Is Upfront Autologous Transplantation Necessary in Multiple Myeloma

For many years, autologous stem cell transplants have been used as part of initial therapy for multiple my- eloma in eligible patients. The French IFM 90 trial (and more recently an MRC trial) showed improvement in overall survival with autologous stem cell transplantation compared to conventional dose chemotherapy. In today's Simultaneous Session Autologous Transplantation: Multiple Myeloma (4:15 p.m. - 5:45 p.m.), Dr. Bart Barlogie will present the results of S9321, a large Intergroup randomized trial that looked at the role of stem cell transplantation in the therapy of multiple myeloma. In this study, 899 patients were treated with VAD as induction therapy. After induction, patients were randomized to a single autologous stem cell transplantation versus conventional chemo- therapy with VBMCP. A third arm looking at the role of allogeneic transplantation was closed prematurely after accruing 39 patients due to excessive treatment related mortality.

There was no significant difference in complete or partial response rates between the autologous stem cell transplantation arm and VBMCP chemotherapy arm. Similarly, overall survival was not different between the two groups, with median times of 58 versus 53 months, respectively, (p=0.8). Median progression-free survival was 25 and 21 months, respectively, (p=0.5). These results suggest no significant advantage with autologous stem cell transplantation compared to conventional chemotherapy in the therapy of multiple myeloma. How- ever, it must be noted that 52% of patients in the VBMCP arm received autologous stem cell transplantation as salvage at the time of relapse. Thus, in effect, this study turned out to be a comparison of early versus delayed transplant strategies.

Patients in this trial were also randomized to maintenance therapy with interferon versus no maintenance therapy. The study shows no significant benefit with maintenance interferon in terms of progression free sur- vival or overall survival.

The results of this study may have far reaching effects. Dr. Kenneth Anderson from the Dana Farber Cancer Institute says, "the results of this study along with those of an earlier trial published by Fermand and col- leagues suggest that there is no significant advantage of early transplant compared to delayed transplant used as salvage therapy at the time of relapse." He also notes, "Future studies will need to study the role of novel agents used earlier in the treatment of myeloma." Alternatively, other studies are looking at whether a double (tandem) transplant approach would improve survival. Dr. Barlogie will present preliminary data on the re- sults using a tandem transplant approach in a separate abstract at the same session.

The findings of S9321 are also supported by results of the PETHEMA trial that will be presented by Dr. Joan Bladé at the same session. In this trial, patients who responded to initial chemotherapy were randomized to autologous stem cell transplantation or conventional chemotherapy. No significant differences in overall sur- vival were noted between the two arms.

Preliminary results from the IFM trials comparing double autologous transplantation versus auto followed by mini-allogeneic transplantation will also be presented at this session.

Clearly, a greater understanding of the disease biology is necessary to further improve myeloma therapy. Several presentations at today's Simultaneous Session on Genetics of multiple Multiple Myeloma (4:15 p.m. - 5:45 p.m.), provide data highlighting genetic events critical to the pathogenesis and progression of multiple my- eloma.