A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma

Study Overview
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Brief Summary
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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).

Detailed Description
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This study consists of 3 phases: Screening Phase (up to 35 days), an Active Monitoring Phase or a Treatment Phase of 39 cycles or 36 months (whichever occurs first), and a Follow-up Phase which will continue until death, lost to follow-up, consent withdrawal, or study end (approximately 8 years after the first participant is randomized), whichever occurs first. Active monitoring cycles and treatment cycles are 4 weeks in length. For all participants, disease evaluations will be performed every 12 weeks until confirmed progressive disease (PD). After PD, survival is to be followed at least every 6 months, until the end of the study. Participants will undergo tumor assessments, pharmacokinetics, biomarkers and safety evaluations (adverse events, laboratory tests, vital sign measurements, physical examinations, Eastern Cooperative Oncology Group [ECOG] performance status) over the time.

Official Title
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A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in Subjects With High-Risk Smoldering Multiple Myeloma

Conditions
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Smoldering Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab SC: daratumumab + rHuPH20


Participation Criteria
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Eligibility Criteria
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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: 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) 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 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 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 Clonal BMPC percentage >=60% Serum FLC ratio (involved:uninvolved) >=100 (the involved FLC must be >=100 mg/L) 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: Prior exposure to daratumumab or prior exposure to other anti-Cluster of Differentiation 38 (anti-CD38) therapies 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 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 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 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)

