RATIONALE: Giving chemotherapy and bortezomib before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and bortezomib. It is not yet known whether high-dose melphalan given together with a second stem cell transplant is more effective than low-dose cyclophosphamide in treating patients with relapsed multiple myeloma.

PURPOSE: This randomized phase III trial is studying giving high-dose melphalan together with a second stem cell transplant to see how well it works compared with low-dose cyclophosphamide in treating patients with relapsed multiple myeloma after chemotherapy.

OBJECTIVES:

Primary

• To determine the effect on freedom from disease progression in patients with relapsed multiple myeloma treated with re-induction therapy comprising bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD) followed by a second autologous stem cell transplantation (ASCT) with high-dose melphalan vs low-dose cyclophosphamide consolidation therapy.

Secondary

• To assess the response rate of PAD in patients following a previous autograft.
• To compare the overall response rate of patients following high-dose melphalan chemotherapy and autologous stem cell transplantation with low-dose cyclophosphamide consolidation therapy.
• To assess the overall survival of patients treated with this regimen.
• To assess the safety and toxicity of a second ASCT in these patients.
• To assess the safety and toxicity of PAD in these patients.
• To assess the feasibility of stem cell collection following PAD in these patients.
• To determine the impact of this regimen on pain and quality of life in these patients.

OUTLINE: This is a multicenter study.

• Re-induction (PAD) therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11, doxorubicin hydrochloride IV continuously on days 1-4, and oral dexamethasone on days 1-4 (and days 8-11 and 15-18 of course 1 only). Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
• Peripheral blood stem cell (PBSC) mobilization and harvest: Within 6-12 weeks, some patients receive cyclophosphamide IV on day 0 and filgrastim (G-CSF) subcutaneously (SC) beginning on day 1 and continuing to time of PBSC harvest. PBSCs are then collected.

Patients who successfully complete re-induction therapy and have adequate PBSC mobilization are stratified according to length of first remission or plateau (≤ vs ≥ 24 months) and response to PAD re-induction therapy (stable disease vs ≥ partial response). Patients are randomized to 1 of 2 arms.

• Arm I (high-dose melphalan consolidation therapy): Patients receive high-dose melphalan IV on day -1 followed by autologous stem cell transplantation (ASCT) on day 0.
• Arm II (low-dose cyclophosphamide consolidation therapy): Patients receive low-dose cyclophosphamide IV or orally once a week for 12-20 weeks for a total of 12 courses.

Patients complete the EORTC QLQ-C30 and EORTC QLQ-MY20, the Brief Pain Inventory Short Form (BPI-SF), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self Assessment) Pain Scale (S-LANSS) questionnaires at baseline and after completion of re-induction therapy.

Patients are followed monthly for up to 100 days after ASCT or at 30 days after low-dose cyclophosphamide and then every 3 months for 5 years.

DISEASE CHARACTERISTICS:

• Diagnosis of relapsed multiple myeloma

  • Symptomatic disease, including non-secretory

• Previously treated with standard chemotherapy and autologous stem cell transplantation

• Requires therapy for first progressive disease AND at least 18 months since first stem cell transplantation

  • Patients who were previously immunofixation-negative and are now immunofixation-positive must have > 5 g/L absolute increase in paraprotein

• Registered in the Myeloma X Relapse (Intensive) Trial and received 2-4 courses of PAD re-induction chemotherapy according to the protocol (consolidation phase)

• Adequate stem cell mobilization available for transplantation defined as ≥ 2x10^6 CD34 + cells/kg or ≥ 2x10^8 PBMC/kg including cells stored from a previous harvest (consolidation phase)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• ANC ≥ 1 x 10^9/L
• Platelet count ≥ 50 x 10^9/L
• Creatinine clearance ≥ 30 mL/min
• Total bilirubin < 2 times upper limit of normal (ULN)
• ALT or AST < 2.5 times ULN
• History of pulmonary disease allowed provided carbon monoxide diffusion in the lungs (KCO/DLCO) is ≥ 50% and/or no requirement for supplementary continuous oxygen
• Left ventricular ejection fraction ≥ 40% by ECG or MUGA scan
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No peripheral neuropathy ≥ grade 2
• No known HIV or Hepatitis B or C positivity (testing is not required)
• No known resistance to combined bortezomib, doxorubicin hydrochloride, and dexamethasone therapy
• No known history of allergy to compounds containing boron or mannitol
• No other previous or concurrent malignancies except for appropriately treated localized epithelial skin cancer or carcinoma in situ of the cervix, or remote histories of other cured tumors within the past 5 years
• No medical or psychiatric condition which, in the opinion of the investigator, contraindicates the patient's participation in the study
• No other contra-indication to treatment that would make the patient ineligible for consolidation phase

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No other prior therapy for relapsed disease except for local radiotherapy, therapeutic plasma exchange, or ≤ 200 mg of dexamethasone

  • Radiotherapy since prior transplantation sufficient to alleviate or control pain of local invasion is permitted

• No hemi-body radiation since prior transplantation (consolidation phase)

• At least 4 weeks since prior and no concurrent investigational drugs