Multiple Myeloma
Conditions
Brief summary
Background of the study: The combination of daratumumab with VRd is anticipated to further improve response rates in patients and may lead to improved long-term outcomes in newly diagnosed patients with multiple myeloma. Given this potential, and based upon the initial safety and efficacy observed in the ongoing Phase 2 Study MMY2004, as well as continued positive results with daratumumab in various disease settings and combination regimens, this Phase 3 study is designed to demonstrate improved outcomes for patients treated with daratumumab+VRd. The Phase 3 study will utilize the subcutaneous (SC) formulation of daratumumab instead of the IV formulation utilized in the Phase 2 study, which may limit additional toxicity to patients treated with the quadruplet regimen.
Interventions
DRUGDaratumumab
Daratumumab will be given at a dose of 1800 mg SC weekly in Cycles 1 and 2, then every 2 weeks in Cycles 3-6. In maintenance Cycles 7+, subjects will receive daratumumab once every 4 weeks until disease progression or unacceptable toxicity. MRD-negative subjects will stop daratumumab after sustained MRD negativity for 12 months \& after a min. of 24 months of maintenance. Daratumumab should be restarted at recurrence of MRD or confirmed loss of CR without disease progression.
DRUGVelcade
Bortezomib will be given at a dose of 1.3 mg/m2 SC twice a week (Days 1, 4, 8, and 11) in Cycles 1-6; four 28-day induction cycles (Cycles 1 to 4), and two 28-day consolidation cycles (Cycles 5-6). Subjects will not receive bortezomib after Cycle 6. On treatment days when both bortezomib and daratumumab are administered, bortezomib must be administered after the daratumumab administration.
DRUGLenalidomide
Lenalidomide will be administered PO at 25 mg on Days 1 to 21 in Cycles 1-6; four 28-day induction cycles and two 28-day consolidation cycles. Following consolidation, subjects will then start maintenance therapy, during which they will receive lenalidomide 10 mg daily PO on Days 1 to 28 (continuously) of each 28-day cycle until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily, at the discretion of the investigator.
DRUGdexamethasone
Dexamethasone will be administered PO at 40 mg daily on Days 1-4 and Days 9-12 of each 28-day cycle during induction and consolidation (Cycles 1-6). On daratumumab administration days, during induction/consolidation, dexamethasone may be administered intravenously 1 hour before the daratumumab administration. On days when daratumumab is not administered, dexamethasone is administered PO. Dexamethasone tablets are to be taken with or immediately after a meal or snack, preferably in the morning.
Sponsors
Stichting European Myeloma Network
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1.18 to 70 years of age, inclusive. 2.Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: CRAB criteria: 1. Hypercalcemia: serum calcium \>0.25 mmol/L (\>1 mg/dL) higher than upper limit of normal (ULN) or \>2.75 mmol/L (\>11 mg/dL) 2. Renal insufficiency: creatinine clearance \<40 mL/min or serum creatinine \>177 μmol/L (\>2 mg/dL) 3. Anemia: hemoglobin \>2 g/dL below the lower limit of normal or hemoglobin \<10 g/dL 4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or Positron-emission tomography (PET)-CT Biomarkers of Malignancy: a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum free light chain (FLC) ratio ≥100 c. \>1 focal lesion on magnetic resonance imaging (MRI) studies 3.Measurable disease as defined by any of the following: 1. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or 2. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio 4.Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation (ASCT) is part of the intended treatment plan. 5.Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 6.Clinical laboratory values meeting the following criteria during the Screening Phase (Screening hematology and chemistry tests should be repeated if done more than 3 days before C1D1): Adequate bone marrow function: 1. Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted however transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count); 2. Absolute neutrophil count (ANC) ≥1.0 x 109/L (granulocyte-colony stimulating factor (G-CSF) use is permitted); 3. Platelet count ≥50 x 109/L if bone marrow is \>50% involved in myeloma. Otherwise ≥75 x 109/L Adequate liver function: 1. Aspartate aminotransferase (AST) ≤2.5 x ULN; 2. Alanine aminotransferase (ALT) ≤2.5 x ULN; 3. Total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤1.5 x ULN) Adequate renal function: 1. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, estimated Glomerular filtration rate (eGFR) (Modified Diet in Renal Disease (MDRD)), or Chronic Kidney Disease (CKD)-epi formula 2. Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L) 7\. Female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device (IUD), 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 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy. 8\. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing. 9\. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen. 10\. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy). 11\. Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment. 12\. Signed an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. 13\. Able to adhere to the prohibitions and restrictions specified in this protocol
