This study is being done because, despite major advances in therapy, MM is still considered an incurable disease. The purpose of this study is to determine the efficacy (how well it works) of the study treatment that combines the following drugs: daratumumab, carfilzomib, lenalidomide, dexamethasone in subjects who have a recent diagnosis of multiple myeloma (MM). Normal plasma (blood) cells are found in the bone marrow and are an important part of the immune system. MM is a cancer formed by malignant (cancerous) plasma cells. Daratumumab, one of the study drugs, is a man-made protein that works with your immune system by attaching itself to the cancerous cells. Once daratumumab attaches itself to these cells, it gets your body's immune system to attack and destroy the MM cells. Daratumumab has shown to be effective in subjects with MM when combined with medicines like bortezomib, or lenalidomide + dexamethasone.

This single arm, two-stage, open-label Phase II study is designed with the primary objective of evaluating the efficacy of induction therapy comprised of 8 cycles of carfilzomib, lenalidomide, dexamethasone and daratumumab (KRd+daratumumab) in terms of complete response or better (CR) in subjects with NDMM, and comparing to relevant historical controls. Post induction, all subjects will undergo disease evaluation, including assessment of minimal residual disease (MRD). Post-induction disease evaluation will be followed by an MRD-based treatment algorithm. This trial will allow us to gather preliminary data on use of MRD status to direct post-induction therapy.

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

1. Written informed consent and HIPAA authorization for release of personal health information signed by the subject or his/her legally authorized representative. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix A, Section 18.1) within 28 days prior to day 1 of treatment.

4. Confirmation of newly diagnosed multiple myeloma (NDMM) as per the IMWG 2014 criteria (see Appendix D, Section 18.4). Newly diagnosed MM patients who may have deferred transplant are also allowed.

5. Measurable disease present at baseline assessments. Baseline disease assessments are defined as disease assessments collected within 28 days of initiation of the first pre-study induction cycle (subjects who received prior therapy) or within 28 days prior to day 1 of study treatment (subjects with no prior therapy). Measurable disease is defined as:

   1. Serum M-protein ≥ 1 g/dL (> 0.5 g/dL for IgA or IgM) OR
   2. Urine M-protein ≥ 200 mg/24 h OR
   3. Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is abnormal

6. No more than one prior cycle of systemic therapy (completed within 6 weeks of consent) for MM (to accommodate subjects who needed emergent therapy at diagnosis); any prior radiotherapy must be completed at least 14 days prior to day 1 of treatment. Subject must have recovered from treatment-induced toxicities to ≤ grade 1 or baseline.

7. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in the table below:

   Hematological:

   • White Blood Cell (WBC) : ≥ 2,000/mm3
   • Absolute Neutrophil Count (ANC) : ≥ 1,000/mm3 without growth factors within 1 week of day 1 of treatment
   • Hemoglobin (Hgb) : ≥ 8 g/dL
   • Platelet count : ≥ 70,000/mm3 if bone marrow plasmacytosis of <50%; otherwise ≥ 50,000/mm3

   Renal:

   Serum creatinine with Creatinine clearance : ≤ 1.5 × upper limit of normal (ULN) with creatinine clearance

   ≥ 30 mL/min as measured by a 24-hour urine collection or estimated by the Cockcroft - Gault formula ( See formula in Appendix B, Section 18.2 )

   Hepatic:

   • Bilirubin : ≤ 2 × ULN; < 3.0 for subjects with Gilbert's Syndrome
   • Aspartate aminotransferase (AST) : ≤ 2.5× ULN
   • Alanine aminotransferase (ALT) : ≤ 2.5 × ULN

8. Adequate cardiac function as defined by ≥ 45% Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment.

9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day 1 of treatment, and be willing to undergo serial serum or urine pregnancy testing. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).

10. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) plus a second contraceptive method (considered acceptable [failure rate of >1% per year] or highly effective) from the time of informed consent until 3 months after the last protocol prescribed therapy (which also includes FCBP on carfilzomib) has been discontinued. NOTE: estrogens may further increase the risk of thrombosis (beyond that associated with lenalidomide) and their use should be based on a benefit-risk decision. For the highly effective contraceptive method, a method with low user dependency is preferable but not required (see tables, adapted from: http://www.hma.eu/fileadmin/dateien/Human\_Medicines/01-About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf)

    Highly Effective Birth Control Methods:

    • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation

      • oral
      • intravaginal
      • transdermal

    • progestogen-only hormonal contraception associated with inhibition of ovulation

      • oral
      • injectable
      • implantable (Contraception method considered to have low user dependency)

    • intrauterine devide (IUD) (Contraception method considered to have low user dependency)

    • intrauterine hormone-releasing system (IUS) (Contraception method considered to have low user dependency)

    • vasectomised partner (Contraception method considered to have low user dependency) Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant

    • sexual abstinence (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 treatments)

    Acceptable Birth Control Methods:

    • Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
    • Male or female condom with or without spermicide (A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods.

11. Male subjects (even those who have had a vasectomy) who are sexually active with a FCBP must be willing to use latex or synthetic condoms from initiation of study treatment until 3 months after the last protocol prescribed therapy has been discontinued. They must also refrain from donating sperm for at least 90 days after the last dose of carfilzomib and at least 90 days from the last dose of daratumumab. The FCBP partner should also consider contraception recommendations (see inclusion #10).

12. As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

1. Any infection requiring systemic therapy (i.e. involving IV antibiotics) (NOTE: at discretion of investigator, subjects with uncomplicated urinary tract infections may be eligible).
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study, and any female subject must agree not to donate eggs during the study and for 3 months after the last protocol prescribed therapy has been discontinued).
3. Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, carcinoma of the prostate with a current PSA value of <0.5 ng/mL or other cancer for which the subject has completed treatment, been disease-free for at least five years, and is considered by Sponsor-Investigator to be at <30% risk of relapse, or on hormonal therapy for a history of either prostate cancer or breast cancer, provided that there has been no evidence of disease progression during the previous three years.
4. Non-secretory MM.
5. Active involvement of the central nervous system by MM.
6. Prior cardiovascular cerebrovascular accident with persistent neurological deficit.
7. Has chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. FEV1 is required for subjects suspected of having chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of predicted normal.
8. Has had moderate or severe persistent asthma within the past 2 years from enrollment and/or has currently uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
10. Had major surgery within 2 weeks prior to day 1 of treatment.
11. Exposure to any investigational drug (including investigational vaccine) or invasive investigational medical device within 4 weeks or 5 pharmacokinetic half-lives prior to day 1 of treatment, whichever is longer.
12. Uncontrolled clinically significant illness including, but not limited to, uncontrolled hypertension (as per the most updated Joint National Committee for the Management of Hypertension definitions), symptomatic congestive heart failure (as per New York Heart Association [NYHA] class III or IV [see Appendix C, Section 18.3], uncontrolled angina pectoris, myocardial infarction within the past 6 months from consent, known or suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator, or any other condition (including laboratory abnormalities) that would, in the opinion of the investigator, place the subject at unacceptable risk if he/she were to participate in the study.
13. Known allergies, hypersensitivity or intolerance to monoclonal antibodies or human proteins, daratumumab +hyaluronidase or its excipients or known sensitivity to mammalian-derived products, carfilzomib or its excipients, lenalidomide or its excipients, or dexamethasone or its excipients.
14. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real time polymerase chain reaction (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 (anti-HBs positivity as the only serologic marker) AND a known history of HBV vaccination do not need to be tested for HBV DNA by PCR.
15. Is known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). Subject is not required to have hepatitis C testing at screening.
16. Is known to be seropositive for human immunodeficiency virus.
17. Transplant ineligible subjects > 70 years old only: Defined frail, per IMWG criteria of 'frailty'. Frailty assessment does not need to be performed unless the subject is transplant ineligible and > 70 years old. "Frail" is defined as a frailty score of ≥ 2.
18. Prior or current exposure to daratumumab or other anti-CD-38 therapies.
19. Focal radiation therapy within 14 days prior to C1D1 with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.