Smoldering Multiple Myeloma
Conditions
Brief summary
The primary objective of this study is to determine whether treatment with daratumumab administered subcutaneously (SC) prolongs progression-free survival (PFS) compared with active monitoring in participants with high-risk smoldering multiple myeloma (SMM).
Interventions
DRUGDaratumumab SC: daratumumab + rHuPH20
Participants will receive daratumumab SC injection (daratumumab 1800 mg + rHuPH20 \[2000 U/mL\]) once weekly for Cycles 1 and 2 (Days 1, 8, 15, and 22 of each week), every 2 weeks for Cycle 3 to Cycle 6 (Days 1 and 15), and thereafter every 4 weeks (Day 1) until 39 cycles or up to 36 months or until confirmed disease progression, unacceptable toxicity or withdrawal from the study treatment, study termination or study completion. Each cycle is 28 days in duration.
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 high risk smoldering multiple myeloma (SMM) (per International Myeloma Working Group \[IMWG\] criteria) for less than or equal to (\<=) 5 years with measurable disease at the time of randomization, defined as serum M protein greater than or equal to (\>=) 10 gram per liter (g/L) or urine M protein \>= 200 milligram per 24 hours (mg/24 hours) or involved serum free light chain (FLC) \>=100 milligram per liter (mg/L) and abnormal serum FLC ratio * Clonal bone marrow plasma cells (BMPCs) \>= 10 percentage (%); and at least 1 of the following risk factors; Serum M protein \>= 30 g/L, immunoglobulin (Ig)A SMM, immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only IgA, IgM, and IgG should be considered in determination for immunoparesis; IgD and IgE are not considered in this assessment), serum involved: uninvolved FLC ratio \>= 8 and less than (\<) 100, or clonal BMPCs greater than (\>) 50% to \<60% with measurable disease * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 * Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use highly effective method of contraception * A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization * During the study and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
Exclusion criteria
* Multiple myeloma (MM), requiring treatment, defined by any of the following: 1. Bone lesions (1 or more osteolytic lesions on low-dose whole body computed tomography \[LDCT\], positron-emission tomography with computed tomography \[PET-CT\] or CT). Participants who have benign/post-traumatic bone lesions visible on screening images as well as previous imaging, may be considered for inclusion. Details (diagnosis, location, duration) on benign/post-traumatic pre-existing bone lesions that can be seen on the screening images (example \[eg.\], old fractures) and were also present on previous imaging are to be reported in the case report form (CRF) 2. Hypercalcemia (serum calcium greater than \[\>\]0.25 millimoles per liter \[mmol/L\] \[\>1 milligram per deciliter {mg/dL}\] higher than upper limit of normal \[ULN\] or \>2.75 mmol/L \[\>11 mg/dL\]). Participants who have clinically stable hypercalcemia attributable to a disease other than multiple myeloma (eg, hyperparathyroidism) may be considered for inclusion after a case by case review by the medical monitor 3. Renal insufficiency, preferably determined by creatinine clearance less than (\<)40 milliliter per minute (mL/min) measured or estimated using the Modification of Diet in Renal Disease (MDRD), or serum creatinine \>177 micromole per liter (μmol/L). Participants who have clinically stable renal insufficiency attributable to a disease other than multiple myeloma (eg, glomerulonephritis) may be considered for inclusion after a case by case review by the medical monitor 4. Anemia, defined as hemoglobin \<10 gram per deciliter (g/dL) or \>2 g/dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted. Participants who have clinically stable anemia attributable to a disease other than multiple myeloma (eg, thalassemia, vitamin B12 deficiency, iron deficiency) may be considered for inclusion after a case by case review by the medical monitor 5. Clonal BMPC percentage \>=60% 6. Serum FLC ratio (involved:uninvolved) \>=100 (the involved FLC must be \>=100 mg/L) 7. More than 1 focal lesion \>=5 millimeter (mm) in diameter by magnetic resonance imaging (MRI) * Primary systemic amyloid light-chain (AL) (immunoglobulin light chain) amyloidosis * Exposure to any of the following: 1. Prior exposure to daratumumab or prior exposure to other anti-Cluster of Differentiation 38 (anti-CD38) therapies 2. Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory agent \[IMiDs\], or proteasome inhibitor \[PIs\]). Stable standard dosing of bisphosphonate and denosumab as indicated for osteoporosis is acceptable 3. Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1 4. Ongoing treatment with corticosteroids with a dose \>10 milligram (mg) prednisone or equivalent per day at the time of randomization; or \>280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization 5. Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab), immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine) or other treatments that are likely to interfere with the study procedures or results * Received treatment (chemotherapy, surgery, et cetera \[etc\]) for a malignancy (other than SMM) within 3 years before the 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), which is considered cured with minimal risk of recurrence within 3 years * Medical or psychiatric condition or disease (for example, active systemic disease \[including presence of auto-antibodies\], uncontrolled diabetes) 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 * Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, hyaluronidase, or other human proteins, or their excipients, or known sensitivity to mammalian-derived products (including dairy allergy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | From randomization (Day -5) up to 77 months | PFS was defined as the duration from the date of randomization to either progressive to multiple myeloma (MM), according to the International Myeloma Working Group (IMWG) diagnostic criteria for MM, or death due to any cause, whichever occurred first. Per IMWG criteria, active MM by SLiM-CRAB defined as: greater than or equal to (\>=) 60 percent (%) bone marrow plasma cells (BMPCs), free light chain (FLC) involved/uninvolved ratio \>=100, greater than (\>)1 focal bone lesions on magnetic resonance imaging (MRI), calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease due to lytic bone lesions. Kaplan-Meier estimate was used. |
Secondary
| Measure | Time frame |
|---|---|
| Time to Biochemical or Diagnostic (SLiM-CRAB) Progression Per Computerized Algorithm Analyses | From randomization (Day -5) up to 8 years |
| Overall Response Rate (ORR) | From randomization (Day -5) up to 8 years |
| Complete Response (CR) Rate | From randomization (Day -5) up to 8 years |
| Time to First-Line Treatment for Multiple Myeloma | From randomization (Day -5) up to 8 years |
| Progression-Free Survival on First-Line Treatment for Multiple Myeloma (PFS2) | From randomization (Day -5) up to 8 years |
| Best Response on First-line Therapy for Multiple Myeloma | From randomization (Day -5) up to 8 years |
| Overall Survival (OS) | From randomization (Day -5) up to 8 years |
| Percentage of Participants Who Progressed to Multiple Myeloma With Adverse Prognostic Features | From randomization (Day -5) up to 8 years |
| Maximum Observed Serum Concentration (Cmax) of Daratumumab | Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; end of the treatment (EOT, 37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days |
| Minimum Observed Serum Concentration (Cmin) of Daratumumab | Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; EOT( 37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days |
| Number of Participants With Anti-daratumumab Antibodies | Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; EOT (37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days |
| Number of Participants With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies | Cycles 1, 3, 5, 7, 12, and 24 : Predose on Day 1; EOT (37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score | From Baseline (Day -35) up to 8 years |
| Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale | From Baseline (Day -35) up to 8 years |
| Change From Baseline in European Quality (EuroQoL) 5-Dimension 5-Level Health Status (EQ-5D-5L) Questionnaire Score | From Baseline (Day -35) up to 8 years |
| Duration of Response | From randomization (Day -5) up to 8 years |
| Time to Response | From randomization (Day -5) up to 8 years |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Netherlands, Norway, Poland, Russia, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Pre-assignment details
Results are currently reported until the primary completion date (01 May 2024). Results of remaining duration will be posted upon study completion.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Active Monitoring (ACTM) Participants in the active monitoring group did not receive any study medication but underwent disease evaluations for every 12 weeks until disease progression (PD) as those randomized to receive daratumumab. | 196 |
| Arm B: Daratumumab SC Participants received daratumumab 1800 milligrams (mg) co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 units per milliliter (U/mL) as subcutaneous (SC) injection once every week (Q1W) (Days 1, 8, 15, and 22 of each week) in Cycles 1 and 2, every 2 weeks (Q2W) (Days 1 and 15) from Cycle 3 to Cycle 6, and thereafter every 4 weeks (Day 1) from Cycle 7 to Cycle 39, for a maximum of 36 months, or until confirmed disease progression, unacceptable toxicity or withdrawal from the study treatment. In addition, disease evaluations were performed every 12 weeks until PD. Each treatment cycle was 28 days. After end of treatment, participants were followed up for safety until death, lost to follow up, consent withdrawal or study end, whichever occurred first (up to 8 years). | 194 |
| Total | 390 |
Baseline characteristics
| Characteristic | Total | Arm A: Active Monitoring (ACTM) | Arm B: Daratumumab SC |
|---|---|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 10.97 | 63.0 Years STANDARD_DEVIATION 10.76 | 61.9 Years STANDARD_DEVIATION 11.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 9 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 345 Participants | 176 Participants | 169 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants | 11 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 31 Participants | 13 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 9 Participants | 10 Participants |
| Race (NIH/OMB) White | 323 Participants | 162 Participants | 161 Participants |
| Region of Enrollment Argentina | 9 Participants | 5 Participants | 4 Participants |
| Region of Enrollment Australia | 15 Participants | 10 Participants | 5 Participants |
| Region of Enrollment Belgium | 10 Participants | 6 Participants | 4 Participants |
