Reply to J.C. Regelink et al (2010)

We appreciate Regelink et al’s comments on our manuscript updating several large first-line myeloma trials. We would like to emphasize two critical aspects of clinical trial research that our article and the Dutch group’s response should bring into focus. As reporting on survival in myeloma and other cancer therapeutic trials for elderly patients is confounded by deaths from other causes, it is particularly important to consider potential underlying noncancer morbidity–aggravating circumstances of myeloma therapy that may result in late manifestations. For example, genotoxic interventions, such as high-dose melphalan, can promote treatmentrelated myelodysplasia, which we have shown to be linked to alkylating-agent therapies preceding hematopoietic progenitor cell collection. Novel agents exhibit less acute toxicity profiles, more often resulting in cumulative neuropathy as in the case of thalidomide and bortezomib. Moreover, hematopoietic progenitor cell–supported myeloma therapy is an acute intervention attended to closely by highly specialized health care teams so that corrective actions are executed promptly. Severity and duration of toxicities can be alleviated by melphalan dose reduction, as routinely performed in the setting of advanced age and renal failure. In the case of chronic novel-agent therapy, onset of peripheral neuropathy and orthostatic hypotension can be quite insidious and, when not recognized promptly, can result in irreversible patient debilitation. The importance of Paget’s soil in disease progression and therapeutic response of the cancer seed is now widely appreciated in myeloma. Unique properties (ie, exerting immunomodulatory, antiangiogenic, and stroma tumor–cell interaction disruptive properties), initially associated with novel agents, may indeed pertain to classical genotoxic agents. These indirect antitumor effects may explain cancer cures as seemingly inconceivable in the context of classical first-order tumor-cell kill kinetics, such as the albeit low cure fraction observed in the early trials with cytarabine for acute myeloblastic leukemia and high sustained complete responses elicited by short courses of purine analogs in hairy cell leukemia. It is in such context that the late benefit of early treatment intervention with thalidomide in Total Therapy 2 and second transplantation in the Dutch trial may be explained. We are currently investigating, by serial gene expression profiling studies of whole bone marrow biopsies through the course of Total Therapy 2, whether differences can be detected in both myeloma and bone marrow microenvironment gene expression signatures on the two study arms that may explain the late benefit from thalidomide’s early and time-limited exposure. We hypothesize that favorable priming was exerted by thalidomide on the microenvironment; this will be evaluated in comparison to similar studies in healthy ageand sex-matched volunteers. In summary, as myeloma therapy advances, our work and the response by Regelink et al will hopefully stimulate further reporting of late results on tumor status, toxicity, and translational data, potentially explaining treatment success or failure of the various modalities applied in attempted long-term myeloma control. Bart Barlogie University of Arkansas for Medical Sciences, Little Rock, AR