Exclusion criteria
1. Prior or current systemic therapy or stem cell transplant (SCT) for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment. 2. 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 5. 3. Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion 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). 4. Radiation therapy within 14 days of randomization. 5. Plasmapheresis within 28 days of randomization. 6. Clinical signs of meningeal involvement of multiple myeloma. 7. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) \<50% of predicted normal (for subjects ≥65 years old FEV1 \<50% or diffusing capacity of the lungs for carbon monoxide \[DLCO\] \<50%) 8. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study). 9. Any of the following: 1. Seropositive for human immunodeficiency virus (HIV) 2. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (ie, subjects who are positive for antibodies to hepatitis B core antigen \[antiHBc\] and/or antibodies to hepatitis B surface antigen \[antiHBs\]) must be screened using real-time PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by polymerase chain reaction (PCR). 3. Seropositive for hepatitis C (HCV) (anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as viremia at least 12 weeks after completion of antiviral therapy. 10. Concurrent medical or psychiatric condition or disease (such as but not limited to, systemic amyloidosis, POEMS, 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. 11. Any of the following: 1. myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV) 2. uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities 3. screening 12-lead ECG showing a baseline QT interval \>470 msec 4. left ventricular ejection fraction (LVEF) \<40% for subjects age 65-70 years old 12. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization 13. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or sensitivity to mammalian-derived products or lenalidomide. 14. Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. 15. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. 16. Major surgery within 2 weeks before randomization or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery. 17. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study. 18. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information. 19. Gastrointestinal disease that may significantly alter the absorption of oral drugs 20. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration 21. Unable or unwilling to undergo antithrombotic prophylactic treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From the date of randomization to either progressive disease or death whichever occurred first, up to a maximum follow-up time of 54.41 months. | PFS was defined as duration from date of randomization to either progressive disease (PD)/death whichever occurred first. PD was defined as meeting any one of the following criteria: Increase of \>= 25 % in level of serum M-protein form lowest response value and absolute increase must be \>= 0.5 g/dL; Increase of \>=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be \>=200 mg/24 hours; Only in participants without measurable serum and urine M-protein levels; increase of \>=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be \> 10 mg/dL; 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) that can be attributed solely to PC proliferative disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall MRD Negativity Rate | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months. | Overall MRD-negativity rate was defined as the percentage of participants in the ITT population who achieved both MRD-negativity by NGS (at or below a sensitivity threshold of 10-5) in bone marrow aspirate and a CR or better response at any time after the date of randomization (and prior to disease progression, receipt of subsequent therapy, or both). |