| Region of Enrollment Brazil | 11 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Canada | 8 Participants | 6 Participants | 2 Participants |
| Region of Enrollment Czech Republic | 8 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Denmark | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment France | 16 Participants | 9 Participants | 7 Participants |
| Region of Enrollment Germany | 8 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Greece | 11 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Hungary | 12 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Israel | 56 Participants | 28 Participants | 28 Participants |
| Region of Enrollment Italy | 12 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Japan | 28 Participants | 13 Participants | 15 Participants |
| Region of Enrollment Netherlands | 9 Participants | 6 Participants | 3 Participants |
| Region of Enrollment Norway | 15 Participants | 8 Participants | 7 Participants |
| Region of Enrollment Poland | 12 Participants | 6 Participants | 6 Participants |
| Region of Enrollment Russian Federation | 13 Participants | 9 Participants | 4 Participants |
| Region of Enrollment Spain | 24 Participants | 14 Participants | 10 Participants |
| Region of Enrollment Sweden | 5 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Turkey | 14 Participants | 5 Participants | 9 Participants |
| Region of Enrollment United Kingdom | 35 Participants | 17 Participants | 18 Participants |
| Region of Enrollment United States | 57 Participants | 27 Participants | 30 Participants |
| Sex: Female, Male Female | 202 Participants | 103 Participants | 99 Participants |
| Sex: Female, Male Male | 188 Participants | 93 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 196 | 15 / 194 |
| other Total, other adverse events | 140 / 196 | 178 / 193 |
| serious Total, serious adverse events | 38 / 196 | 56 / 193 |
Outcome results
Primary
Progression-Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
PFS was defined as the duration from the date of randomization to either progressive to multiple myeloma (MM), according to the International Myeloma Working Group (IMWG) diagnostic criteria for MM, or death due to any cause, whichever occurred first. Per IMWG criteria, active MM by SLiM-CRAB defined as: greater than or equal to (\>=) 60 percent (%) bone marrow plasma cells (BMPCs), free light chain (FLC) involved/uninvolved ratio \>=100, greater than (\>)1 focal bone lesions on magnetic resonance imaging (MRI), calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease due to lytic bone lesions. Kaplan-Meier estimate was used.
Time frame: From randomization (Day -5) up to 77 months
Population: Intent-to-treat (ITT) analysis set included all participants randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Active Monitoring (ACTM) | Progression-Free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | 41.46 Months |
| Arm B: Daratumumab SC | Progression-Free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | NA Months |
p-value: <0.000195% CI: [0.36, 0.67]Log Rank
Secondary
Best Response on First-line Therapy for Multiple Myeloma
Time frame: From randomization (Day -5) up to 8 years
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
Time frame: From Baseline (Day -35) up to 8 years
Secondary
Change From Baseline in European Quality (EuroQoL) 5-Dimension 5-Level Health Status (EQ-5D-5L) Questionnaire Score
Time frame: From Baseline (Day -35) up to 8 years
Secondary
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale
Time frame: From Baseline (Day -35) up to 8 years
Secondary
Complete Response (CR) Rate
Time frame: From randomization (Day -5) up to 8 years
Secondary
Duration of Response
Time frame: From randomization (Day -5) up to 8 years
Secondary
Maximum Observed Serum Concentration (Cmax) of Daratumumab
Time frame: Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; end of the treatment (EOT, 37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days
Secondary
Minimum Observed Serum Concentration (Cmin) of Daratumumab
Time frame: Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; EOT( 37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days
Secondary
Number of Participants With Anti-daratumumab Antibodies
Time frame: Cycles 1 and 3 : Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; EOT (37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days
Secondary
Number of Participants With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies
Time frame: Cycles 1, 3, 5, 7, 12, and 24 : Predose on Day 1; EOT (37.11 months); and 8 weeks after the last daratumumab dose (up to 38.11 months). Each Cycle was 28 days
Secondary
Overall Response Rate (ORR)
Time frame: From randomization (Day -5) up to 8 years
Secondary
Overall Survival (OS)
Time frame: From randomization (Day -5) up to 8 years
Secondary
Percentage of Participants Who Progressed to Multiple Myeloma With Adverse Prognostic Features
Time frame: From randomization (Day -5) up to 8 years
Secondary
Progression-Free Survival on First-Line Treatment for Multiple Myeloma (PFS2)
Time frame: From randomization (Day -5) up to 8 years
Secondary
Time to Biochemical or Diagnostic (SLiM-CRAB) Progression Per Computerized Algorithm Analyses
Time frame: From randomization (Day -5) up to 8 years
Secondary
Time to First-Line Treatment for Multiple Myeloma
Time frame: From randomization (Day -5) up to 8 years
Secondary
Time to Response
Time frame: From randomization (Day -5) up to 8 years