Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Bortezomib, Velcade, Melphalan, Prednisone, Daratumumab
Brief summary
The purpose of this study is to determine if the addition of daratumumab to velcade (bortezomib) melphalan-prednisone (VMP) will prolong progression-free survival (PFS) compared with VMP alone in participants with previously untreated multiple myeloma who are ineligible for high dose chemotherapy and autologous stem cell transplant (ASCT).
Detailed description
The study consists of 3 phases: Screening Phase (within 21 days prior to randomization), Treatment Phase (Cycle 1 Day 1 to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, withdrawal of consent, or the study ends, whichever occurs first). Treatment phase will include 2 treatments (Treatment A: participants will receive Velcade MelphalanPrednisone (VMP) alone and Treatment B: participants will receive daratumumab in combination with VMP).Two interim analyses are planned. The first will be to evaluate safety after a total of approximately 100 participants have been treated for at least 2 cycles or discontinued the study treatment. The second will be to evaluate cumulative interim safety and efficacy data, and will be performed when approximately 216 PFS events have been accumulated. The final OS analysis will occur when approximately 382 deaths have occurred. Efficacy will be primarily measured by comparison of PFS between the two treatment arms. Participants' safety will be monitored throughout the study.
Interventions
DRUGVelcade
Participants will receive velcade 1.3 mg/m\^2, as subcutaneous injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at Weeks 1, 2, 4 and 5 in Cycles 2 to 9.
DRUGMelphalan
Participants will receive melphalan 9 mg/m\^2, orally, once daily on Days 1 to 4 of each cycle up to Cycle 9.
DRUGPrednisone
Participants will receive prednisone 60 mg/m\^2, orally, once daily, on Days 1 to 4 of each cycle up to Cycle 9.
DRUGDaratumumab IV
Participants will receive daratumumab 16 mg/kg as intravenous infusion, once weekly, for 6 weeks in Cycle 1 and then once every 3 weeks, in Cycle 2 to 9 and thereafter, once every 4 weeks until documented progression, unacceptable toxicity, or until the end of study .
DRUGDexamethasone
Participants administered with dexamethasone 20 mg IV or PO is given 1 hour or less prior to daratumumab administration as pre medication and prednisone substitute.
DRUGDaratumumab SC
Daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or until the end of study. Following amendment 7, participants can switch from daratumumab IV to daratumumab SC.
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
* Participant must have documented multiple myeloma satisfying the calcium elevation, renal insufficiency, anemia, and bone abnormalities (CRAB) diagnostic criteria, monoclonal plasma cells in the bone marrow greater than or equal to 10 percent (%) or presence of a biopsy proven plasmacytoma, and measurable secretory disease, as assessed by the central laboratory, and defined in protocol * Participants who are newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation (SCT) due to: being age \>=65 years, or in participants \<65 years: presence of important comorbid conditions likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation * Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 * Meet the clinical laboratory criteria as specified in the protocol * A woman of childbearing potential must have a negative serum pregnancy test at screening within 14 days prior to randomization * Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy
Exclusion criteria
* Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma * Participant has a diagnosis of Waldenstrom's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions * Participant has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for 4 days) of corticosteroids before treatment * Participant has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the national cancer institute common terminology criteria for adverse events (NCI CTCAE) Version 4 * Participant has a history of malignancy (other than multiple myeloma) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy 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) * Participant has had radiation therapy within 14 days of randomization * Participant has had plasmapheresis within 28 days of randomization * Participant has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume in 1 second \[FEV1\] \<50% of predicted normal), known moderate or severe persistent asthma within the last 2 years or currently has uncontrolled asthma of any classification (controlled intermittent asthma or controlled mild persistent asthma is allowed) * Participants with known or suspected COPD must have a FEV1 test during screening * Participant is known to be seropositive for human immunodeficiency virus (HIV), known to have hepatitis B surface antigen positivity, or history of to have a history of hepatitis C * Participant has any concurrent medical or psychiatric condition or disease (example active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) 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 |
|---|---|---|
