Overview

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

Status:
Active, not recruiting
Trial end date:
2029-11-01
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 3
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
European Myeloma Network
Collaborator:
Janssen Research & Development, LLC
Treatments:
Antibodies, Monoclonal
BB 1101
Bortezomib
Daratumumab
Dexamethasone
Dexamethasone acetate
Lenalidomide
Thalidomide
Criteria
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.