Even in the era of targeted novel agents, autologous stem cell transplantation (autoSCT) remains the standard frontline approach for patients with multiple myeloma who are eligible for high-dose therapy. With the incorporation of novel agents during the induction, consolidation, and maintenance phases, as in the Total Therapy 3 protocol, the five-year estimates of overall survival (OS) and event-free survival (EFS) reach 70 percent. Does this imply that allogeneic transplantation (alloSCT) might also be an option for myeloma? Use of alloSCT with myeloablative conditioning in myeloma has been limited by severe toxicity and a high incidence of treatment-related mortality (TRM) in the range of 30 to 50 percent. On the other hand, reducedintensity conditioning (RIC) alloSCT is associated with less toxicity, and the combination of autoSCT followed by RIC alloSCT has reduced TRM to 15 percent or less. However, the role of RIC alloSCT in relation to autoSCT in the frontline approach to myeloma remains undefined.
Björkstrand and colleagues from the Karolinski Institute in Sweden compared single (auto) or double autoSCT (auto-auto) to autoSCT followed by RIC matched sibling donor alloSCT (auto-allo) in previously untreated patients with multiple myeloma. All patients received induction with conventional chemotherapy, and none were treated with novel agents. Patients with an HLA-identical sibling donor were assigned to the auto-allo arm (n=108), while the others were randomized to either auto (n=145) or auto auto (n=104). Median follow-up was 61 months, and long-term outcomes (at 60 months) of progression-free survival (35% vs. 18%, P=.001), overall survival (65% vs. 58%, P=.006), and relapse rate (49% vs. 78%, P=.003) were superior after autoallo compared with auto only. However, the cumulative non-relapse mortality rates at 24 and 60 months were 12 percent and 16 percent for the auto-allo group and 3 percent and 4 percent for the auto group (P=.001). Furthermore, the patients in the auto-allo arm did worse during the first and second year, with favorable outcomes not emerging until after two to three years. The incidence of grade 2 to 4 acute graft-versus-host disease (aGVHD) was 20 percent, and the incidence of limited and extensive chronic GVHD was 31 percent and 23 percent. The authors did not comment on the ability to start a salvage treatment or the benefits of salvage therapy in relapsed patients who developed either aGVHD or cGVHD. Of the evaluable patients alive after day 100, long-term outcome was inferior in patients with aGVHD, 32 percent versus 74 percent in patients without aGVHD (P=.0012). Interestingly, with respect to the effect of cGVHD, there was no significant difference in OS, PFS, relapse incidence, or non-relapse mortality.
In Brief
AlloSCT is a treatment with curative potential for myeloma, in part due to the GVH effect, best illustrated by the induction of sustained remissions after donor lymphocyte infusions. Favorable outcome may also be due in part to absence of contaminating myeloma cells in the donor graft. Still, the role of alloSCT in myeloma remains under debate because of the high mortality and morbidity, while convincing evidence for a survival benefit is lacking. Furthermore, many questions remain unanswered, especially who should receive alloSCT and when to transplant. However, one must keep in mind that the expected median survival of patients with myeloma is unlikely to exceed seven to 10 years using current approaches, even with the introduction of maintenance therapy and the addition of novel agents at each step of the intensive autoSCT procedure. This study confirms that some patients with myeloma might benefit from alloSCT, and, considering that myeloma is an incurable malignancy, we therefore cannot deny alloSCT to patients – especially young patients – with myeloma as an additional option for treatment.
Competing Interests
Dr. Leleu indicated no relevant conflicts of interest.
