Inclusion Criteria:
* Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of PD requiring initiation of treatment.
* Patients must be either untreated or have not received more than two months of MM therapy. However, bisphosphonates and localized radiation are allowed.
* Patients must have clinical features of high-risk disease, at time of initial diagnosis or initial assessment prior to enrollment, which may include one or more of the following:
* High-risk cytogenetic abnormalities, including t(4;14), t(14;16), t(14;20), del17p13, del1p, or gain 1q with del1p by FISH, with a cutoff point of 20% or greater.
* Beta-2-microglobulin \>5.5 mg/L with normal kidney function test per the institutional reference.
* Presence of extramedullary disease defined as soft tissue plasmacytoma (excluding Paramedullary/Paraskeletal plasmacytoma)
* ≥ 3 focal lesions on F18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging
* LDH ≥ 360 U/L (Rule out hemolysis and infection; contact Principal Investigator if any doubt.)
* Circulating plasma cells ≥5 percent of white blood cells on conventional peripheral blood smear (manual white blood cell differential count) or peripheral blood flow cytometry.
* ECOG ≤ 2, unless solely due to symptoms of MM-related bone disease.
* Patients must have a platelet count ≥ 50,000/μL and hemoglobin level of ≥7.5 g/dl and absolute neutrophilic count (ANC) of 1.0x10\^9/L unless lower levels are explained by extensive BM plasmacytosis.
* Patients must be at least 18 years of age and not older than 75 years of age at the time of consent.
* Patients must have adequate renal function with baseline serum creatinine level \< 3 mg/dL and estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, eGFR (MDRD), or CKD-epi formula and baseline Alanine Aminotransferase (ALT) \< 3x Upper Limit of Normal (ULN).
* Patients must have an ejection fraction by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan ≥ 45%
* Patients must have adequate pulmonary function studies \> 50% of predicted on mechanical aspects (FEV1, FVC, etc.) and diffusion capacity (DLCO) \> 50% of predicted. If the patient is unable to complete pulmonary function tests (PFT) due to MM related pain or other conditions, an exception may be granted if the Principal Investigator documents that the patient is a candidate for high dose therapy.
* Patients must have signed an IRB-approved informed consent form (ICF) indicating their understanding of the proposed treatment and that the protocol has been approved by the IRB.
* Female subjects must use effective methods of birth control during the course of the study and for 6 months after stopping study medications.
* Female subjects must not donate eggs during the study and for 6 months after the last dose of study medications.
* Male subjects must not donate sperm during the study and for 3 months after the last dose of study medications.
Exclusion Criteria:
* Poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
* Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low Gleason score prostate cancer on active surveillance or having had surgery/radiation with curative intent within one year of consent or other cancer for which the patient has not received treatment for one year prior to consent. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
* 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. Women of childbearing potential (WOCBP) must have a negative pregnancy documented within one week of consent. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
* 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 patients must be excluded if FEV1 is \<50% of predicted normal.
* Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
* Active autoimmune disease
* Active systematic viral, fungal or bacterial infection, requiring systemic therapy.
* Clinically significant cardiac disease, including Myocardial infarction within 6 months before consent, or Uncontrolled cardiac arrhythmia or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class 3-4) (Appendix 1)
* Patient is:
* seropositive for human immunodeficiency virus (HIV)
* 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) deoxyribonucleic acid (DNA) levels. Those with active infection will be excluded. Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
* 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).
* Patients who received plasmapheresis within 28 days of start of study treatment at Induction with Dara-KRD.
* Patients with focal radiation therapy within 14 days prior to consent with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
* Known history of allergy to Captisol ® (a cyclodextrin derivative used to solubilize carfilzomib).
* Known history of allergy, hypersensitivity, or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients.
* Known intolerance or allergy to lenalidomide.