| Progression Free Survival (PFS) | From randomization (Day -3) up to 2.4 years | PFS: duration from date of randomization to progressive disease (PD)/death, whichever occurs first. PD per IMWG criteria-Increase of 25% from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 grams per deciliter \[g/dL\]); Urine M-component (absolute increase \>=200 milligrams \[mg\]/24 hours); Only participants without measurable serum and urine M-protein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase \>10 mg/dL); Only participants without measurable serum and urine M-protein levels, without measurable disease by FLC levels, bone marrow Plasma cells (PC) percentage (%) (absolute % \>=10%); Bone marrow PC%: absolute% \>10%; Definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Very Good Partial Response (VGPR) or Better | From randomization (Day -3) up to 2.4 years | VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response\[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level less than (\<) 100 milligram (mg) per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \< 5% plasms cells (PCs) in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry. |
| Percentage of Participants With Complete Response (CR) or Better | From randomization (Day -3) up to 2.4 years | CR or better rate was defined as the percentage of participants with a CR or better (i.e. CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (\<) 5 percent plasma cells in bone marrow; sCR: CR plus normal free light chain (FLC) ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. |
| Percentage of Participants With Stringent Complete Response (sCR) | From randomization (Day -3) up to 2.4 years | sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. CR: Negative immunofixation on the serum and urine; Disappearance of any soft tissue plasmacytomas; \<5% plasma cells (PCs) in bone marrow. |
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | From randomization (Day -3) up to 8.3 years | The Minimal Residual Disease negativity rate was defined as the percentage of participants who had negative MRD (detection of less than 1 malignant cell among 100,000 normal cells) assessment at any timepoint after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood at 10\^-5 threshold. MRD was evaluated by using Deoxyribonucleic acid (DNA) sequencing of immunoglobulin genes. MRD was assessed in participants who achieved complete response or stringent complete response (CR/sCR). |
| Overall Survival (OS) | From randomization (Day -3) up to 8.3 years | Overall Survival (OS) was measured from the date of randomization to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method. |
| Progression Free Survival on Next Line of Therapy (PFS2) | From randomization (Day -3) up to 8.3 years | Progression-free survival after next-line therapy is defined as the time from randomization to progression on the next line of subsequent antimyeloma therapy or death due to any cause (prior to start of second line of antimyeloma therapy), whichever comes first. Disease progression on next line of treatment was based on investigator judgment. |
| Time to Disease Progression (TTP) | From randomization (Day -3) up to 2.4 years | TTP: Time from date of randomization to date of first documented evidence of PD or death due to PD, whichever occurs first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cells (PC)% (absolute % \>=10%); Bone marrow PC %: absolute % \>10%; Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. |
| Overall Response Rate (ORR) | From randomization (Day -3) up to 2.4 years | The Overall response rate was defined as the percentage of participants who achieved a partial response (PR) or better, according to the International Myeloma Working Group (IMWG) criteria, during the study or during follow up. IMWG criteria for PR: greater than or equal to (\>=) 50 percentage (%) 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, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%, in addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was also required. |
| Duration of Response (DOR) | From first documentation of response up to 2.4 years | DOR: participants with confirmed response (PR or better) as time between first documentation of response and disease progression per IMWG response criteria, or death due to PD, whichever occurs first. PD: Increase of 25% from lowest response value in any one of following: Serum M-component (absolute increase\>=0.5 g/dL); Urine M-component (absolute increase\>=200 mg/24 hours); Only participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10mg/dL); Only participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC%(absolute%\>=10%); Bone marrow PC's %: absolute%\>10%; Definite development of new bone lesions/soft tissue plasmacytomas/definite increase in the size of existing bone lesions or soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder. |
| Time to Next Treatment (TNT) | From randomization (Day -3) up to 8.3 years | Time to next treatment is defined as the time from randomization to the start of the next-line treatment. Kaplan-Meier method was used for the analysis. |
| Percentage of Participants With Best M-protein Response | Up to 2.4 years | Percentage of participants with Best M- protein response of 100% reduction and \>=90% to \< 100% reduction were assessed. Best M-protein response was defined as the maximal percent reduction or the lowest percent increase from baseline in serum M-protein for participants with measurable heavy chain at baseline or urine M-protein for participants without measurable heavy chain, but with measurable light chain disease at baseline. For participants without measurable heavy chain and light chain disease at baseline, best response in serum free light chain (FLC) was defined as the maximal percent reduction or the lowest percent increase from baseline in the difference between involved and uninvolved serum FLC level (dFLC). |
| Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48 | The EORTC QLQ-C30 is a 30 items self-reporting questionnaire, with a 1 week recall period, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall QoL. Scores are transformed to a 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values for function and GHS scale indicated deterioration in quality of life or functioning and positive values indicate improvement. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48 | The EORTC QLQ-C30 is a 30 items self-reporting questionnaire, with a 1 week recall period, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall QoL. Scores are transformed to a 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values for function and GHS scale indicated deterioration in quality of life or functioning and positive values indicate improvement. |
| Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Baseline (Day- 24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48 | EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. |
| Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48 | EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L descriptive system provides a profile of the participant's health state 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The participant was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. Responses to the 5 dimension scores were combined and converted into a single preference-weighted health utility index score 0 (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of the individual based on the UK scoring algorithm. |
| Time to Response | From randomization (Day -3) up to 2.4 years | Time to response, defined as the time between the date of randomization and the first efficacy evaluation that the participant has met all criteria for PR or better. 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, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was also required. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Croatia, Czechia, Georgia, Germany, Greece, Hungary, Japan, North Macedonia, Poland, Portugal, Romania, Russia, Serbia, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Velcade, Melphalan and Prednisone (VMP) Participants received Velcade (bortezomib) 1.3 milligrams per square meter (mg/m\^2) as subcutaneous (SC) injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at Weeks 1, 2, 4 and 5 in Cycles 2 to 9, melphalan 9 mg/m\^2 orally once daily on Days 1 to 4 and prednisone 60 mg/m\^2 orally once daily on Days 1 to 4 of each cycle up to Cycle 9. Each treatment cycle was of 6 weeks. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group \[IMWG\] criteria). After implementation of Amendment 7, post interim overall survival (OS) analysis, sponsor confirmation of disease progression was no longer required prior to initiation of subsequent anti-myeloma therapy, except for participants who progressed on VMP arm and requested subsequent therapy with daratumumab. | 356 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) Participants received Velcade 1.3 mg/m\^2 as SC injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at weeks 1, 2, 4 and 5 in Cycles 2 to 9, melphalan 9 mg/m\^2, orally once daily on Days 1 to 4 and prednisone 60 mg/m\^2, orally once daily on Days 2 to 4 of each cycle up to Cycle 9. In addition, participants also received daratumumab 16 milligrams per kilogram (mg/kg) as intravenous (IV) infusion once weekly for 6 weeks in Cycle 1 and then once every 3 weeks in Cycle 2 to 9 and thereafter, once every 4 weeks (post-VMP treatment phase) until documented progression, unacceptable toxicity, or study end. On Day 1 of each cycle, dexamethasone 20 mg IV or per oral (PO) was given 1 hour or less prior to daratumumab infusion as pre-medication and prednisone substitute. Each treatment cycle was of 6 weeks. After implementation of Amendment 7, participants who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab SC injection on Day 1 of any cycle, as per investigator's discretion. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria). | 350 |
| Total | 706 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 217 | 171 |
| Overall Study | Discontinued at clinical cutoff (due to end of data collection period) | 87 | 130 |
| Overall Study | Lost to Follow-up | 18 | 15 |
| Overall Study | Other | 3 | 4 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 30 | 30 |
Baseline characteristics
| Characteristic | Velcade, Melphalan and Prednisone (VMP) | Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Total |
|---|---|---|---|
| Age, Continuous | 71.5 Years STANDARD_DEVIATION 5.82 | 71.3 Years STANDARD_DEVIATION 6.66 | 71.4 Years STANDARD_DEVIATION 6.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 24 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 332 Participants | 320 Participants | 652 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 45 Participants | 47 Participants | 92 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) White | 304 Participants | 297 Participants | 601 Participants |
| Region of Enrollment Argentina | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Australia | 10 Participants | 5 Participants | 15 Participants |
| Region of Enrollment Belgium | 8 Participants | 6 Participants | 14 Participants |
| Region of Enrollment Brazil | 2 Participants | 4 Participants | 6 Participants |
| Region of Enrollment Bulgaria | 15 Participants | 8 Participants | 23 Participants |
| Region of Enrollment Croatia | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Czech Republic | 29 Participants | 21 Participants | 50 Participants |
| Region of Enrollment Georgia | 11 Participants | 11 Participants | 22 Participants |
