Inclusion Criteria:

• PRE-REGISTRATION-INCLUSION CRITERIA:
• Age >= 18 years and =< 80 years.
• Patient must have suspected or confirmed newly diagnosed multiple myeloma by International Myeloma Working Group (IMWG) criteria.
• Left ventricular ejection fraction (LVEF) >= 40% =< 30 days prior to pre-registration.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up during the active treatment phase of the trial.
• Willing to provide blood and bone marrow samples for planned research.
• Life expectancy > 6 months.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation.
  • Note: subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.
• REGISTRATION-INCLUSION CRITERIA:
• High risk myeloma, which is untreated, defined as any two of:
• • Beta-2 microglobulin >5.5
  • Gain or amplification of chr1q
  • del17p or monosomy 17 or TP53 mutation (if known)
  • t(4;14) or t(14;16)
  • >= 5% circulating plasma cells
  • presence of extramedullary disease (does not include bone contiguous disease)
• Creatinine clearance >= 30 mL/min (using Crockroft-Gault equation) (obtained =< 14 days prior to registration).
• Absolute neutrophil count (ANC) >= 1000/mm^3 (without the use of growth factors) (obtained =< 14 days prior to registration).
• Platelet count >= 75000/mm^3 (obtained =< 14 days prior to registration).
• Hemoglobin >= 8.0 g/dL.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration).
• Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (obtained =< 14 days prior to registration).
• Registration must be completed =< 30 days after pre-registration.
• Patients must not have received more than one cycle of treatment between pre-registration and registration.
• All 4 drugs in the study regimen approved by insurance.

Exclusion Criteria:

• PRE-REGISTRATION EXCLUSION:
• Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis with organ involvement.
• Diagnosed or treated for another malignancy =< 1 year prior to pre- registration or previously diagnosed with another malignancy and have any evidence of residual disease.
  • Note: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. NOTE: Concurrent chemotherapy is any treatment not related to multiple myeloma.
• Other co-morbidity which would interfere with subject's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease.
• Other concurrent chemotherapy, or any ancillary therapy considered investigational.
  • NOTE: Concurrent chemotherapy is any treatment not related to multiple myeloma 
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain =< 30 days prior to registration.
• Major surgery =< 14 days prior to pre-registration.
• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  • Note: Prior to trial entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant.
• New York Heart Association (NYHA) II, III, IV heart failure.
• Known human immunodeficiency virus (HIV) positive.
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie., 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 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 prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Known or suspected active hepatitis C infection.
• Any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure) or known sensitivity to mammalian-derived products. Known allergies, hypersensitivity, or intolerance to trial drugs.
• Inability to comply with protocol/procedures.
• REGISTRATION-EXCLUSION CRITERIA:
• If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).