High-dose chemotherapy followed by autologous stem cell rescue is proven to prolong disease-free and OS in eligible patients with multiple myeloma and has therefore been part of the standard care for patients younger than 65 years of age.1 On the other hand, the role of allo-SCT is yet to be established; although it can induce molecular remission, treatment-related morbidity and mortality are high especially with myeloablative regimens.2 Allo-SCTs with non-myeloablative regimens have been offered in clinical trials to selected younger patients including those with high-risk disease features such as deletion of chromosome 13 and high β-2 microglobulin levels.3
We report a 48-year-old African-American woman who initially presented in June 1999 with right shoulder pain and a pathologic humeral fracture, which was proven to be a plasmacytoma on biopsy. She was treated with internal fixation and 10 fractions of local radiotherapy. BM biopsy showed 50% involvement with plasma cells that had κ-light chain restriction and a normal karyotype. Serum Igs, serum and urine protein electrophoresis with immunofixation were within normal limits. Skeletal survey revealed multiple lytic lesions involving the right humerus, right scapula, sternum, ribs, spine and pelvis. She received two cycles of VAD (vincristine, adriamycin and dexamethasone) followed by CY mobilization, a fludarabine and melphalan-based conditioning regimen and HLA-matched allo-SCT from her sister in October 1999. BM biopsy 100 days after the transplant showed CR with 5% plasmacytosis and 100% donor chimerism. She did not develop significant GVHD, despite non-compliance with the immunosuppressive regimen, which was stopped approximately 3 months after the transplant. She has been followed with regular clinic visits and yearly BM biopsies thereafter. She remained in good health with no evidence of relapse until January 2008 when the BM biopsy showed 30% plasmacytosis with κ-light chain restriction. She was also found to have new-onset renal insufficiency with a 50 mL/min estimated glomerular filtration rate and a serum creatinine of 1.4 mg per 100 mL. The skeletal survey was unchanged; serum and urine paraprotein studies were still within normal limits. Peripheral blood molecular studies with STR engraftment analysis showed 100% donor chimerism. She received four cycles of lenalidomide and dexamethasone. A repeat BM biopsy showed reactive plasmacytosis and normal cytogenetics. She then underwent stem cell mobilization with 10 μcg/kg/day of G-CSF, and 4.63 × 106 CD34+ cells/kg were collected over 3 days. This was followed by conditioning with a melphalan-based regimen and autologous stem cell infusion in July 2008. The hospital course was uncomplicated with engraftment on day 11.
The post transplant period was mostly uneventful and no acute GVHD was observed. Renal function completely normalized during the immediate post transplant period. A BM biopsy on day 100 showed a hypercellular marrow with no evidence of residual myeloma, and PCR was indeterminate for light chain rearrangement. She was doing well and in CR, but fell and fractured her proximal femur in November 2009. At that time she had an internal pinning and fixation. Restaging at this time revealed no evidence of disease. By March 2010, the patient was doing well, but it was noted she now had a small amount of monoclonal κ-free light chains on urine immunofixation, suggesting an early disease relapse.
Non-myeloablative allo-SCT may improve survival compared with autografting and produce durable remissions for multiple myeloma, suggesting a curative potential.4 However, relapse continues to be a significant cause of treatment failure and prognosis in this setting is grim. Therapeutic options after relapse include withdrawal of immunosuppressive therapy, donor lymphocyte infusion (DLI), salvage chemotherapy or second allo-SCT. Withdrawal of immunosuppression is commonly used before DLI or salvage chemotherapy; however, it is rarely effective. Second allo-SCT can be offered to a very small subset of patients because of high non-relapse mortality. DLI is the most common treatment modality in the setting of relapse after allo-SCT. The goal of DLI can be prevention or treatment of relapse as well as conversion of mixed chimerism to full donor chimerism. Response rates to DLI for myeloma relapsing after allo-SCT are usually between 30 and 50%; however, only 20–30% of patients achieved durable remission after DLI.5 There is a strong correlation between response and GVHD, which supports the notion of a graft-versus-myeloma effect with DLI.5, 6 In addition to the cellular immunity with alloreactive donor T cells, humoral immunity with Ab responses to highly expressed myeloma Ags has also been reported to have a role in the graft-versus-myeloma effect.7 The largest experience with DLI for multiple myeloma has been published by a European multicenter group, which has reported 63 patients who relapsed after allogeneic transplantation.6 The response rate was 38% with 19% complete responses. OS was 23.6 months and PFS was 27.8 months among responders. The only significant prognostic factors for response were occurrence of acute and chronic GVHD. There was a trend toward significance for time between transplantation and DLI, and the response. Response to DLI was 55, 36.4 and 23.8% in patients who received DLI within 6 months, between 6 and 12 months and after 12 months post transplant, respectively, suggesting a decreased efficacy of DLI after 1 year. Recent reports describe successful incorporation of novel antimyeloma agents such as thalidomide and bortezomib with DLI, reporting better outcomes compared with the previous reports of DLI alone.8
Our case was an unusual presentation with relapse observed several years after the transplant while the patient maintained full donor chimerism and showed no signs of GVHD. This is the first report describing a durable benefit of high-dose chemotherapy with stem cell rescue for relapse after allo-SCT. Here, it is unique that the stem cells were harvested from the patient instead of from the donor, which may significantly increase the risk of GVHD. It also underscores the importance of high-dose melphalan in the treatment of multiple myeloma. Thus, high-dose chemotherapy followed by stem cell rescue using cells harvested from the patient can be considered in combination with novel antimyeloma agents as an alternative to DLI, especially in patients who suffer late relapse and have chemosensitive disease. In the setting of early relapse, high-dose chemotherapy with stem cell rescue before DLI may be explored to achieve cytoreduction and maximize the benefit of DLI.
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.
Shaw BE, Peggs K, Bird JM, Cavenagh J, Hunter A, Madrigal JA et al. The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma. Br J Haematol 2003; 123: 886–895.
Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H et al. Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36: 963–969.
Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed multiple myeloma. N Engl J Med 2007; 356: 1110–1120.
Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 2004; 103: 4362.
van de Donk NW, Kroger N, Hegenbart U, Corradini P, San Miguel JF, Goldschmidt H et al. Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37: 1135–1141.
Bellucci R, Wu CJ, Chiaretti S, Weller E, Davies FE, Alyea EP et al. Complete response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood 2004; 103: 656–663.
van de Donk NW, Kroger N, Hegenbart U, Corradini P, San Miguel JF, Goldschmidt H et al. Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation. Blood 2006; 107: 3415–3416.
The authors declare no conflict of interest.
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Tuncer, H., Gregory, S. & Fung, H. High-dose chemotherapy with autologous stem cell rescue for relapse after allo-SCT in multiple myeloma. Bone Marrow Transplant 46, 1156–1157 (2011). https://doi.org/10.1038/bmt.2010.251