| Region of Enrollment Germany | 2 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Greece | 15 Participants | 14 Participants | 29 Participants |
| Region of Enrollment Hungary | 12 Participants | 14 Participants | 26 Participants |
| Region of Enrollment Italy | 26 Participants | 28 Participants | 54 Participants |
| Region of Enrollment Japan | 26 Participants | 24 Participants | 50 Participants |
| Region of Enrollment Korea, Republic of | 18 Participants | 23 Participants | 41 Participants |
| Region of Enrollment Macedonia | 10 Participants | 1 Participants | 11 Participants |
| Region of Enrollment Poland | 27 Participants | 39 Participants | 66 Participants |
| Region of Enrollment Portugal | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment Romania | 18 Participants | 10 Participants | 28 Participants |
| Region of Enrollment Russia | 21 Participants | 22 Participants | 43 Participants |
| Region of Enrollment Serbia | 3 Participants | 7 Participants | 10 Participants |
| Region of Enrollment Spain | 47 Participants | 56 Participants | 103 Participants |
| Region of Enrollment Turkey | 10 Participants | 5 Participants | 15 Participants |
| Region of Enrollment Ukraine | 20 Participants | 28 Participants | 48 Participants |
| Region of Enrollment United Kingdom | 15 Participants | 9 Participants | 24 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 189 Participants | 190 Participants | 379 Participants |
| Sex: Female, Male Male | 167 Participants | 160 Participants | 327 Participants |
| Stage of Disease (ISS) Stage I | 67 Participants | 69 Participants | 136 Participants |
| Stage of Disease (ISS) Stage II | 160 Participants | 139 Participants | 299 Participants |
| Stage of Disease (ISS) Stage III | 129 Participants | 142 Participants | 271 Participants |
| Time from multiple myeloma (MM) diagnosis | 1.27 Months STANDARD_DEVIATION 1.737 | 1.09 Months STANDARD_DEVIATION 1.056 | 1.18 Months STANDARD_DEVIATION 1.442 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 217 / 356 | 172 / 350 |
| other Total, other adverse events | 331 / 354 | 329 / 346 |
| serious Total, serious adverse events | 117 / 354 | 186 / 346 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS: duration from date of randomization to progressive disease (PD)/death, whichever occurs first. PD per IMWG criteria-Increase of 25% from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 grams per deciliter \[g/dL\]); Urine M-component (absolute increase \>=200 milligrams \[mg\]/24 hours); Only participants without measurable serum and urine M-protein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase \>10 mg/dL); Only participants without measurable serum and urine M-protein levels, without measurable disease by FLC levels, bone marrow Plasma cells (PC) percentage (%) (absolute % \>=10%); Bone marrow PC%: absolute% \>10%; Definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder.
Time frame: From randomization (Day -3) up to 2.4 years
Population: Intent-to-treat (ITT) population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Progression Free Survival (PFS) | 18.14 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Progression Free Survival (PFS) | NA Months |
Secondary
Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score
The EORTC QLQ-C30 is a 30 items self-reporting questionnaire, with a 1 week recall period, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall QoL. Scores are transformed to a 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values for function and GHS scale indicated deterioration in quality of life or functioning and positive values indicate improvement.
Time frame: Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48
Population: ITT population: participants randomized into the study; classified according to assigned treatment group, regardless actual treatment received. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at each specified timepoint, for each arm, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 3 | 9.4 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 6 | 10.5 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 9 | 11.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 12 | 11.2 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 18 | 12.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 24 | 11.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 30 | 10.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 36 | 10.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 42 | 6.5 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 48 | 6.2 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 36 | 12.3 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 3 | 8.5 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 24 | 10.7 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 6 | 10.8 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 48 | 10.5 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 9 | 11.1 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 30 | 12.4 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 12 | 12.6 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 42 | 12.8 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score | Month 18 | 12.5 Units on a scale |
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale
The EORTC QLQ-C30 is a 30 items self-reporting questionnaire, with a 1 week recall period, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall QoL. Scores are transformed to a 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values for function and GHS scale indicated deterioration in quality of life or functioning and positive values indicate improvement.
