RATIONALE: Melphalan, a chemotherapeutic agent, has been found to be an effective treatment choice for destroying myeloma cells, especially when given at high (bone marrow ablative) doses. Total marrow irradiation (TMI)/ablative dose radiation therapy is another modality capable of destroying myeloma cells. Autologous peripheral blood/stem cell transplant (ASCT) given after either melphalan or following TMI (aimed at the bone marrow containing areas of the skeleton, the site of origin of myeloma cells) will shorten the duration/alleviate the severity of both melphalan and marrow irradiation-associated side effects. Lenalidomide, an effective agent on its own right for the treatment of myeloma, has been shown to further enhance the beneficial effects of autologous stem cell transplants when given as maintenance therapy.

PURPOSE: This previously phase I trial established the maximum tolerated dose of TMI at 1600 cGy. The phase II part of this study is ongoing and is studying the effects of high-dose melphalan and ASCT, followed by TMI and a second ASCT, with subsequent maintenance lenalidomide. The study is conducted in patients with stages I-III myeloma, with specific emphasis on assessing complete and very good partial response rate conversions, progression-free and overall survival, and safety/feasibility of delivering the planned treatment regimen.

PRIMARY OBJECTIVES:

I. To assess the feasibility and toxicities of tandem cycle ablative therapy consisting first of high-dose melphalan and then escalating doses of fractionated total marrow irradiation (TMI) using helical tomotherapy in patients with advanced multiple myeloma.

II. To establish the maximum tolerated dose of TMI using helical tomotherapy. III. To assess response rate, progression free and over-all survival following treatment with tandem cycle ablative therapy consisting first of high-dose melphalan and then escalating doses of TMI using helical tomotherapy with Dexamethasone/Thalidomide maintenance therapy in patients with advanced multiple myeloma.

IV. To assess the feasibility of adding decadron and thalidomide as maintenance following the second cycle of high-dose therapy.

SECONDARY OBJECTIVES:

I. To perform cytogenetic, gene rearrangement, and fluorescence in situ hybridization (FISH) studies on baseline and post-treatment bone marrow and blood specimens and correlate the presence/persistence of these features with treatment outcome.

II. To bank/develop cell lines developed for future investigations of tumor biology, and for potential assessment of efficacy of novel therapeutic agents.

OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).

PRIMING AND APHERESIS: Patients receive cyclophosphamide IV over 2 hours. Patients also receive filgrastim IV or subcutaneously daily beginning 24 hours after the administration of cyclophosphamide and continuing until apheresis is complete. Patients undergo apheresis until an adequate number of peripheral blood stem cells are collected.

ABLATIVE THERAPY:

Course 1: Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1. Patients then undergo autologous PBSC transplantation on day 0 and receive filgrastim IV or subcutaneously beginning on day 5 and continuing until blood counts recover.

Course 2: Beginning 6-18 weeks later, patients undergo TMI once or twice daily on days -4 to -1. Patients then undergo autologous peripheral blood stem cell transplant and receive filgrastim IV or subcutaneously beginning on day 5 and continuing until blood counts recover.

MAINTENANCE THERAPY: Beginning within 6-8 weeks of day 0 of course 2 (TMI), patients receive oral lenalidomide daily. Courses repeat every 28 days for approximately 3 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 30 days, every 6 months for 1 year, and then annually for at least 2 years.

Criteria

• Patients with multiple myeloma (stages I-III) will be eligible if they are either in response, or have stable disease
• Patients with smoldering myeloma are eligible if there is evidence of progressive disease requiring therapy (>= 25% increase in M protein levels or Bence Jones excretion; Hgb =< 10.5 g/dl; frequent infections; hypercalcemia; rise in serum creatinine above normal on two separate occasion)
• Patients with non-quantifiable monoclonal proteins are eligible provided they meet other criteria for multiple myeloma, or smoldering myeloma, and they have evaluable or measurable disease by other (radiographic) means
• Unlimited prior chemotherapy regimens allowed
• KPS >= 70%
• Patients with Waldenstrom's macroglobulinemia are not eligible
• Less than 18 months since diagnosis
• No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by apheresis
• All patients must have signed a voluntary, informed consent in accordance with institutional and federal guidelines
• Adequate hepatic function as demonstrated by bilirubin, =< 1.5 mg/dl, and SGOT and SGPT < 2.5 x upper limits of normal
• Adequate renal function as demonstrated by: 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 MUGA scan and/or by echocardiogram
• Adequate pulmonary function as demonstrated by FEV1 > 60% and DLCO > 50% of predicted lower limit
• Hepatitis B antigen, Hepatitis C RNA and HIV antibody tests negative
• 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
• Females of reproductive age not using adequate birth control measures/ or who are pregnant are not eligible
• History of other malignancies within the last 3 years, as long as patients have remained in complete remission for at least 2 years, except for non-melanoma skin cancer and in situ carcinoma of the cervix
• Patients should have finished their prior chemotherapy at least 14 days prior to cyclophosphamide priming, and should have received their last dose of thalidomide, dexamethasone, or bisphosphonate > 10 days prior to cyclophosphamide priming
• Pre-treatment tests must have been performed within 6 weeks prior to initiation of cyclophosphamide; A CBC, platelet count and comprehensive chemistry panel should be performed within 1 week prior to initiating cyclophosphamide priming
• Known hypersensitivity to Filgrastim or to E. coli derived proteins is an exclusion
• Inability to lie supine in a full body cast for approximately 30 minutes, the anticipated duration of each treatment session, is an exclusion
• Previous radiation therapy to more than 20% of bone marrow containing areas, or to any area exceeding 2000 cGy, is an exclusion
• Patients must be fully aware of the teratogenic potential of thalidomide 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 thalidomide