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
- Multiple myeloma10024324
- Registration Number
- NL-OMON52378
- Lead Sponsor
- European Myeloma Network
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 75
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 <40mL/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/dL4. Bone lesions: one or more osteolytic lesions on skeletal
radiography, CT, or PET-CTBiomarkers of Malignancy:a. Clonal bone marrow plasma
cell percentage >=60%b. Involved: uninvolved serum FLC ratio >=100c. >1 focal
lesion on magnetic resonance imaging (MRI) studies3. Measurable disease as
defined by any of the following:a. Serum monoclonal paraprotein (M-protein)
level >=1.0 g/dL or urine M-protein level >=200 mg/24 hours; orb. 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
ratio4. Newly diagnosed subjects for whom high-dose therapy and autologous stem
cell transplantation is part of the intended treatment plan.5. Eastern
Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 26.
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:a. 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);b. Absolute
neutrophil count (ANC) >=1.0 x 109/L (G-CSF use is permitted);c. Platelet count
>=50 x 109/L if bone marrow is >50% involved in myeloma. Otherwise >=75 x
109/LAdequate liver function:a. Aspartate aminotransferase (AST) <=2.5 x ULN;b.
Alanine aminotransferase (ALT) <=2.5 x ULN;c. 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:a. Estimated creatinine clearance
>=30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, eGFR
(MDRD), or CKD-epi formulab. 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 or 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, vagi
1. Prior or current systemic therapy or 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:a.
Seropositive for human immunodeficiency virus (HIV)b. Seropositive for
hepatitis B (defined by a positive test for hepatitis B surface antigen
[HBsAg]). c. Seropositive for hepatitis C (anti-HCV antibody positive or
HCV-RNA quantitation positive), except in the setting of a sustained virologic
response (SVR), defined as aviremia at least 12 weeks after completion of
antiviral therapy.10. Concurrent medical or psychiatric condition or disease
(eg, 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:
a. 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)b. uncontrolled cardiac arrhythmia or clinically significant
electrocardiogram (ECG) abnormalitiesc. screening 12-lead ECG showing a
baseline QT interval >470 msecd. left ventricular ejection fraction (LVEF)
<40% for subjects age 65-70 years old12. Received a strong CYP3A4 inducer
within 5 half-lives prior to randomization(Flockhart 2016:
http://medicine.iupui.edu/flockhart/)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 i
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary objective is to determine if the addition of daratumumab to<br /><br>bortezomib, lenalidomide, and dexamethasone (VRd) will prolong progression-free<br /><br>survival (PFS) defined as the time from the date of randomization to the date<br /><br>of disease progression (assessed by International Myeloma Working Group [IMWG]<br /><br>criteria) or death, compared with VRd alone.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Key secondary objectives include the following:<br /><br>• To determine if the addition of daratumumab to VRd will improve clinical<br /><br>outcome as measured by:<br /><br>* Minimal residual disease (MRD) negativity rate post-consolidation and overall<br /><br>MRD negativity rate<br /><br>achieved at any time during the study<br /><br>* Overall response rate (ORR), rate of very good partial response (VGPR) or<br /><br>better, rate of complete<br /><br>response (CR) or better, rate of stringent CR (sCR) at post-induction,<br /><br>post-transplant,<br /><br>post-consolidation, and overall<br /><br>* Time to response<br /><br>* Duration of response<br /><br>* Progression-free survival on the next line of therapy (PFS2)<br /><br>* Overall survival (OS)<br /><br>• To assess the safety profile of daratumumab+VRd (D-VRd)</p><br>