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 |
| --- | --- |
| No Intervention: Arm A: Active Monitoring<br>Participants randomized to active monitoring will receive no study medication, but will undergo the same disease evaluations at the same frequency as participants randomized to daratumumab. | |
| Experimental: Arm B: Daratumumab SC<br>Participants will receive 1800 milligram (mg) of daratumumab co-formulated with 2000 units per milliliter (U/mL) of recombinant human hyaluronidase (rHuPH20) by subcutaneous (SC) injection 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. | Drug: Daratumumab SC: daratumumab + rHuPH20<br>* 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.<br>* Other names: JNJ-54767414;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is time from randomization to active MM according to International Myeloma Working Group (IMWG) criteria or death. Per IMWG criteria, active MM (SLiM-CRAB) is 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. | From the date of randomization to active multiple myeloma (MM) or the date of death, whichever occurs first (up to approximately 8 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Biochemical or Diagnostic (SLiM-CRAB) Progression | Time to biochemical or diagnostic progression is defined as the earlier of time to biochemical progression or diagnostic (SLiM-CRAB) progression. SLiM-CRAB is defined as >=60% bone marrow plasma cells, free light chain involved/uninvolved ratio >=100, >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. | Up to biochemical or diagnostic progression (up to approximately 8 years) | 
| Overall Response Rate (ORR) | ORR is defined as percentage of participants with partial response (PR) or better (very good partial response [VGPR], complete response [CR], and stringent complete response [sCR]) as defined by IMWG criteria. PR: >=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >=90% or to less than (<)200 mg/24 hours; if serum and urine M-protein are not measurable, >=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a >=50% reduction in BMPC, with baseline BMPC percentage >=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. CR: negative immunofixation on serum and urine, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4- color flow cytometry. | Up to approximately 8 years | 
| Complete Response (CR) Rate | CR rate was defined as the percentage of participants with a CR (or better [sCR]) as defined by the IMWG response criteria. IMWG criteria for CR: negative immunofixation on serum and urine, and <5% PCs in bone marrow. IMWG criteria for sCR: CR as defined above, plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. | Up to approximately 8 years | 
| Time to First-Line Treatment for Multiple Myeloma (MM) | Time to first-line treatment for MM was defined as the time from the date of randomization to the date of the first-line treatment given for MM (post disease progression). | Post-progressive disease (PD) follow-up, every 6 months until end of study (up to approximately 8 years) | 
| Progression-Free Survival on First-Line Treatment for MM (PFS2) | PFS2 is time from date of randomization to date of documented PD on first line treatment given for MM or death, whichever comes first. IMWG criteria for PD: >=25% from lowest response level in serum M-component (the absolute increase must be >=0.5 gram per deciliter [g/dL]) and/or in urine M-component (the absolute increase must be >=200 mg/24 hour); only in participants without measurable serum and urine M-protein levels: increase of >=25% in the difference between involved and uninvolved free light chain levels and the absolute increase must be >10 mg/dL. BMPC%: the absolute % must be >=10%; definite increase in size of existing bone lesions or soft tissue plasmacytomas; definite development of new bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 millimoles per liter [mmol/L]) that can be attributed solely to PC proliferative disorder. | Post-PD follow-up, every 6 months until end of study (up to approximately 8 years) | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of the participant's death. | Throughout study, and at least every 3 months until PD; post-PD, every 6 months until end of study (up to approximately 8 years) | 
| Percentage of Participants who Progress to MM With Adverse Prognostic Features | Adverse prognostic features includes International Staging System Stage III (based on beta2 [β2]-microglobulin >=5.5 milligram per liter [mg/L] [median survival 29 months]) and adverse cytogenetic characteristics. | At screening and PD (up to approximately 8 years) | 
| Serum Daratumumab Pharmacokinetic (PK) Concentration | PK concentration of Daratumumab will be measured. | 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: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks) | 
| Maximum Observed Concentration (Cmax) of Daratumumab | The Cmax is the maximum observed plasma concentration 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: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks) | 
| Minimum Observed Concentration (Cmin) of Daratumumab | The Cmin is the minimum observed plasma concentration 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: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks) | 
| Number of Participants With Anti-daratumumab Antibodies | Participant's serum samples will be collected and screened for antibodies binding to daratumumab using validated immunoassay methods for evaluation of potential immunogenicity. | Cycles 1,3,5,7,12, and 24: Predose on Day 1; end of treatment (28 days after the last daratumumab dose), and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks) | 
| Number of Participants With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies | Participant's plasma samples will be collected and screened for antibodies binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary for the rHuPH20 immunogenicity assessment. | Cycles 1,3,5,7,12, and 24: Predose on Day 1; end of treatment (28 days after the last daratumumab dose), and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score | EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer participants. It is composed of 30 items, multiitem measure (28 items) and 2 single-item measures. For the multiple item measure, 4 point scale is used and the score for each item range from 1 = not at all to 4 = very much. Higher scores indicate worsening. The 2 single-item measure involves question about the overall health and overall quality of life which will be rated on a 7 point scale ranging from 1 = very poor to 7 = excellent. Lower scores indicate worsening. Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning | Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 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 | EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. EORTC QLQ-MY20 includes two scales: disease symptoms (6 questions) and future perspective (3 questions). Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future; and higher score for the disease symptoms scale indicates higher level of symptomatology. | Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 8 years) | 
| Change From Baseline in European Quality (EuroQoL) 5-Dimension 5-Level Health Status (EQ-5D-5L) Questionnaire | The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and as overall health using a thermometer visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). | Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 8 years) | 
| Duration of Response | Duration of response is defined as date of onset of first response (PR or better [VGPR, CR, sCR]) until date of disease progression or death. PR: >=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >=90% or to <200 mg/24 hours; if the serum and urine M-protein are not measurable, >=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a >=50% reduction in bone marrow PC, with baseline bone marrow PC percentage >=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. CR: negative immunofixation on serum and urine, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. | From the date of initial documentation of a response to the date of first documented evidence of PD (up to approximately 8 years) | 
| Time to Response | Time to response is defined as the time from randomization until onset of first response (PR or better [VGPR, CR, sCR]). PR: >=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >=90% or to <200 mg/24 hours; if the serum and urine M-protein are not measurable, >=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a >=50% reduction in bone marrow PC, with baseline bone marrow PC percentage >=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. CR: negative immunofixation on serum and urine, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. | Up to End of Treatment (up to approximately 39 cycles [each cycle of 28 days] or 36 months, whichever occurs first) |