Multiple myeloma: Certain types of stem cell transplantation should be further investigated

As robust data are lacking, at present the benefit of certain types of stem cell transplantation in patients with multiple myeloma cannot be reliably assessed. Firstly, many of the available studies are susceptible to bias. Secondly, the results of some important older studies have not been fully published. This is the finding of a final report and supplementary working paper published by the German Institute for Quality and Efficiency in Health Care (IQWiG) on 12 January 2012.

Various approaches to therapy

Multiple myeloma is a cancerous disease of the bone marrow with a varying course. The disease is usually treated only after patients develop symptoms. The prognosis is poor. For many patients in this situation, clinical practice guidelines recommend autologous stem cell transplantation, a procedure in which a patient's own stem cells are used.

In stem cell transplantation, the patient's affected bone marrow is first destroyed with high-dose chemotherapy (conditioning). Stem cells of a donor are then transplanted and settle in the bone marrow. In autologous stem cell transplantation the stem cells are taken from the patient's body before high-dose chemotherapy and then reinfused. If the transplant originates from a different person, the procedure is called allogeneic stem cell transplantation. In this context a distinction is made between related and unrelated donors. Allogeneic stem cell transplantation is also currently used in patients with multiple myeloma.

Studies are only available for 5 possible comparisons

IQWiG was commissioned by the Federal Joint Committee (G-BA). The Institute was to compare the benefit of repeated autologous transplantation with the standard therapy, a single autologous transplantation. Furthermore, several types of allogeneic stem cell transplantation, differing, for example, in donor type or intensity of conditioning, were to be investigated. In total, nine treatment comparisons were possible. However, IQWiG could only investigate five, as no studies (or no appropriate ones) were available for the other comparisons.

No data on quality of life

The literature search conducted by IQWiG retrieved a total of 17 relevant studies reporting evaluable data for the benefit assessment, such as data on survival time or adverse events. However, many of these studies were highly susceptible to bias, and therefore their results cannot be clearly interpreted. These studies contained no data at all on quality of life.

Proof of benefit of repeated autologous transplantation revised

In the preliminary report by IQWiG, in the interpretation of available study results, the Institute concluded that an autologous transplantation performed twice could prolong the time to recurrence compared with a single procedure. However, this conclusion had to be revised in the final report, as IQWiG identified further studies which had in part been supervised by German investigators. Extracts of results of these studies had been reported at scientific meetings, for example, but not been fully published.

The research groups responsible did not provide the data required for an appropriate assessment, despite repeated requests from IQWiG. Consequently, in total, data were missing for more than half of all study participants. As an assessment based solely on published data could lead to a biased result (publication bias), in IQWiG's opinion the studies provide neither proof nor an indication (or even a "hint”) of an added benefit of repeated autologous transplantation.

Harm from allogeneic transplantation with aggressive pre-treatment

The results for allogeneic stem cell transplantation with a related donor give reason for caution. According to the available data, the survival time of patients receiving an allogeneic transplantation with aggressive pre-treatment may actually be shortened compared with patients receiving an autologous transplantation. It is proven that stem cells donated by another person can trigger a potentially fatal rejection reaction in some patients. This side effect cannot occur if the patient's own cells are transplanted.

Conflicting answers for dose-reduced conditioning

Shortly after IQWiG completed the final report, the results of a further large study were published. IQWiG analysed these data in a separate working paper. The study compared two treatment strategies: one group of patients underwent autologous transplantation twice; the other received a combination of autologous and allogeneic transplantation (hybrid transplantation) with dose-reduced conditioning. This type of conditioning is less aggressive (toxic) and can therefore be better tolerated.

If one considers these new data, the overall evidence base provides an indication of an added benefit of hybrid transplantation with dose-reduced conditioning, as survival time in this group was longer than in patients receiving autologous transplantation twice. However, the data also provided indications of greater harm, as more patients receiving hybrid transplantation died due to treatment-related causes, even though dose-reduced conditioning was applied. However, whereas this higher risk of death is detectable at an early stage, improved survival chances only become evident after long-term observation.

Incomplete publication of study data cannot be justified

Due to gaps in the evidence and several unanswered questions, the use of certain types of stem cell transplantation in patients with multiple myeloma is currently only acceptable within the framework of clinical studies. In addition, patients must be comprehensively informed about the potential benefits and harms of these interventions. In order to help fill in the gaps in the evidence, future studies should preferably be randomized and also include data on quality of life.

The Institute Director Jürgen Windeler made the following comments on the final report: "The fact that researchers did not publish the study data or provide them to our Institute, even after repeated requests, cannot be justified, especially in view of the severity of the disease and the high treatment-related risk of some of these interventions. We have in the past frequently experienced the withholding of data in industry-sponsored studies. Now we must also conclude that the results of studies that are mainly publicly funded are also not completely disclosed. I do not know the reasons for this behaviour.”

Procedure of report production

IQWiG published the preliminary results in the form of the preliminary report at the beginning of January 2011 and interested parties were invited to submit comments. When the commenting procedure ended, the preliminary report was revised and sent as a final report to the contracting agency, the Federal Joint Committee, in September 2011.

The working paper, which considered the study published after completion of the final report, was sent to the G-BA in December 2011. The written comments were published in a separate document at the same time as the final report and working paper. The report was produced in collaboration with external experts; this does not apply to the working paper.

The following executive summary provides an overview of the results of the final report by IQWiG.

Contact: Tel. ++49(0)221-35685-0, presse@iqwig.de