We have developed a novel submyeloablative allograft regimen for myeloma (Mehta J, Singhal S. Graft-versus-myeloma. Bone Marrow Transplant 1998;22:835-843) comprising 100 mg/m2 melphalan followed by G-CSF-mobilized blood stem cells from HLA-identical siblings on day 0, and, in the absence of GVHD, on days 21, 42 and 114 as well. Cyclosporine is used as a single agent for GVHD prophylaxis, and is tapered from day 43. In the absence of GVHD, cyclosporine is stopped by day 98. No G-CSF is administered post-transplant to avoid possible stimulation of endogenous hematopoiesis. 4 patients (48-59 y; median 54) were allografted from sex-mismatched donors after 1 (n=2) or 2 (n=2) preceding autografts. All patients had progressive, refractory myeloma at the time of the allograft. 2 had mildly compromised renal function and 1 had microbiologically-confirmed sinopulmonary aspergillosis. Rapid hematologic recovery was seen with neutrophils and platelets reaching 0.5 and 50 x 109/L respectively by day 14. 90-100% donor-type chimerism was seen in all on day 21. Grade III cutaneous acute GVHD responding to prednisone and mycophenolate mofetil was seen in 1 patient. This patient received no further infusions of donor stem cells. The other 3 received 2 additional infusions each. All 4 patients developed limited chronic GVHD involving the oral mucosa and the liver. The 2 patients autografted twice previously also developed impaired pulmonary function tests with normal CT scans over a year post-transplant, but have improved markedly on systemic immunosuppresion with mycophenolate mofetil and low-dose prednisone. CR was achieved 3 weeks to 4 months post-transplant in all 4 patients. Renal function normalized post-transplant and aspergillosis resolved completely. All 4 patients are alive in 5-20 months (median 11) post-transplant; all with chronic GVHD that is improving on immunosuppressiion with mycophenolate mofetil and low-dose prednisone. Responses have been sustained in 3, whereas 1 patient has had intermittent immunofixation-positivity for paraprotein in the urine since immunosuppression was started for the treatment of GVHD. However, there is no other evidence of recurrent disease. We conclude that 100 mg/m2 melphalan is sufficient to permit alloengraftment in previously autografted myeloma patients. Early treatment-related morbidity is limited and response rates are high even with refractory disease. While chronic GVHD is universal, it is possible that this is central to the high, sustained disease response rates as evidenced by the development of immunofixation-positivity in 1 patient as GVHD improved. We are now using this procedure in myeloma patients who have not been previously autografted as well as in patients with other malignant diseases with the addition of 50 mg/kg cyclophosphamide to provide greater pre-transplant immunosuppression. Mycophenolate mofetil has been added as a second immunosuppressive agent post-transplant in view of the high incidence of chronic GVHD.
Full conference title:
43rd American Society of Hematology (ASH) Annual Meeting
- ASH 43rd (2001)