Biology, treatment, and time

Barlogie and colleagues report that patients with abnormal baseline metaphase cytogenetics and enrolled on TT2 had better overall survival (OS) rates when randomized to thalidomide.

Total therapy 2 (TT2) was a randomized prospective treatment trial composed of a complex regimen (induction, 2 autologous peripheral blood stem cell transplantations [ASCTs], consolidative chemotherapy, and maintenance) given with or without thalidomide during all phases of treatment.¹  In their original report with 42 months' follow-up, the higher complete response and event-free survival rates enjoyed by patients on the thalidomide arm had not translated into superior OS. However, in the current paper at 72 months' follow-up, a distinct survival advantage was seen for the 30% of patients with abnormal cytogenetics.

This paper carries 3 important messages. The first but simplest is a reminder that early reports of OS may be misleading. The second is that with novel agents and transplantation, in selected patient populations, unprecedented OS rates can be achieved; for TT2, the median OS was 8 years!

The third concept is that thalidomide administration as part of the initial treatment strategy for patients with myeloma has an important impact on long-term OS for the subgroup of patients with abnormal cytogenetics. Given the potential for toxicity using this drug (grade 3-4 peripheral neuropathy in 27% for TT2 with thalidomide vs 17% without)¹  and 80% 5 year OS in other less complex tandem transplant strategies for low-risk patients (low β-2 microglobulin and no deletion 17, deletion 13, or t[4;14]) by fluorescence in situ hybridization [FISH]),⁹  it is a critical observation that the 70% of patients with normal cytogenetics do not benefit from thalidomide incorporated into TT2.

There are 7 other randomized trials that address the role of thalidomide in association with alkylator-based therapy; however, none focuses on the heterogeneity of myeloma biology and its interaction with thalidomide. The Intergroupe Francophone du Myelome (IFM) 99-02 was a maintenance trial for patients undergoing tandem autologous stem cell transplantation (ASCT) who had either or neither increased β-2 microglobulin or FISH deletion 13.²  Although there was a modest survival benefit among patients receiving maintenance thalidomide, the authors did not dissect the influence of genetic factors on OS but did note that thalidomide-treated patients with deletion 13 had no event-free survival benefit.²  The Tunisian trial was a consolidation trial, in which patients were randomized to either 6 months of thalidomide or a second ASCT.³  In the Australian trial, after a single ASCT, all patients received prednisolone maintenance, but half were randomized to receive 1 year of thalidomide consolidation as well.⁴  In both, preliminary OS data favored the thalidomide arm as shown in the table, but no data were provided about interactions between thalidomide and myeloma genetics. Among the 4 randomized trials comparing melphalan and prednisone (MP) and MP plus thalidomide (MPT), the results are inconsistent.^5-8  The 2 trials that included thalidomide both as induction and maintenance did not show a survival benefit.^5,7  The other 2 trials, both conducted by the IFM, tested 18 months of MP versus MPT in patients aged 65 to 75⁶  and in those 75 or older.⁸  Both of these studies demonstrated an OS benefit for the MPT arm,^6,8  and it appeared that thalidomide canceled the deleterious effect of FISH deletion 13.⁶ 

Despite this very important contribution by Barlogie et al, questions remain about thalidomide use with regards to timing, dose, duration of therapy, and optimal patient populations. It is unclear whether thalidomide is best used as in TT2, from induction through transplantation, consolidation, and maintenance. It is noteworthy that post hoc Barlogie et al found no impact of the duration or cumulative dose of thalidomide on clinical outcomes. In fact, 43% of patients stopped thalidomide at a median of 30 months, which is a lower attrition rate than for other trials. As shown in the table, the median duration of thalidomide treatment, regardless of trial design, was about 12 months. Therefore, it appears that relatively brief exposure to thalidomide may provide survival benefits in a subset of patients.

The question of which patient populations thalidomide best serves relates both to the substrate of the patient (eg, age and comorbidity) and to the myeloma biology, and it is quite likely that the inconsistent results in the MPT trials reflect this heterogeneity. A major challenge for synthesizing the impact that the treatment regimens have on myeloma genetic characteristics lies in the differential methodology employed. Barlogie and colleagues' work relies heavily on metaphase cytogenetics and on gene expression profiling, whereas those of the IFM and others are largely FISH-based. The different information derived makes cross-validation among studies difficult, but each may add to the current work by continuing to unravel complex interactions between myeloma biology, treatment, and long-term outcomes.