Melphalan, Total Marrow Irradiation, and Autologous Stem Cell Transplantation in Treating Patients With High-Risk Multiple Myeloma

Inclusion Criteria:

* Patients with will be eligible if they are either in partial response, or have stable disease after no more than two attempts of induction therapy
* Patients with high-risk cytogenetics, t(4:14); t(14;16), t(14:20), deletion p17, gain in 1q, are eligible
* Patients with plasma cell leukemia in \>= partial remission are eligible
* Patients with non-quantifiable monoclonal proteins are eligible provided they meet other criteria for multiple myeloma and they have evaluable or measurable disease by other (radiographic, magnetic resonance imaging \[MRI\], computed tomography \[CT\], lytic measurable lesion on x-ray,) means
* Karnofsky performance status (KPS) \>= 70%
* Less than 12 months since diagnosis
* No contraindication to the collection of a minimum of 4 x 10\^6 CD34+ cells/kg by apheresis
* Bilirubin =\< 1.5 mg/dl
* Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) \< 2.5 x upper limits of normal
* Creatinine of measured or calculated creatinine clearance of \>= 50 cc/min
* Absolute neutrophil count of \> 1000/ul
* Platelet count of \> 100,000/ul
* Cardiac ejection fraction \>= 50% by multi-gated acquisition (MUGA) scan and/or by echocardiogram
* Forced expiratory volume in 1 second (FEV1) \> 60% and diffusion capacity of the lung for carbon monoxide (DLCO) \> 50% of predicted lower limit
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately; patients must be fully aware of the teratogenic potential of immunomodulatory drugs (ImIDs) and agree to fully comply with the mandated guidelines regarding contraception as stated in the informed consent and the patient warning document attached to the consent form; women of childbearing potential must have a negative pregnancy test performed within 24 hours prior to beginning thalidomide, except for woman who have been postmenopausal for at least 2 years, or underwent hysterectomy; use of effective means of contraceptive should be started at least 2 weeks prior to initiating lenalidomide
* All subjects must have the ability to understand and the willingness to sign a written informed consent; they are to give voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
* Patients should have finished their prior systemic therapy or radiation therapy, at least 3 weeks before cyclophosphamide or granulocyte colony-stimulating factor (G-CSF)/plerixafor mobilization, and should have finished dexamethasone at least 7 days prior to Plerixafor priming; administration of bisphosphonates needs to be completed at least 2 weeks before cyclophosphamide priming; bisphosphonates can be resumed or started after day 30

Exclusion Criteria:

* Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy
* Known hypersensitivity to filgrastim or to Escherichia coli (E. coli) derived proteins
* Inability to lie supine in a full body cast for approximately 30 minutes, the anticipated duration of each treatment session
* Previous radiation therapy to more than 20% of bone marrow containing areas, or to any area exceeding 2000 cGy, is an exclusion
* Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
* No other medical, or psychosocial problems, which in the opinion of the primary physician or principal investigator would place the patient at unacceptably high risk from this treatment regimen