Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Previously Untreated Multiple Myeloma Who Are Eligible for High-dose Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab
* Drug: velcade
* Drug: Lenalidomide
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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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: 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) Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL) Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL 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: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or 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: 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); Absolute neutrophil count (ANC) ≥1.0 x 109/L (granulocyte-colony stimulating factor (G-CSF) use is permitted); Platelet count ≥50 x 109/L if bone marrow is >50% involved in myeloma. Otherwise ≥75 x 109/L Adequate liver function: Aspartate aminotransferase (AST) ≤2.5 x ULN; Alanine aminotransferase (ALT) ≤2.5 x ULN; 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: 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 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: 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. 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. 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). Radiation therapy within 14 days of randomization. Plasmapheresis within 28 days of randomization. Clinical signs of meningeal involvement of multiple myeloma. 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%) 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). Any of the following: Seropositive for human immunodeficiency virus (HIV) 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). 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. 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. Any of the following: 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) uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities screening 12-lead ECG showing a baseline QT interval >470 msec left ventricular ejection fraction (LVEF) <40% for subjects age 65-70 years old Received a strong CYP3A4 inducer within 5 half-lives prior to randomization 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. 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. 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. 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. 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. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information. Gastrointestinal disease that may significantly alter the absorption of oral drugs Vaccination with live attenuated vaccines within 4 weeks of first study agent administration Unable or unwilling to undergo antithrombotic prophylactic treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Velcade Lenalidomide dexamethasone (VRd)<br>VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity. | Drug: velcade<br>* 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.<br>* Other names: bortezomib;Drug: Lenalidomide<br>* 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.<br>Drug: dexamethasone<br>* 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.<br>|
| Experimental: Daratumumab + VRd (D-VRd)<br>D-VRd: Subjects will receive D-VRd for induction and consolidation followed by daratumumab and lenalidomide maintenance until disease progression or unacceptable toxicity. Minimal residual disease (MRD)-negative subjects in Arm B will stop therapy with daratumumab after sustained MRD negativity for 12 months and after a minimum of 24 months of maintenance therapy. These subjects will continue lenalidomide maintenance therapy until disease progression or unacceptable toxicity. After stopping daratumumab therapy, subjects with sustained MRD negativity should restart therapy with daratumumab if there is a recurrence of MRD or a confirmed loss of Complete Response (CR) without International Myeloma Working Group (IMWG)-defined disease progression. After reinitiating daratumumab, the subject will continue daratumumab and lenalidomide therapy until disease progression or unacceptable toxicity. | Drug: Daratumumab<br>* 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.<br>* Other names: dexamethasone;Drug: velcade<br>* 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.<br>* Other names: bortezomib;Drug: Lenalidomide<br>* 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.<br>Drug: dexamethasone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization to the date of disease progression (as assessed by IMWG criteria) or death due to any cause, whichever occurs first. | from randomization to the date of disease progression or death (approximately up to 9 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-consolidation MRD negativity rate, | Post-consolidation MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (at or below the threshold of 10-5) at the end of consolidation. | at the end of consolidation, average of 9 months | 
| Overall Response Rate (ORR) | Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieve PR or better (or VGPR or better, or CR or better, or sCR) per the IMWG criteria at post-induction, post-transplant, post-consolidation, and overall. | post-induction (approx 4 months), post-transplant (approximately 7 months), post-consolidation (approximately 9 months), and overall assessed up to approximately 9 years | 
| 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. | the time from randomization to progression on the next line of treatment or death, whichever comes first., assessed up to 9 years | 
| Overall Survival (OS) | Overall Survival (OS), measured from the date of from randomization to the date the subject's death | from the date of from randomization to the date the subject's death, assessed up to 9 years | 
| 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) | every 4 weeks up to 2 years, every 8 weeks up to 9 years | 
| 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. | 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 | Pharmacokinetic concentrations of daratumumab | cycle 1 Day 1&4, Cycle 3 day 1&4, Cycle 4 day 15, cycle 5 day 1&4, cycle 7,9&12 day 1, post treatment week 8 (each cycle is 28 days) | 
| 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 | cycle 1,4,5,7&12 day 1, post treatment week 8 (each cycle is 28 days) | 
| 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. | Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy. | 
| 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. | Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy. | 
| 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 | Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy. | 
| Stem cell yield after mobilization |  | after mobilization, average of 5 months | 
| 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 | post-ASCT, average of 7 months |