This study will assess whether adding one of the newest multiple myeloma therapies, daratumumab, into the Total Therapy approach helps patients live longer with fewer side effects

Past studies conducted at the Myeloma Institute and at other institutions have shown that many patients with high-risk disease (as determined by gene array studies - studies that look at specific genes using special equipment) tend to have shorter remissions (disappearance of signs and symptoms of myeloma) and do not survive as long as participants with low-risk myeloma. The Total Therapy approach to treatment carried out at the Myeloma Institute where multiple chemotherapy agents are given as induction followed by a stem cell transplant, post-transplant consolidation, and maintenance therapy has proven to be the best available treatment strategy. However, the availability of new treatments that work in different ways offers the possibility of improving the effectiveness of Total Therapy treatment while potentially reducing the number of side effects patients' experience. Daratumumab is a human monoclonal antibody or protein drug. It recognizes a specific protein, CD38, which is found at high levels on multiple myeloma cells. An antibody is something that finds and kills foreign objects in your body, in this case, myeloma cells. The other drugs that will be used in the study treatment regimen include carfilzomib or bortezomib, thalidomide, lenalidomide, dexamethasone, cisplatin, adriamycin, cyclophosphamide, etoposide, lenalidomide and dexamethasone.

Inclusion Criteria:

• Patients must have newly diagnosed active Multiple Myeloma (MM) requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
• Patients must be either untreated or have not received more than four cycles of systemic MM therapy (e.g. Revlimid Dexamethasone (RD), Bortezomib Revlimid Dexamethasone (VRD). Prior bisphosphonates and localized radiation are allowed.
• Participants must have high-risk disease, as defined by at least one of the following:
• Myeloma Prognostic Risk Signature (MyPRS) risk score ≥ 50.4
• Lactate Dehydrogenase (LDH) ≥ 360 U/L (Rule out hemolysis and infection; contact PI if any doubt.)
• Diagnosis of primary plasma cell leukemia.
• Eastern Cooperative Oncology Group (ECOG) ≤ 2, unless solely due to symptoms of MM-related bone disease.
• Patients must have a platelet count ≥ 50,000/μL, unless lower levels are explained by extensive bone marrow plasmacytosis.
• Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
• Participants must have a baseline serum creatinine level < 3 mg/dL and baseline Alanine Aminotransferase (ALT) < 3x Upper Limit of Normal (ULN).
• Participants must have an ejection fraction by echocardiogram (ECHO) or Multiple-gated Acquisition Scan (MUGA) scan ≥ 45%
• Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (Forced Expiratory Volume 1 (FEV1), Forced Vital Capacity (FVC) and diffusion capacity (DLCO) > 50% of predicted. If the patient is unable to complete pulmonary function tests 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 Institutional Review Board (IRB)-approved informed consent indicating their understanding of the proposed treatment and that the protocol has been approved by the Institutional Review Board (IRB).

Exclusion Criteria:

• No evidence of high-risk disease
• Poorly controlled hypertension, diabetes mellitus, active or uncontrolled hepatitis, 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, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
• Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration.
• Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.