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Daratumumab

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.

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.

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.

Daratumumab SC: daratumumab + rHuPH20

Janssen Research & Development, LLC Clinical Trial

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).

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.

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

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

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.

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.

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.

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.

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).

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.

OS was defined as the time from the date of randomization to the date of the participant's death.

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.

PK concentration of Daratumumab will be measured.

The Cmax is the maximum observed plasma concentration of Daratumumab.

The Cmin is the minimum observed plasma concentration of Daratumumab.

Participant's serum samples will be collected and screened for antibodies binding to daratumumab using validated immunoassay methods for evaluation of potential immunogenicity.

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.

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

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.

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).

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.

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.

Spots Global Cancer Trial Database for daratumumab sc: daratumumab + rhuph20