High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy

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.

Sex

All

Minimum age

18 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

• DERIVEDde Tute RM, Cook G, Cairns DA, Brown JM, Cavenagh J, Ashcroft AJ, Snowden JA, Yong K, Tholouli E, Jenner M, Hockaday A, Drayson MT, Morris TCM, Rawstron AC, Owen RG. Impact of minimal residual disease (MRD) in salvage autologous stem cell transplantation for relapsed myeloma: results from the NCRI Myeloma X (intensive) trial. Bone Marrow Transplant. 2024 Mar;59(3):431-434. doi: 10.1038/s41409-023-02164-4. Epub 2024 Jan 9. No abstract available. PMID 38195983
• DERIVEDCook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. doi: 10.1016/S2352-3026(16)30049-7. PMID 27374467
• DERIVEDParrish C, Morris CTCM, Williams CD, Cairns DA, Cavenagh J, Snowden JA, Ashcroft J, Cavet J, Hunter H, Bird JM, Chalmers A, Brown JM, Yong K, Schey S, Chown S, Cook G; National Cancer Research Institute Haemato-Oncology Clinical Studies Group. Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial. Biol Blood Marrow Transplant. 2016 Jun;22(6):1009-1016. doi: 10.1016/j.bbmt.2016.01.016. Epub 2016 Jan 28. PMID 26827659
• DERIVEDCook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. doi: 10.1016/S1470-2045(14)70245-1. Epub 2014 Jun 16.