Multiple Myeloma
Conditions
Keywords
Smoldering multiple myeloma (SMM), Daratumumab
Brief summary
The purpose of this study is to evaluate three daratumumab dose schedules in participants with Smoldering Multiple Myeloma.
Detailed description
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.
Interventions
DRUGdaratumumab
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).
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 No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Complete Response (CR) by International Myeloma Working Group (IMWG) Criteria | From Cycle 1 Day 1 up to 1.58 years | Percentage of participants who achieved a CR by IMWG Criteria were reported. CR was defined as CR plus stringent complete Response (sCR) by IMWG criteria. Per IMWG criteria, CR response was defined as a negative immunofixation on the serum and urine, and less than (\<) 5 percentage (%) plasma cells in bone marrow; sCR was defined as CR plus normal free light chain (FLC) ratio, and absence of clonal plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. |
| Progressive Disease or Death Rate | From Cycle 1 Day 1 up to 2.07 years | Progressive disease (PD) or death rate were reported. PD or death rate per patient-year was defined as number of events (PD or death) divided by total progression-free survival (PFS) for all participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) Negative Rate | From Cycle 1 Day 1 up to 91.6 months | MRD negative rate were reported. The MRD negativity rate was defined as the percentage of participants with a CR or better response who had negative MRD (10\^-4 and 10\^-5) assessment at any timepoint after the first dose of study drugs by evaluation of bone marrow aspirates at any time after the randomization and prior to progressive disease, subsequent therapy. |
| Time to Next Treatment (TNT) for Active Myeloma | From randomization (Day -5) up to the date of first subsequent antimyeloma treatment (up to 7.89 years) | Time to next treatment (TNT) for active myeloma were reported. Time to next treatment was defined as the time from the date of randomization to the date of the first subsequent multiple myeloma treatment. Kaplan-Meier estimate was used. |
| Percentage of Participants Who Achieved Partial Response or Better Response (Stringent Complete Response [sCR] Plus Complete Response [CR] Plus Very Good Partial Response [VGPR] or a Partial Response [PR]) | From start of the treatment (Cycle 1 Day 1) until confirmed PD, death, start of new anticancer therapy, withdrawal of consent, lost to follow-up, or end of the study, whichever occurred first (up to 7.89 years) | Per IMWG criteria, CR: was defined as a negative immunofixation on serum and urine, and \<5% plasma cells in bone marrow; sCR: CR plus normal FLC ratio, and absence of clonal plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hours; PR: \>=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>= 90% or to \<200 mg/24 hours; if serum and urine M-protein were not measurable, a decrease of \>=50% in difference between involved and uninvolved FLC levels was required instead of M-protein criteria. If serum and urine M-protein were not measurable and serum free light assay was also not measurable, \>=50% reduction in bone marrow plasma cells was required in place of M-protein, provided baseline bone marrow plasma cells percentage was \>=30%. |
| Progression Free Survival (PFS) | From randomization (Day -5) until disease progression or death whichever occurred first (up to 7.89 years) | PFS: time from dates of randomization to initial documented PD per Sixty percent, bone marrow plasma cells (BMPC), Light chains, focal lesions per MRI, elevated Calcium, Renal failure, Anemia, Bone lesions (SLiM-CRAB) criteria, or date of death, whichever was first. SLiM-CRAB criteria: clonal BM PCs percentage (%): \>=60%, Involved: uninvolved serum free LC ratio \>=100, \>1 focal lesion on MRI studies, calcium:\>0.25 millimole/liter (mmol/L)(\>1 mg/dL) higher than upper limit of normal or \>2.75 mmol/L (\>11 mg/dL); creatinine clearance \<40 mL/min or serum creatinine \>177 micromole/liter (\>2 mg/dL); hemoglobin \<10 g/dL(\<6.5 mmol/L) or \>2 g/dL(\>1.25 mmol/L) lower than lower limit of normal;\>1 osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT). Kaplan-Meier estimate was used. |
| Percentage of Participants With Symptomatic Multiple Myeloma With Adverse Prognostic Features | From start of treatment (Cycle 1 Day 1) until PD or prior to any subsequent anti-Multiple myeloma therapy (up to 7.89 years) | Percentage of participants with symptomatic multiple myeloma with adverse prognostic features were reported. The International Staging System (ISS) for multiple myeloma (MM) was based on serum beta-2 microglobulin (S beta-2M) and serum albumin; that is, participants progressed to symptomatic multiple myeloma (SymT MM) with stage III (S beta2M\>= 5.5 mg/L) of ISS, Participants progressed to SymT MM with adverse cytogenetic characteristics (ACC), participants progressed to SymT MM with stage III of ISS or adverse cytogenetic characteristics. Adverse cytogenetic characteristics included Fluorescence in situ hybridization (FISH) findings of del(17p13), t(14;16), t(4;14), amp(1q21) or karyotype findings of t(4;14), del(17p) or a combination of these. |
| Number of Participants With Response to First Subsequent Multiple Myeloma Treatment | From Cycle 1 Day 1 up to 7.89 years | Response (IMWG Criteria) to first subsequent MM treatment: sCR: CR + normal FLC ratio and absence of clonal plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: a negative immunofixation on serum and urine, and \<5% plasma cells in BM; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein \<100mg/24 hours; PR:\>=50% reduction of serum M-protein and \>=90% reduction in urine M-protein in 24 hour or to \<200 mg/24 hours; if serum and urine M-protein were not measurable, a decrease of \>=50% difference between involved and uninvolved FLC levels was required instead of M-protein criteria. If serum and urine M-protein and serum free light assay was also not measurable, \>=50% reduction in bone marrow plasma cells was required instead of M-protein, provided bone marrow plasma cells percentage was \>=30%. |
| Overall Survival | From randomization (Day -5) till death (up to 7.89 years) | Overall Survival (OS) was defined as the time from the date of randomization to the date of death. Median OS was estimated by using the Kaplan-Meier method. |
Countries
Australia, Canada, Czechia, France, Germany, Israel, Netherlands, Russia, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 8.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 117 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 107 Participants |
| Region of Enrollment Australia | 10 Participants |
| Region of Enrollment Canada | 9 Participants |
| Region of Enrollment France | 1 Participants |
| Region of Enrollment Germany | 5 Participants |
| Region of Enrollment Israel | 1 Participants |
| Region of Enrollment Italy | 9 Participants |
| Region of Enrollment Netherlands | 3 Participants |
| Region of Enrollment Russian Federation | 3 Participants |
| Region of Enrollment Turkey | 9 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Region of Enrollment United States | 11 Participants |
| Sex: Female, Male Female | 68 Participants |
| Sex: Female, Male Male | 17 Participants |
| Stage of Disease (ISS) Stage I | 34 Participants |
| Stage of Disease (ISS) Stage II | 22 Participants |
| Stage of Disease (ISS) Stage III | 0 Participants |
| Weight | 81.11 Kilograms (Kg) STANDARD_DEVIATION 17.434 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 41 | 5 / 41 | 4 / 41 |
| other Total, other adverse events | 38 / 41 | 41 / 41 | 32 / 40 |
| serious Total, serious adverse events | 20 / 41 | 14 / 41 | 4 / 40 |
Outcome results
None listed