| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
to determine if the addition of daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) will prolong progression-free survival (PFS) defined as the time from the date of randomization to the date of disease progression (assessed by International Myeloma Working Group [IMWG] criteria) or death, compared with VRd alone.
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| E.2.2 | Secondary objectives of the trial |
Key secondary objectives include the following:
• To determine if the addition of daratumumab to VRd will improve clinical outcome as measured by:
− Minimal residual disease (MRD) negativity rate post-consolidation and overall MRD negativity rate achieved at any time during the study
− Overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR) at post-induction, post-transplant, post-consolidation, and overall
− Time to response
− Duration of response
− Progression-free survival on the next line of therapy (PFS2)
− Overall survival (OS)
• To assess the safety profile of daratumumab+VRd (D-VRd)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <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/dL
4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
Biomarkers of Malignancy:
a. Clonal bone marrow plasma cell percentage ≥60%
b. Involved: uninvolved serum FLC ratio ≥100
c. >1 focal lesion on magnetic resonance imaging (MRI) studies
3. 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; or
b. 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 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:
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/L
Adequate 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 formula
b. 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, 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. For requirements during the Treatment Phase
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. Subjects in emergency situations that do not
allow for collection of informed consent are excluded.
13. Able to adhere to the prohibitions and restrictions specified in this protocol
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| E.4 | Principal exclusion criteria |
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 for treatment of plasmacytoma within 14 days of
randomization.
5. Plasmapheresis within 28 days of randomization.
6. Clinical signs of meningeal involvement of multiple myeloma.
7. a. Subjects <65 years old with chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
7. b. Subjects ≥65 years old with a 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. Known to be seropositive for human immunodeficiency virus (HIV)
b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).
c. Known to be seropositive for hepatitis C 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
c. screening 12-lead ECG showing a baseline QT interval >470 msec (exception: subjects with pacemaker)
d. screening ECHO or MUGA scan for subjects aged >65-70: left ventricular ejection fraction (LVEF) <40%
12. 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 or its excipients.
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 or 5 half-lives of the respective drug/investigational medicinal product (IMP)
(whichever is longer) 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS (progression-free survival) is defined as the time from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For the entire duration of the study. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
• 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.
• Overall MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (10^-5) at any time during the study.
• Overall ORR, rate of VGPR or better, rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieved 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-consolidation ORR, rate of VGPR or better rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieved PR or better (or VGPR or better, or CR or better, or sCR) by the end of consolidation per the IMWG criteria.
• 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.
• OS, measured from the date of from randomization to the date the subject's death.
• 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 (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, or
death due to PD, whichever occurs first.
• Pharmacokinetic concentrations of daratumumab
• Immunogenicity of daratumumab and rHuPH20
• Change in health-related quality of life, symptoms, and functioning using two European Organization for Research and Treatment of Cancer (EORTC) questionnaires and the EuroQol Group Five Dimensions Five Levels Questionnaires (EQ-5D-5L)
• Stem cell yield after mobilization
• Time to engraftment post-ASCT defined as absolute neutrophil count (ANC) ≥0.5 x 10^9/L and platelet count ≥20 x 10^9/L
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For the entire duration of the study. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 121 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Australia |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Türkiye |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study is considered completed when 310 deaths have been observed or 9 years have elapsed after the last subject is randomized or when the sponsor decides to stop the study (whichever occurs earlier). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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