Time frame: Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48
Population: ITT population: participants randomized into the study; classified according to assigned treatment group, regardless actual treatment received. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at each specified timepoint, for each arm, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 3 | 4 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 6 | 8.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 9 | 10.2 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 12 | 10.7 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 18 | 11.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 24 | 11.5 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 30 | 10.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 36 | 8.6 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 42 | 4.8 Units on a scale |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 48 | 8.9 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 36 | 11.9 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 3 | 7.5 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 24 | 9.5 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 6 | 8.5 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 48 | 9.8 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 9 | 10.6 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 30 | 11.8 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 12 | 11.4 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 42 | 10.4 Units on a scale |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Global Health Scale | Month 18 | 12.8 Units on a scale |
Secondary
Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L descriptive system provides a profile of the participant's health state 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The participant was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. Responses to the 5 dimension scores were combined and converted into a single preference-weighted health utility index score 0 (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of the individual based on the UK scoring algorithm.
Time frame: Baseline (Day -24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48
Population: ITT population: participants randomized into the study; classified according to assigned treatment group, regardless actual treatment received. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at each specified timepoint, for each arm, respectively. n=0 indicated that no participant was available for assessment at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 3 | 0.09 Units on a scale | Standard Deviation 0.312 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 6 | 0.12 Units on a scale | Standard Deviation 0.269 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 9 | 0.16 Units on a scale | Standard Deviation 0.27 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 12 | 0.15 Units on a scale | Standard Deviation 0.281 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 18 | 0.14 Units on a scale | Standard Deviation 0.268 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 24 | 0.15 Units on a scale | Standard Deviation 0.252 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 30 | 0.16 Units on a scale | Standard Deviation 0.291 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 36 | 0.16 Units on a scale | Standard Deviation 0.315 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 42 | 0.08 Units on a scale | Standard Deviation 0.303 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 48 | 0.07 Units on a scale | Standard Deviation 0.246 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 36 | 0.21 Units on a scale | Standard Deviation 0.306 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 3 | 0.12 Units on a scale | Standard Deviation 0.266 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 24 | 0.18 Units on a scale | Standard Deviation 0.312 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 6 | 0.14 Units on a scale | Standard Deviation 0.271 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 48 | 0.15 Units on a scale | Standard Deviation 0.319 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 9 | 0.16 Units on a scale | Standard Deviation 0.271 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 30 | 0.19 Units on a scale | Standard Deviation 0.303 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 12 | 0.17 Units on a scale | Standard Deviation 0.288 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 42 | 0.2 Units on a scale | Standard Deviation 0.287 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score | Month 18 | 0.17 Units on a scale | Standard Deviation 0.293 |
Secondary
Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS)
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Time frame: Baseline (Day- 24), Months 3, 6, 9, 12 ,18, 24, 30, 36, 42 and 48
Population: ITT population: participants randomized into the study; classified according to assigned treatment group, regardless actual treatment received. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at each specified timepoint, for each arm, respectively. n=0 indicated that no participant was available for assessment at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 9 | 10.08 Units on a scale | Standard Deviation 19.475 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 24 | 10.62 Units on a scale | Standard Deviation 19.531 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 6 | 7.51 Units on a scale | Standard Deviation 17.957 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 30 | 12.38 Units on a scale | Standard Deviation 21.817 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 12 | 11.1 Units on a scale | Standard Deviation 19.139 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 36 | 12 Units on a scale | Standard Deviation 23.856 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 42 | 12.88 Units on a scale | Standard Deviation 23.789 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 3 | 4.27 Units on a scale | Standard Deviation 18.38 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 48 | 9.17 Units on a scale | Standard Deviation 18.612 |
