Original 2000 Guideline
The Hematology Disease Site Group (DSG) was asked to develop a broad guideline on the management of patients with multiple myeloma. The DSG considered the potential of developing a more comprehensive guideline and concluded that the complexity and importance of the high-dose therapy transplant topic warranted a specific guideline; the possibility remains for subsequently merging this guideline into a document dealing with a wider range of issues in myeloma.
On appraising the published literature regarding transplant therapy, there were two major issues that yielded considerable debate. The first issue related to the quality and volume of data assessing the transplant question. Specifically, debate centered on the strength of the recommendation for transplantation given that the supporting data were limited to only one well-conducted positive randomized trial. After careful consideration, there was unanimous agreement that patients ought to be informed about the results of this study and this was reflected in the wording of the recommendations. There was further discussion about whether there was sufficient evidence to not only offer, but to "recommend" this treatment as the preferred therapeutic option. While the DSG felt that patients should have a choice, they felt that that the current evidence is sufficient to warrant the "recommend" terminology.
The second point of debate dealt with the role of interferon. Some members of the group felt that as interferon was part of the treatment maneuver in the Attal study, and was reported by Cunningham et al to result in superior time-to-disease progression, the use of interferon should be included in transplant treatment strategies. Other members felt that in the absence of data demonstrating a survival advantage, the toxicity of this agent precludes routine use. The DSG was unable to reach consensus, and a recommendation about using interferon was therefore not included.
The DSG members considered whether a firm recommendation should be made regarding the timing of transplantation. Members felt that the best available evidence found a survival benefit when transplantation was used as part of the initial therapy. In a randomized trial of early versus delayed transplantation in patients in whom stem cells had been collected at diagnosis, delaying transplant did not shorten survival although there was a suggestion that quality of life was adversely affected; however the 95% confidence intervals overlapped. For this reason, the DSG members did not feel that a strong recommendation could be made regarding the timing of transplantation, although there was consensus that if a delayed transplant is contemplated, stem cells should be collected soon after diagnosis.
The initial draft recommendations were circulated for practitioner feedback in May 1999 and received wide support. The initial Practice Guideline was approved by the Practice Guidelines Coordinating Committee in October 1999. Since the release of the initial guideline, new data emerged in abstract form that included assessment of the role of total-body irradiation (TBI) and a further randomized trial evaluating autologous transplantation in patients over age 55 years.
The DSG concluded that the study comparing melphalan 140 mg/m2 plus total-body irradiation with melphalan 200 mg/m2 required modification of the previous recommendation regarding the details of the high-dose therapy regimen (bullet five). The reworded recommendation now permits either option (see "Major Recommendations" field). There was considerable discussion regarding the results of the report by Fermand et al. This trial, published in abstract form, compared a transplant strategy with standard dose treatment in patients 55 years and greater and failed to detect a survival benefit. The DSG considered whether these data should lead to a rewording of the overall recommendation regarding "offering" versus "recommending" high-dose therapy transplantation and/or whether an age restriction should be suggested. The DSG concluded that while the Fermand trial was large and appeared to be well conducted, insufficient information was provided in the abstract to change the initial recommendations. However, the wording of the new recommendation (bullet one) highlights the indication by age. The DSG acknowledges that the final results of the Fermand trial and other ongoing studies may influence the nature and wording of the recommendations in the future.
The DSG did not consider these new data and the resulting modifications sufficiently different from the initial guideline to warrant another cycle of practitioner feedback. This revised guideline was circulated to the Practice Guidelines Coordinating Committee.
October 2003 Update
The Hematology DSG's evaluation of new evidence resulted in extensive discussions of two topics: the role of autologous stem cell transplantation in comparison with standard-dose therapy and the nature of the high-dose therapy regimen.
The publication of the Medical Research Council (MRC) trial has strengthened the evidence in favor of high-dose therapy and autologous transplantation over standard dose therapy for newly diagnosed patients with myeloma. While a meta-analysis will be required to better define the magnitude of benefit, the DSG concluded that high-dose therapy should continue to be recommended for patients with myeloma and that the text of the recommendation should be amended to indicate that the evidence is strongest in patients under the age of 65 years.
Given the updated evidence regarding high-dose therapy preparative regimens, the DSG unanimously concluded that melphalan 200 mg/m2 as a single modality should be the recommended regimen for patients undergoing autologous transplantation outside a clinical trial setting. In comparison with melphalan 140 mg/m2 and total body radiation, melphalan given as 200 mg/m2 was associated with superior survival and less toxicity, and was less resource intensive.
The DSG discussed whether the publication of the Attal study should lead to a change in the recommendation regarding double (tandem) autologous transplantation. The DSG concluded that the survival benefit reported in that trial was potentially important, but noted that other trials did not report a benefit. The DSG also noted that the high-dose therapy regimen used in the single transplant arm in that trial no longer represents the standard of care, as it has been shown to be inferior to melphalan (200 mg/m2) alone. The DSG members concluded that the recommendations should not be changed until new data are available from those studies. The DSG concluded that new evidence regarding the role of post-transplantation interferon maintenance did not warrant a change in the recommendations.