| Percentage of Participants With Overall Response Rate (ORR) | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | ORR- percentage of participants who achieved partial response (PR) or better (PR, Very Good Partial Response \[VGPR\], CR or sCR) based on computerized algorithm as per IMWG 2011 criteria. PR -greater than or equal to (\>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to \<200 mg//24 hours. If serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required. A \>=50% reduction in the size of soft tissue plasmacytomas is also required; 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 the serum and urine, and disappearance of any soft tissue plasmacytomas, and \<5% PCs in bone marrow. sCR- in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry. |
| Percentage of Participants With Overall Complete Response (CR) or Better | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Percentage of participants achieving CR or better were reported. CR or better rate was defined as the percentage of participants achieving CR or sCR based on the computerized algorithm, according to IMWG response criteria. IMWG 2011 criteria for CR: Negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas (PCs), and \<5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry. |
| Progression-free Survival on the Next Line of Therapy (PFS2) | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. |
| Overall Survival (OS) | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Overall Survival (OS), measured from the date of from randomization to the date the subject's death |
| Time to Response | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Time to response (PR or better), time to CR/sCR are defined as the time from randomization to date of initial response (or initial CR/sCR) |
| Duration of Response | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD-negative status, are calculated from the date of the initial documentation of a response (PR or better), or CR or better, or sCR, or MRD-negative status to the date of the first documented evidence of disease progression, as defined in the IMWG criteria, whichever occurs first. |
| Pharmacokinetic Concentrations of Daratumumab | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Pharmacokinetic concentrations of daratumumab |
| Determine the Incidence of Anti-daratumumab Antibodies (Immunogenicity) for All Subjects Who Receive at Least 1 Dose of Daratumumab and Determine the Incidence of Anti-rHuPH20 Antibodies | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | Immunogenicity of daratumumab serum samples will be screened for antibodies binding to daratumumab and serum titer will also be determined from confirmed positive samples using validated immunoassay methods. Other immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to further characterize the immune responses that are generated. Plasma samples will be screened for antibodies binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary |
| Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module (EORTC QLQ-C30) Score and the Difference Between-treatment Arms | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | The EORTC QLQ-C30 is a 30-item questionnaire containing both single and multi-item measures. These include five functional scales (Physical, Role, Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a Global Health Status/ Quality-of-Life (QoL) scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). The scores ranges from 0-100, a high score for functional scales and for Global Health Status/QoL represent better functioning ability or Health-Related Quality-of-Life (HRQoL), whereas a high score for symptom scales and single items represents significant symptomatology. |
| Change in EORTC QLQ- 20-item Multiple Myeloma Module (MY-20) Score and the Difference Between-treatment Arms | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | The EORTC QLQ-MY20 is a supplement to the QLQ-C30 instrument used in subjects with MY. The module comprises 20 questions that address four myeloma-specific HRQoL domains: Disease Symptoms, Side Effects of Treatment, Future Perspective, and Body Image. A high score for Disease Symptoms and Side Effects of Treatment represents a high level of symptomatology or problems, whereas a high score for Future Perspective and Body Image represents better outcomes. |
| EQ-5D-5L Health Utility Values and the Difference Between-treatment Arms | From randomization to the clinical cutoff date. Maximum follow up was 54.41 months | The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self care, usual activities, pain/discomfort, and anxiety/depression plus a visual analog scale rating "health today" |
| Stem Cell Yield After Mobilization | From randomization to the clinical cutoff date. | Median CD34+ cell yield |
| Time to Engraftment Post-ASCT | From randomization to the clinical cutoff date. | Time to engraftment post-ASCT defined as absolute neutrophil count (ANC) ≥0.5 x 109/L and platelet count ≥20 x 109/L |
Countries
