Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone in Transplant-ineligible NDMM Patients

Inclusion Criteria: 1. Diagnosed with multiple myeloma and started induction therapy within 6 months prior to study entry 2. Received bortezomib-based induction therapy, with corticosteroids, with or without alkylators 3. Determined by investigator to be transplant-ineligible 4. Failed to achieve a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group \[IMWG\] criteria) 5. Measurable disease at time of enrolment including: * Serum M-protein ≥ 0.5 g/dL, or * Urine M-protein ≥ 200 mg/24 hour, or * Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa/lambda ratio, or * In patients with immunoglobulin A (IgA) type MM, whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA), qIgA ≥ 750 mg/dL (0.75 g/dL) 6. Male/female, ≥ 18 years of age 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 8. Adequate hepatic function within 28 days prior to treatment initiation, with bilirubin \< 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN 9. Left ventricular ejection fraction ≥ 40% 10. Absolute neutrophil count (ANC) ≥ 1500/mm3 within 28 days prior to enrollment, and reconfirmed within 7 days prior to first dose. Screening ANC should be independent of growth factor support for ≥ 1 week. 11. Hemoglobin ≥ 8.0 g/dL within 28 days prior to treatment initiation, and reconfirmed within 7 days prior to first dose. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days of obtaining Screening hemoglobin. 12. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is \> 50%) within 28 days prior of treatment initiation, and reconfirmed within 7 days prior to first dose. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the Screening platelet count. 13. Calculated or measured creatinine clearance (CrCL) of ≥ 30 mL/min within 28 days prior to treatment initiation. Calculation should be based on standard formula such as the Cockcroft and Gault: \[(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)\]; multiply result by 0.85 if female. 14. Written informed consent in accordance with local regulations 15. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to treatment initiation and agree to use an effective method of contraception throughout the treatment period and for 3 months following last dose. Female of childbearing potential is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 16. Male patients must use an effective barrier method of contraception during the treatment period and for 3 months following the last dose, if sexually active with a FCBP - Exclusion Criteria: 1. Prior therapy with any immunomodulatory drug (IMiD) or with Carfilzomib 2. Any unresolved Grade 2 or higher toxicity from bortezomib based induction treatment 3. Multiple myeloma of immunoglobulin M (IgM) subtype 4. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome 5. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10e9/L 6. Waldenström macroglobulinemia 7. Patients with known amyloidosis 8. Focal radiation therapy within 7 days prior to treatment initiation; radiation therapy to an extended field, involving a significant volume of bone marrow, within 21 days prior to enrollment (i.e., prior radiation must have been to less than 30% of the bone marrow) 9. Major surgery (excluding kyphoplasty) within 28 days prior to treatment initiation 10. Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention; myocardial infarction within 4 months prior to treatment initiation 11. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to treatment initiation 12. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen \[SAg\] and core antibody receiving and responding to antiviral therapy directed at hepatitis B; these patients are allowed). 13. Patients with known cirrhosis 14. Second malignancy within the past 3 years except: A. Adequately treated basal cell or squamous cell skin cancer B. Carcinoma in situ of the cervix C. Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA) over 12 months D. Breast carcinoma in situ with full surgical resection E. Treated medullary or papillary thyroid cancer 15. Patients with myelodysplastic syndrome 16. Female patients who are pregnant or lactating 17. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize Carfilzomib) 18. Patients with hypersensitivity to Carfilzomib, 19. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment 20. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to treatment initiation 21. Subject has either one of the following: 1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is \<50% of predicted normal. 2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study. 22. Patients who discontinued bortezomib due to bortezomib related adverse events. 23. Any other clinically significant medical disease or psychiatric condition that, in the investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent 24. Any prior treatment with investigational anti-MM drugs -