| Velcade, Melphalan and Prednisone (VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 18 | 10.75 Units on a scale | Standard Deviation 21.146 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 48 | 11.93 Units on a scale | Standard Deviation 24.031 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 3 | 9.37 Units on a scale | Standard Deviation 20.222 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 6 | 11.02 Units on a scale | Standard Deviation 20.168 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 9 | 12.51 Units on a scale | Standard Deviation 20.564 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 12 | 10.93 Units on a scale | Standard Deviation 20.447 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 18 | 15.35 Units on a scale | Standard Deviation 21.168 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 24 | 12.17 Units on a scale | Standard Deviation 22.592 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 30 | 14.41 Units on a scale | Standard Deviation 21.305 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 42 | 14.33 Units on a scale | Standard Deviation 21.502 |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS) | Month 36 | 13.94 Units on a scale | Standard Deviation 21.984 |
Secondary
Duration of Response (DOR)
DOR: participants with confirmed response (PR or better) as time between first documentation of response and disease progression per IMWG response criteria, or death due to PD, whichever occurs first. PD: Increase of 25% from lowest response value in any one of following: Serum M-component (absolute increase\>=0.5 g/dL); Urine M-component (absolute increase\>=200 mg/24 hours); Only participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10mg/dL); Only participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC%(absolute%\>=10%); Bone marrow PC's %: absolute%\>10%; Definite development of new bone lesions/soft tissue plasmacytomas/definite increase in the size of existing bone lesions or soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
Time frame: From first documentation of response up to 2.4 years
Population: Response-evaluable set: participants who have a confirmed diagnosis of MM and measurable disease at baseline or screening. Participants must have received at least one component of study treatment and have adequate post-baseline disease assessments. Here 'N'(overall number of participants analyzed) signifies number of participants evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Duration of Response (DOR) | 21.3 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Duration of Response (DOR) | NA Months |
Secondary
Overall Response Rate (ORR)
The Overall response rate was defined as the percentage of participants who achieved a partial response (PR) or better, according to the International Myeloma Working Group (IMWG) criteria, during the study or during follow up. IMWG criteria for PR: greater than or equal to (\>=) 50 percentage (%) 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, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%, in addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was also required.
Time frame: From randomization (Day -3) up to 2.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Overall Response Rate (ORR) | 73.9 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Overall Response Rate (ORR) | 90.9 Percentage of participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) was measured from the date of randomization to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method.
Time frame: From randomization (Day -3) up to 8.3 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Overall Survival (OS) | 53.59 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Overall Survival (OS) | 82.96 Months |
Secondary
Percentage of Participants With Best M-protein Response
Percentage of participants with Best M- protein response of 100% reduction and \>=90% to \< 100% reduction were assessed. Best M-protein response was defined as the maximal percent reduction or the lowest percent increase from baseline in serum M-protein for participants with measurable heavy chain at baseline or urine M-protein for participants without measurable heavy chain, but with measurable light chain disease at baseline. For participants without measurable heavy chain and light chain disease at baseline, best response in serum free light chain (FLC) was defined as the maximal percent reduction or the lowest percent increase from baseline in the difference between involved and uninvolved serum FLC level (dFLC).
Time frame: Up to 2.4 years
Population: Response-evaluable set: participants have confirmed diagnosis of MM and measurable disease at baseline or screening. Participants must receive at least one component of study treatment, have adequate post-baseline disease assessments. Here, 'n' (number analyzed) signifies number of participants analyzed for each specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in serum: 100% reduction | 38.7 Percentage of participants |
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in serum:>= 90 to < 100% | 14.6 Percentage of participants |
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in urine:100% reduction | 69.4 Percentage of participants |
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in urine:>=90 to < 100% | 13.9 Percentage of participants |
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best response in dFLC:100% reduction | 0 Percentage of participants |
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Best M-protein Response | Best response in dFLC: >=90% to < 100% reduction | 77.8 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best response in dFLC:100% reduction | 0 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in serum: 100% reduction | 58.5 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in urine:>=90 to < 100% | 7.1 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in serum:>= 90 to < 100% | 15.2 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best response in dFLC: >=90% to < 100% reduction | 100.0 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Best M-protein Response | Best M-protein response in urine:100% reduction | 90.5 Percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR) or Better
CR or better rate was defined as the percentage of participants with a CR or better (i.e. CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (\<) 5 percent plasma cells in bone marrow; sCR: CR plus normal free light chain (FLC) ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Time frame: From randomization (Day -3) up to 2.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Complete Response (CR) or Better | 24.4 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Complete Response (CR) or Better | 42.6 Percentage of participants |
Secondary
Percentage of Participants With Negative Minimal Residual Disease (MRD)
The Minimal Residual Disease negativity rate was defined as the percentage of participants who had negative MRD (detection of less than 1 malignant cell among 100,000 normal cells) assessment at any timepoint after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood at 10\^-5 threshold. MRD was evaluated by using Deoxyribonucleic acid (DNA) sequencing of immunoglobulin genes. MRD was assessed in participants who achieved complete response or stringent complete response (CR/sCR).
