Arm | Count |
|---|---|
| Daratumumab + Lenalidomide Participants received daratumumab 1800 milligrams (mg) subcutaneous (SC) injection weekly during Cycle 1 and Cycle 2 (that is, on Day 1, Day 8, Day 15 and Day 22 of each Cycle), followed by every-2-week dosing from Cycle 3 to Cycle 6 (that is, on Weeks 9, 11, 13, 15, 17, 19, and 21) and then every-4-week dosing from Cycle 7 onwards (that is, from Week 25). In addition, participants received maintenance therapy with lenalidomide 10 mg capsule orally (PO) from Day 1 to 28 in each treatment cycle. Participants received study treatment until confirmed disease progression (PD), unacceptable toxicity, or until end of study treatment, whichever occurred first. After Cycle 3, if lenalidomide was well tolerated, dose might be increased to 15 mg at the discretion of the investigator. Each treatment cycle was of 28 days. | 99 |
| Lenalidomide Participants received lenalidomide 10 mg capsule PO as maintenance therapy from Day 1 to Day 28 of each 28-day treatment cycle until confirmed PD, unacceptable toxicity, or the end of the study treatment, whichever occurred first. After Cycle 3, if lenalidomide was well tolerated, dose might be increased to 15 mg at the discretion of the investigator. | 101 |
| Total | 200 |
Baseline characteristics
| Characteristic | Daratumumab + Lenalidomide | Lenalidomide | Total |
|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 8.12 | 60.8 years STANDARD_DEVIATION 9.54 | 61 years STANDARD_DEVIATION 8.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 6 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 81 Participants | 89 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants | 24 Participants | 44 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 67 Participants | 68 Participants | 135 Participants |
| Region of Enrollment Canada | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 97 Participants | 101 Participants | 198 Participants |
| Sex: Female, Male Female | 38 Participants | 43 Participants | 81 Participants |
| Sex: Female, Male Male | 61 Participants | 58 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 99 | 9 / 101 |
| other Total, other adverse events | 95 / 96 | 97 / 98 |
| serious Total, serious adverse events | 29 / 96 | 22 / 98 |
Outcome results
Primary
Percentage of Participants Who Had Minimal Residual Disease (MRD) Conversion From Baseline to 12 Months After Start of Maintenance Treatment as Determined by Next Generation Sequencing (NGS)
Percentage of participants who achieved MRD negative (MRD conversion) status from baseline to 12 months after maintenance treatment was defined as percentage of participants who were MRD positive at baseline (randomization) and achieved MRD negative status (at 10\^-5) during the time period from randomization to 12 months plus 2 months window, but prior to progressive disease (PD) and subsequent anti-myeloma therapy.
Time frame: From randomization up to 12 months
Population: The full analysis set (FAS) which included all participants randomly assigned to daratumumab in combination with lenalidomide or the lenalidomide alone.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daratumumab + Lenalidomide | Percentage of Participants Who Had Minimal Residual Disease (MRD) Conversion From Baseline to 12 Months After Start of Maintenance Treatment as Determined by Next Generation Sequencing (NGS) | 50.5 percentage of participants |
| Lenalidomide | Percentage of Participants Who Had Minimal Residual Disease (MRD) Conversion From Baseline to 12 Months After Start of Maintenance Treatment as Determined by Next Generation Sequencing (NGS) | 18.8 percentage of participants |
p-value: <0.000195% CI: [2.37, 8.57]stratified Cochran-Mantel-Haenszel (CMH)
Secondary
Duration of Complete Response (CR)
Time frame: From date of initial documentation of CR or sCR up to first documented disease progression or death due to disease progression whichever occurs first (up to 7.1 years)
Secondary
Health-related Quality of Life: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-C30 (EORTC QLQ-C30)
Time frame: From baseline (Cycle 1 Day 1) up to 7.1 years
Secondary
Health-related Quality of Life: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Multiple Myeloma Module (EORTC QLQ-MY20)
Time frame: From baseline (Cycle 1 Day 1) up to 7.1 years
Secondary
Health-related Quality of Life: Change From Baseline in European Quality of Life Five Dimensions Questionnaire-5-level (EQ-5D-5L)
Time frame: From baseline (Cycle 1 Day 1) up to 7.1 years
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: From Cycle 1 Day 1 up to 30 days after the last study treatment or day prior to start of subsequent antimyeloma therapy (up to 7.1 years)
Secondary
Overall Survival (OS)
Time frame: From randomization up to 7.1 years
Secondary
Percentage of Participants Who Achieved Durable (Greater Than or Equal to [>=] 12 Months) MRD Negative Status (10^-5)
Time frame: From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years)
Secondary
Percentage of Participants Who Achieved Overall MRD (at 10^-5) Negativity Conversion From Baseline to End of Study Treatment Period
Time frame: From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years)
Secondary
Progression-free Survival (PFS)
Time frame: From randomization to either disease progression or death (up to 7.1 years)
Secondary
Response Rates by International Myeloma Working Group (IMWG) 2016 Criteria
Time frame: From randomization up to 30 days after last dose of study treatment or disease progression or initiation of subsequent therapy, whichever occurs first (up to 3 years)