Daratumumab, Carfilzomib, Lenalidomide and Low Dose Dexamethasone (DKRd) in Newly Diagnosed, Multiple Myeloma

Inclusion Criteria:

• Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy

• Prior treatment of hypercalcemia or spinal cord compression or active and/oraggressively progressing myeloma with corticosteroids or lenalidomide orbortezomib-based regimens does not disqualify the patient (the treatment dose shouldnot exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not morethan 1 cycle of Proteasome Inhibitor / Immunomodulatory-based therapy)

• Both transplant and non-transplant candidates are eligible.

• Diagnosis of symptomatic multiple myeloma as per current International MyelomaWorking Group (IMWG) uniform criteria prior to initial treatment

• Monoclonal plasma cells in the Bone Marrow (BM) ≥ 10% or presence of a biopsy-provenplasmacytoma

• Measurable disease, prior to initial treatment as indicated by one or more of thefollowing:

• Serum M-protein ≥ 1 g/dL

• Urine M-protein ≥ 200 mg/24 hours

• If serum protein electrophoresis is felt to be unreliable for routine M-proteinmeasurement, then quantitative immunoglobulin levels are acceptable

• Serum freelite measurable disease as per current IMWG criteria

• Bone marrow specimen will be required at study entry; available DNA sample frompre-induction BM will be used for calibration step for MRD evaluation by genesequencing.

• Males and females ≥ 18 years of age

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Adequate hepatic function, with bilirubin ≤ 1.5 x upper limit of normal (ULN) andaspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

• Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.

• Calculated creatinine clearance (by Cockroft-Gault) ≥ 50 mL/min or serum creatininebelow 2 g/dL

• Woman of childbearing potential must have 2 negative pregnancy tests prior toinitiating lenalidomide.

• Woman of childbearing potential must agree to use 2 reliable forms of contraceptionsimultaneously or to practice complete abstinence from heterosexual intercourseduring the following time periods related to this study: 1) for at least 28 daysbefore starting lenalidomide; 2) while participating in the study; and 3) for atleast 30 days after discontinuation from the study.

• Male subjects must agree to use a latex condom during sexual contact with females ofchildbearing potential while participating in the study and for at least 90 daysfollowing discontinuation from the study even if he has undergone a successfulvasectomy.

• All study participants in the US must be consented to and registered into themandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS®) program and bewilling and able to comply with the requirements of Revlimid REMS®.

• Voluntary written informed consent.

Exclusion Criteria:

• Frail non-transplant candidates, defined as in Palumbo et al, Blood 2015.

• Non-secretory or hyposecretory multiple myeloma, prior to initial treatment definedas <1.0 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, and no measurabledisease as per IMWG by Freelite.

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,and skin changes)

• Amyloidosis

• Plasma cell leukemia

• Waldenström's macroglobulinemia or Immunoglobulin M-producing (IgM) myeloma

• Radiotherapy to multiple sites or immunotherapy within 4 weeks before start ofprotocol treatment (localized radiotherapy to a single site at least 1 week beforestart is permissible)

• Participation in an investigational therapeutic study within 3 weeks or within 5drug half-lives (t1/2) prior to first dose, whichever time is greater

• Potential subjects with evidence of progressive disease as per IMWG criteria

• Patients not able to tolerate daratumumab, carfilzomib, lenalidomide ordexamethasone

• Peripheral neuropathy ≥ Grade 2 at screening

• Diarrhea > Grade 1 in the absence of antidiarrheals

• Central Nervous System (CNS) involvement

• Pregnant or lactating females

• Major surgery within 3 weeks prior to first dose.

• Myocardial infarction within 6 months prior to enrollment, New York HeartAssociation (NYHA) Class III or IV heart failure, uncontrolled angina, severeuncontrolled ventricular arrhythmias, or electrocardiographic evidence of acuteischemia or active conduction system abnormalities

• Prior or concurrent pulmonary embolism

• Known moderate or severe persistent asthma or known chronic obstructive pulmonarydisease (COPD)

• Known or suspected chronic obstructive pulmonary disease (COPD) with a forcedexpiratory volume in 1 second (FEV1) <50% of predicted normal

• Moderate or severe persistent asthma within the past 2 years, or currently hasuncontrolled asthma of any classification. Note that subjects who currentlyhave controlled intermittent asthma or controlled mild persistent asthma areallowed in the study.

• Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECGduring screening

• Uncontrolled hypertension or diabetes

• Acute infection requiring systemic antibiotics, antivirals, or antifungals withintwo weeks prior to first dose

• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who areseropositive because of hepatitis B virus vaccine are eligible.

• Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3years except a) adequately treated basal cell, squamous cell skin cancer, thyroidcancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 withstable prostate specific antigen levels or cancer considered cured by surgicalresection alone

• Any clinically significant medical disease or condition that, in the Investigator'sopinion, may interfere with protocol adherence or a subject's ability to giveinformed consent.