Time frame: From randomization (Day -3) up to 8.3 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Negative Minimal Residual Disease (MRD) | 7.0 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Negative Minimal Residual Disease (MRD) | 28.3 Percentage of participants |
Secondary
Percentage of Participants With Stringent Complete Response (sCR)
sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. CR: Negative immunofixation on the serum and urine; Disappearance of any soft tissue plasmacytomas; \<5% plasma cells (PCs) in bone marrow.
Time frame: From randomization (Day -3) up to 2.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Stringent Complete Response (sCR) | 7.0 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Stringent Complete Response (sCR) | 18.0 Percentage of participants |
Secondary
Percentage of Participants With Very Good Partial Response (VGPR) or Better
VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response\[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level less than (\<) 100 milligram (mg) per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \< 5% plasms cells (PCs) in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
Time frame: From randomization (Day -3) up to 2.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Percentage of Participants With Very Good Partial Response (VGPR) or Better | 49.7 Percentage of participants |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Percentage of Participants With Very Good Partial Response (VGPR) or Better | 71.1 Percentage of participants |
Secondary
Progression Free Survival on Next Line of Therapy (PFS2)
Progression-free survival after next-line therapy is defined as the time from randomization to progression on the next line of subsequent antimyeloma therapy or death due to any cause (prior to start of second line of antimyeloma therapy), whichever comes first. Disease progression on next line of treatment was based on investigator judgment.
Time frame: From randomization (Day -3) up to 8.3 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Progression Free Survival on Next Line of Therapy (PFS2) | 42.41 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Progression Free Survival on Next Line of Therapy (PFS2) | 66.73 Months |
Secondary
Time to Disease Progression (TTP)
TTP: Time from date of randomization to date of first documented evidence of PD or death due to PD, whichever occurs first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cells (PC)% (absolute % \>=10%); Bone marrow PC %: absolute % \>10%; Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder.
Time frame: From randomization (Day -3) up to 2.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Time to Disease Progression (TTP) | 19.35 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Time to Disease Progression (TTP) | NA Months |
Secondary
Time to Next Treatment (TNT)
Time to next treatment is defined as the time from randomization to the start of the next-line treatment. Kaplan-Meier method was used for the analysis.
Time frame: From randomization (Day -3) up to 8.3 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Time to Next Treatment (TNT) | 25.9 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Time to Next Treatment (TNT) | 66.8 Months |
Secondary
Time to Response
Time to response, defined as the time between the date of randomization and the first efficacy evaluation that the participant has met all criteria for PR or better. 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, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was also required.
Time frame: From randomization (Day -3) up to 2.4 years
Population: Response-evaluable population: participants who have a confirmed diagnosis of MM and measurable disease at baseline or screening, must receive at least one component of study treatment and have adequate post-baseline disease assessments. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Time to Response | 0.82 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Time to Response | 0.79 Months |
Post Hoc
Progression Free Survival at Data Cutoff Date of 24 June 2019
PFS: duration from date of randomization to PD/death, whichever occurs first. PD per IMWG criteria-Increase of 25% from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 mg/dL); Only participants without measurable serum and urine M-protein levels, without measurable disease by FLC levels, bone marrow PC %(absolute % \>=10%); Bone marrow PC %: absolute % \>10 %; Definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas and development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder.
Time frame: From randomization (Day -3) up to 4.4 years
Population: ITT population included all participants randomized into the study; classified according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade, Melphalan and Prednisone (VMP) | Progression Free Survival at Data Cutoff Date of 24 June 2019 | 19.29 Months |
| Daratumumab, Velcade, Melphalan and Prednisone (D-VMP) | Progression Free Survival at Data Cutoff Date of 24 June 2019 | 36.40 Months |