“Full length, midi, or mini”: a fashion statement for transplants in myeloma

High-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (AHSCT) is the standard of care for patients with newly diagnosed multiple myeloma.¹  This results in an event-free survival and overall survival (OS) of approximately 30 and 60 months, respectively. Unfortunately, there is no plateau in survival curves. It is highly controversial whether the outcomes of single HDT with planned tandem AHSCT improves survival.²  The final analysis of the Intergroupe Francais Du Myélome 94 (IFM94) trial is the only one of 5 randomized trials (none yet published) to show a survival benefit (although one could argue that the other trials do not have long enough follow-up). Even with tandem AHSCT, plateaus in survival curves are not observed.

The etiology of disease relapse has been hypothesized as due to (1) infusion of contaminating tumor cells in the autograft, and/or (2) inability to eradicate minimal residual disease. Allogeneic transplantation (AlloTx) may overcome both of these obstacles by infusing tumor-free grafts and eradication of minimal residual disease through a graft-versus-myeloma (GVM) effect. There are indications that a plateau may be present following AlloTx. In patients who relapse following AlloTx, a GVM effect has been demonstrated by donor lymphocyte infusions.

Conventional (“full length”) AlloTx's have excessively high mortality rates: the transplant-related mortality (TRM) has ranged from 20% to 57% within the first year. Thus, in the setting of 5-year median survivals with AHSCT, conventional AlloTx's have been terminated by the “fashion police” as too toxic. Is there a “kinder and gentler” approach for patients with myeloma that may lead to a cure? Trials using reduced dose–intensity regimens have been explored in myeloma. The initial trials included intermediate dose (“midi”) regimens (melphalan 100 mg/m² [Badros et al³ ]; melphalan 180 mg/m², and fludarabine 125 mg/m² [Giralt et al⁴ ]) in predominantly heavily pretreated patients with chemoresistant disease. Although high response rates were observed, the majority were not durable and the TRM was only modestly less than conventional AlloTx (one-year TRM, 33% and 40%, respectively).

Maloney and colleagues (page 3447) have combined the 2 transplantation modalities: AHSCT (melphalan 200 mg/m²) to affect maximal tumor cytoreduction followed by a nonmyeloablative (“mini”) AlloTx using only 2 Gy total body irradiation to allow donor alloreactive T lymphocytes to eradicate minimal residual disease via a GVM mechanism. They observed a 52% complete remission (CR) rate, far higher than that observed with either AHSCT (even tandem) or conventional AlloTx. At a median follow-up of 18 months, only 3 of 31 patients with CR have relapsed. The projected 2-year progression-free survival (PFS) for all patients was 55%. However, when scrutinizing the data further, it is apparent that patients with chemosensitive disease before transplantation had superior PFS and OS compared with chemoresistant patients. In addition, although the overall TRM at one year was 17%, TRM was significantly lower in the chemosensitive versus chemoresistant group (2 [7%] of 28 vs 7 [27%] of 26, respectively). These data imply that only patients with chemotherapy-sensitive disease should be considered for this regimen.

I anticipate that future trials will further identify those individuals (early treatment, chemosensitive; perhaps chromosome 13 abnormalities) who may benefit from this approach. Only time will tell if the current “fashion statement” using a combined autologous/mini AlloTx will result in improved survival and, dare I state, be curative! This concept will be further evaluated in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial comparing tandem AHSCT with autologous/mini AlloTx.