Correspondence

Duration of Survival in Patients with Myeloma Treated with Thalidomide

N Engl J Med 2008; 359:210-212July 10, 2008

Article

To the Editor:

Two years ago, we reported that the incorporation of thalidomide into high-dose therapy for myeloma increased the frequency of complete remission but not the duration of remission and extended event-free survival but not overall survival.1 We now report that after a median follow-up of 8 years, 399 patients remain alive and 286 are event-free, for median durations of 9 years and 5 years, respectively. Although the overall difference in the 8-year survival estimates of 56% for 323 patients who were randomly assigned to the thalidomide group and 45% for 345 patients in the control group was not significant (P=0.09), a significant survival advantage was apparent among the 197 patients who had cytogenetic abnormalities in myeloma cells. This baseline feature, which was present in 30% of the patients, was the strongest independent variable linked to a poor prognosis. In the thalidomide group, the 8-year survival estimate for such patients was 46%, as compared with 27% for such patients in the control group (P=0.02) (Figure 1AFigure 1Duration of Overall Survival and Complete Remission among the Patients.).

In results similar to those in our original report, post-relapse survival overall was significantly shorter in the group of patients who were randomly assigned to receive thalidomide than in the control group (P=0.03), whereas this was not the case among the patients with cytogenetic abnormalities (P=0.26). The frequency of complete remission was higher among patients in the thalidomide group, regardless of their cytogenetic status; however, the duration of complete remission was longer only in patients in the thalidomide group who had abnormal karyotypes (5-year estimate, 47% vs. 25%; P=0.05) (Figure 1B). The survival benefit of thalidomide among patients with abnormal karyotypes emerged after 3 years, whereas the remainder of the patients tracked together through 7 years after the initiation of therapy. Two thirds of patients discontinued thalidomide within 4 years because of adverse effects. The duration of thalidomide treatment and the cumulative dose that was administered had no discernible effect on either overall survival or survival in the subgroup of patients with cytogenetic abnormalities.

We were surprised that the survival benefit of thalidomide was limited to patients who had cytogenetic abnormalities, since such disease is considered to be more aggressive, and, as reflected by in vitro cell division of the malignant clone, less dependent on the support of the bone marrow microenvironment.2 Our finding of a delayed response to treatment, with a plateau of disease-free survivorship emerging only after 10 years, justifies long-term follow-up of patients with multiple myeloma in randomized clinical trials.3

Bart Barlogie, M.D.
John D. Shaughnessy, Jr., Ph.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205
barlogiebart@uams.edu

John Crowley, Ph.D.
Cancer Research and Biostatistics, Seattle, WA 98101

3 References

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   Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030
   Full Text | Web of Science | Medline

2. 2

   Shaughnessy J, Jacobson J, Sawyer J, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression. Blood 2003;101:3849-3856
   CrossRef | Web of Science | Medline

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   Barlogie B, van Rhee F, Shaughnessy JD Jr, Anaissie E, Crowley J. Making progress in treating multiple myeloma with total therapies: issue of complete remission and more. Leukemia (in press).
   

Citing Articles (5)

Citing Articles

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   Amrita Krishnan, Marcelo C Pasquini, Brent Logan, Edward A Stadtmauer, David H Vesole, Edwin Alyea, Joseph H Antin, Raymond Comenzo, Stacey Goodman, Parameswaran Hari, Ginna Laport, Muzaffar H Qazilbash, Scott Rowley, Firoozeh Sahebi, George Somlo, Dan T Vogl, Daniel Weisdorf, Marian Ewell, Juan Wu, Nancy L Geller, Mary M Horowitz, Sergio Giralt, David G Maloney. (2011) Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. The Lancet Oncology 12:13, 1195-1203
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   Todd Zimmerman. (2009) Immunomodulatory agents in oncology. Update on Cancer Therapeutics 3:4, 170-181
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   Pellegrino Musto, Fiorella D’Auria, Giuseppe Pietrantuono, Sara Bringhen, Fortunato Morabito, Francesco Di Raimondo, Samantha Pozzi, Stefano Sacchi, Mario Boccadoro, Antonio Palumbo. (2008) Role of thalidomide in previously untreated patients with multiple myeloma. Expert Review of Anticancer Therapy 8:10, 1569-1580
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4. 4

   Barlogie, Bart, Shaughnessy, John D. Jr., , Crowley, John, . (2008) Retraction: Barlogie et al. Duration of Survival in Patients with Myeloma Treated with Thalidomide. N Engl J Med 2008;359:210-2.. New England Journal of Medicine 359:13, 1410-1410
   Full Text | Original Article

5. 5

   F. van Rhee, M. Dhodapkar, J. D. Shaughnessy, E. Anaissie, D. Siegel, A. Hoering, J. Zeldis, B. Jenkins, S. Singhal, J. Mehta, J. Crowley, S. Jagannath, B. Barlogie. (2008) First thalidomide clinical trial in multiple myeloma: a decade. Blood 112:4, 1035-1038
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