Australia, Belgium, Czechia, Denmark, France, Greece, Italy, Netherlands, Norway, Poland, Spain, Switzerland, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Velcade Lenalidomide Dexamethasone (VRd) Arm A: Patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation were treated with h bortezomib, lenalidomide, and dexamethasone for induction and consolidation followed by lenalidomide maintenance in 28-day cycles. After 4 cycles of induction, patients received high dose therapy with autologous stem cell transplantation. | 354 |
| Daratumumab + VRd (D-VRd) Arm B: Patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation were treated with subcutaneous daratumumab in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation followed by subcutaneous daratumumab in combination with lenalidomide maintenance in 28-day cycles. After 4 cycles of induction, patients received high dose therapy with autologous stem cell transplantation. | 355 |
| Total | 709 |
Baseline characteristics
| Characteristic | Velcade Lenalidomide Dexamethasone (VRd) | Total | Daratumumab + VRd (D-VRd) |
|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 8.12 | 58.4 years STANDARD_DEVIATION 7.96 | 58.7 years STANDARD_DEVIATION 7.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 50 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 254 Participants | 496 Participants | 242 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 80 Participants | 163 Participants | 83 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 10 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 9 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 19 Participants | 47 Participants | 28 Participants |
| Race/Ethnicity, Customized Other | 82 Participants | 165 Participants | 83 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 243 Participants | 478 Participants | 235 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 10 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 30 Participants | 12 Participants |
| Race (NIH/OMB) White | 323 Participants | 653 Participants | 330 Participants |
| Region of Enrollment Australia | 38 participants | 72 participants | 34 participants |
| Region of Enrollment Belgium | 10 participants | 17 participants | 7 participants |
| Region of Enrollment Czechia | 4 participants | 5 participants | 1 participants |
| Region of Enrollment Denmark | 9 participants | 19 participants | 10 participants |
| Region of Enrollment France | 70 participants | 153 participants | 83 participants |
| Region of Enrollment Germany | 2 participants | 7 participants | 5 participants |
| Region of Enrollment Greece | 27 participants | 59 participants | 32 participants |
| Region of Enrollment Italy | 86 participants | 150 participants | 64 participants |
| Region of Enrollment Netherlands | 27 participants | 57 participants | 30 participants |
| Region of Enrollment Norway | 7 participants | 9 participants | 2 participants |
| Region of Enrollment Poland | 6 participants | 14 participants | 8 participants |
| Region of Enrollment Spain | 49 participants | 102 participants | 53 participants |
| Region of Enrollment Switzerland | 5 participants | 12 participants | 7 participants |
| Region of Enrollment Turkey | 14 participants | 33 participants | 19 participants |
| Sex: Female, Male Female | 149 Participants | 293 Participants | 144 Participants |
| Sex: Female, Male Male | 205 Participants | 416 Participants | 211 Participants |
| Stage of Disease (ISS) I | 178 Participants | 364 Participants | 186 Participants |
| Stage of Disease (ISS) II | 125 Participants | 239 Participants | 114 Participants |
| Stage of Disease (ISS) III | 50 Participants | 105 Participants | 55 Participants |
| Stage of Disease (ISS) unknown | 1 Participants | 1 Participants | 0 Participants |
| Time Since Initial Diagnosis (months) | 3 months STANDARD_DEVIATION 11.41 | 2.6 months STANDARD_DEVIATION 8.66 | 2.2 months STANDARD_DEVIATION 4.46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 354 | 34 / 355 |
| other Total, other adverse events | 341 / 347 | 348 / 351 |
| serious Total, serious adverse events | 171 / 347 | 200 / 351 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as duration from date of randomization to either progressive disease (PD)/death whichever occurred first. PD was defined as meeting any one of the following criteria: Increase of \>= 25 % in level of serum M-protein form lowest response value and absolute increase must be \>= 0.5 g/dL; Increase of \>=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be \>=200 mg/24 hours; Only in participants without measurable serum and urine M-protein levels; increase of \>=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be \> 10 mg/dL; 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) that can be attributed solely to PC proliferative disorder.
Time frame: From the date of randomization to either progressive disease or death whichever occurred first, up to a maximum follow-up time of 54.41 months.
