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

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 ofnormal (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, orPositron-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 lambdaFLC ratio

4.Newly diagnosed subjects for whom high-dose therapy and autologous stem celltransplantation (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 ScreeningPhase (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 orrecombinant human erythropoietin use is permitted however transfusions are notpermitted 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 ≥75x 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, suchas Gilbert syndrome, direct bilirubin ≤1.5 x ULN)

Adequate renal function:

1. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculatedusing Cockcroft-Gault, estimated Glomerular filtration rate (eGFR) (Modified Diet inRenal 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 ≤6.5mg/dL (≤1.6 mmol/L)

3. Female subjects of reproductive childbearing potential must commit to eitherabstain continuously from heterosexual sexual intercourse or to use 2 methods ofreliable birth control simultaneously during the Treatment Period, during any doseinterruptions, and for 3 months after the last dose of any component of thetreatment regimen. Sexual abstinence is considered a highly effective method only ifdefined as refraining from heterosexual intercourse during the entire period of riskassociated with the study drug. This birth control method must include one highlyeffective form of contraception (tubal ligation, intrauterine device (IUD), hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] orpartner's vasectomy) and one additional effective contraceptive method (male latexor synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeksprior to dosing. Reliable contraception is indicated even where there has been ahistory of infertility, unless due to hysterectomy or bilateral oophorectomy.

4. A woman of childbearing potential must have 2 negative serum or urine pregnancytests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.

5. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction during the study and for a period of 3 months after receiving the lastdose of any component of the treatment regimen.

6. Male subjects of reproductive potential who are sexually active with females ofreproductive potential must always use a latex or synthetic condom during the studyand for 3 months after discontinuing study treatment (even after a successfulvasectomy).

7. Male subjects of reproductive potential must not donate sperm during the studyor for 3 months after the last dose of study treatment.

8. Signed an informed consent form (ICF) (or their legally acceptablerepresentative must sign) indicating that he or she understands the purpose of, andprocedures required for, the study and is willing to participate in the study.

9. 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 celldyscrasia, with the exception of emergency use of a short course (equivalent ofdexamethasone 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 theNational Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE)Version 5.

3. Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 yearsof date of randomization (exceptions are adequately treated basal cell or squamouscell carcinoma of the skin, carcinoma in situ of the cervix or breast, or othernon-invasive lesion that in the opinion of the investigator, with concurrence withthe sponsor's medical monitor, is considered cured with minimal risk of recurrencewithin 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 1second (FEV1) <50% of predicted normal (for subjects ≥65 years old FEV1 <50% ordiffusing capacity of the lungs for carbon monoxide [DLCO] <50%)

8. Moderate or severe persistent asthma within the past 2 years, or currently hasuncontrolled asthma of any classification. (Note that subjects who currently havecontrolled intermittent asthma or controlled mild persistent asthma are allowed inthe study).

9. Any of the following:

10. Seropositive for human immunodeficiency virus (HIV)

11. Seropositive for hepatitis B (defined by a positive test for hepatitis Bsurface antigen [HBsAg]). Subjects with resolved infection (ie, subjects whoare positive for antibodies to hepatitis B core antigen [antiHBc] and/orantibodies to hepatitis B surface antigen [antiHBs]) must be screened usingreal-time PCR measurement of hepatitis B virus (HBV) DNA levels. Those who arePCR positive will be excluded. EXCEPTION: Subjects with serologic findingssuggestive 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 HBVDNA by polymerase chain reaction (PCR).

12. Seropositive for hepatitis C (HCV) (anti-HCV antibody positive or HCV-RNAquantitation positive), except in the setting of a sustained virologic response (SVR), defined as viremia at least 12 weeks after completion of antiviraltherapy.

13. Concurrent medical or psychiatric condition or disease (such as but not limited to,systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acutediffuse infiltrative pulmonary disease) that is likely to interfere with the studyprocedures or results, or that in the opinion of the investigator, would constitutea hazard for participating in this study.

14. Any of the following:

15. myocardial infarction within 6 months before randomization, or an unstable oruncontrolled disease/condition related to or affecting cardiac function (eg,unstable angina, congestive heart failure, New York Heart Association ClassIII-IV)

16. uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities

17. screening 12-lead ECG showing a baseline QT interval >470 msec

18. left ventricular ejection fraction (LVEF) <40% for subjects age 65-70 years old

19. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization

20. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids,monoclonal antibodies or human proteins, or their excipients (refer to theInvestigator's Brochure), or sensitivity to mammalian-derived products orlenalidomide.

21. Not able to comply with the study protocol (eg, because of alcoholism, drugdependency, or psychological disorder). Subject has any condition for which, in theopinion of the investigator, participation would not be in the best interest of thesubject (eg, compromise the well-being) or that could prevent, limit, or confoundthe protocol-specified assessments.

22. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in thisstudy or within 3 months after the last dose of any component of the treatmentregimen. Or, subject is a man who plans to father a child while enrolled in thisstudy or within 3 months after the last dose of any component of the treatmentregimen.

23. Major surgery within 2 weeks before randomization or will not have fully recoveredfrom surgery, or has surgery planned during the time the subject is expected toparticipate in the study. Kyphoplasty or Vertebroplasty is not considered majorsurgery.

24. Received an investigational drug (including investigational vaccines) or used aninvasive investigational medical device within 4 weeks before randomization or iscurrently enrolled in an interventional investigational study.

25. Contraindications to the use of any components of the backbone treatment regimens,per local prescribing information.

26. Gastrointestinal disease that may significantly alter the absorption of oral drugs

27. Vaccination with live attenuated vaccines within 4 weeks of first study agentadministration

28. Unable or unwilling to undergo antithrombotic prophylactic treatment.