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

Phase 3

Active, not recruiting

• Conditions: Multiple Myeloma
• Interventions: Drug: Velcade; Drug: Daratumumab; Drug: Lenalidomide; Drug: dexamethasone

• Registration Number: NCT03710603
• Lead Sponsor: Stichting European Myeloma Network

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-10-08
• Study First Submitted QC: 2018-10-15
• Study First Posted: 2018-10-18
• Study Start: 2018-12-14
• Primary Completion: 2023-08-01
• Results First Submitted: 2024-09-01
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-16
• Last Update Submitted: 2024-12-16
• Results First Posted: 2024-12-24
• Last Update Posted: 2024-12-24
• Study Completion: 2029-11

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 709

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Velcade Lenalidomide dexamethasone (VRd)	Velcade	VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity.
Daratumumab + VRd (D-VRd)	Velcade	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.
Velcade Lenalidomide dexamethasone (VRd)	Lenalidomide	VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity.
Velcade Lenalidomide dexamethasone (VRd)	dexamethasone	VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity.
Daratumumab + VRd (D-VRd)	Daratumumab	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.
Daratumumab + VRd (D-VRd)	Lenalidomide	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.
Daratumumab + VRd (D-VRd)	dexamethasone	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (13)

Alfred Hospital; 🇦🇺 Melbourne, Australia

Odense University Hospital; 🇩🇰 Odense, Denmark

CHRU Hôtel Dieu; 🇫🇷 Nantes, France

University Hospital Ostrava; 🇨🇿 Ostrava, Czechia

Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi Di Ancona; 🇮🇹 Ancona, Italy

Ankara University; 🇹🇷 Ankara, Turkey

Hospital Clinic I Provincial de Barcelona; 🇪🇸 Barcelona, Spain

Kantonsspital St. Gallen; 🇨🇭 Saint Gallen, Switzerland

Regional General Hospital Alexandra; 🇬🇷 Athens, Greece

University Hospital Leuven; 🇧🇪 Leuven, Belgium

Oslo University Hospital; 🇳🇴 Oslo, Norway

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Uniwersytet Jagiellonski Collegium Medicum; 🇵🇱 Kraków, Poland