Population: Randomized population, intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Velcade Lenalidomide Dexamethasone (VRd) | Progression Free Survival (PFS) | 103 Participants |
| Daratumumab + VRd (D-VRd) | Progression Free Survival (PFS) | 50 Participants |
Secondary
Change in EORTC QLQ- 20-item Multiple Myeloma Module (MY-20) Score and the Difference Between-treatment Arms
The EORTC QLQ-MY20 is a supplement to the QLQ-C30 instrument used in subjects with MY. The module comprises 20 questions that address four myeloma-specific HRQoL domains: Disease Symptoms, Side Effects of Treatment, Future Perspective, and Body Image. A high score for Disease Symptoms and Side Effects of Treatment represents a high level of symptomatology or problems, whereas a high score for Future Perspective and Body Image represents better outcomes.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module (EORTC QLQ-C30) Score and the Difference Between-treatment Arms
The EORTC QLQ-C30 is a 30-item questionnaire containing both single and multi-item measures. These include five functional scales (Physical, Role, Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a Global Health Status/ Quality-of-Life (QoL) scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). The scores ranges from 0-100, a high score for functional scales and for Global Health Status/QoL represent better functioning ability or Health-Related Quality-of-Life (HRQoL), whereas a high score for symptom scales and single items represents significant symptomatology.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Determine the Incidence of Anti-daratumumab Antibodies (Immunogenicity) for All Subjects Who Receive at Least 1 Dose of Daratumumab and Determine the Incidence of Anti-rHuPH20 Antibodies
Immunogenicity of daratumumab serum samples will be screened for antibodies binding to daratumumab and serum titer will also be determined from confirmed positive samples using validated immunoassay methods. Other immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to further characterize the immune responses that are generated. Plasma samples will be screened for antibodies binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Duration of Response
Duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD-negative status, are calculated from the date of the initial documentation of a response (PR or better), or CR or better, or sCR, or MRD-negative status to the date of the first documented evidence of disease progression, as defined in the IMWG criteria, whichever occurs first.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
EQ-5D-5L Health Utility Values and the Difference Between-treatment Arms
The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self care, usual activities, pain/discomfort, and anxiety/depression plus a visual analog scale rating health today
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Overall MRD Negativity Rate
Overall MRD-negativity rate was defined as the percentage of participants in the ITT population who achieved both MRD-negativity by NGS (at or below a sensitivity threshold of 10-5) in bone marrow aspirate and a CR or better response at any time after the date of randomization (and prior to disease progression, receipt of subsequent therapy, or both).
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months.
Population: Randomized population, intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Velcade Lenalidomide Dexamethasone (VRd) | Overall MRD Negativity Rate | 168 Participants |
| Daratumumab + VRd (D-VRd) | Overall MRD Negativity Rate | 267 Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS), measured from the date of from randomization to the date the subject's death
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Percentage of Participants With Overall Complete Response (CR) or Better
Percentage of participants achieving CR or better were reported. CR or better rate was defined as the percentage of participants achieving CR or sCR based on the computerized algorithm, according to IMWG response criteria. IMWG 2011 criteria for CR: Negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas (PCs), and \<5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Population: The intent-to-treat (ITT) population included all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade Lenalidomide Dexamethasone (VRd) | Percentage of Participants With Overall Complete Response (CR) or Better | 70.1 percentage of participants with response |
| Daratumumab + VRd (D-VRd) | Percentage of Participants With Overall Complete Response (CR) or Better | 87.9 percentage of participants with response |
Secondary
Percentage of Participants With Overall Response Rate (ORR)
ORR- percentage of participants who achieved partial response (PR) or better (PR, Very Good Partial Response \[VGPR\], CR or sCR) based on computerized algorithm as per IMWG 2011 criteria. PR -greater than or equal to (\>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to \<200 mg//24 hours. If serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required. A \>=50% reduction in the size of soft tissue plasmacytomas is also required; 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 the serum and urine, and disappearance of any soft tissue plasmacytomas, and \<5% PCs in bone marrow. sCR- in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Population: The intent-to-treat (ITT) population included all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade Lenalidomide Dexamethasone (VRd) | Percentage of Participants With Overall Response Rate (ORR) | 93.8 percentage of participants with response |
| Daratumumab + VRd (D-VRd) | Percentage of Participants With Overall Response Rate (ORR) | 96.6 percentage of participants with response |
Secondary
Pharmacokinetic Concentrations of Daratumumab
Pharmacokinetic concentrations of daratumumab
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Progression-free Survival on the Next Line of Therapy (PFS2)
Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first.
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months
Secondary
Stem Cell Yield After Mobilization
Median CD34+ cell yield
Time frame: From randomization to the clinical cutoff date.
Secondary
Time to Engraftment Post-ASCT
Time to engraftment post-ASCT defined as absolute neutrophil count (ANC) ≥0.5 x 109/L and platelet count ≥20 x 109/L
Time frame: From randomization to the clinical cutoff date.
Secondary
Time to Response
Time to response (PR or better), time to CR/sCR are defined as the time from randomization to date of initial response (or initial CR/sCR)
Time frame: From randomization to the clinical cutoff date. Maximum follow up was 54.41 months