Correspondence
High-Dose Chemotherapy in Multiple Myeloma
N Engl J Med 1996; 335:1844-1845December 12, 1996
- Article
To the Editor:
Attal et al. (July 11 issue)1 state that their trial “demonstrates that high-dose therapy improves both event-free and overall survival” in patients with multiple myeloma, but that conclusion is not supported by their data. Although the unadjusted difference in overall survival between the patients receiving high-dose chemotherapy (some of whom also underwent autologous bone marrow transplantation) and those receiving conventional chemotherapy was associated with a P value of 0.03, multivariate analysis revealed that “overall survival was related only to the level of beta2-microglobulin (P<0.001).” This discrepancy between unadjusted and adjusted results indicates that there was substantial confounding. This is not surprising, given the imbalance in the beta2-microglobulin level between the treatment groups (a difference of 20 percent between mean values) and the importance of beta 2-microglobulin as a prognostic variable in multiple myeloma.
The comparison of overall five-year survival between the conventional-dose group and the high-dose group (12 percent vs. 52 percent) is also misleading, since Attal et al. do not mention the wide 95 percent confidence intervals: 1 to 40 percent and 36 to 67 percent, in the respective groups (Figure 2 of the article). The width of these confidence intervals is also not surprising, given the brevity of follow-up in relation to the period included in the survival estimates.
In addition, the authors fail to consider that the differences may have been due to a detrimental effect in the conventional-dose group rather than to a benefit of high-dose therapy. Although they note that drug combinations other than that of melphalan and prednisone “have not led to major improvements in clinical outcome,” they chose to use vincristine, melphalan, cyclophosphamide, and prednisone in alternation with vincristine, carmustine, doxorubicin, and prednisone for a total of 18 cycles in their conventional-dose group. The patients in that group would have received 270 mg of both carmustine and doxorubicin per square meter of body-surface area, whereas those in the high-dose group would have received only 60 to 90 mg of each drug per square meter. These higher cumulative doses may have impaired the bone marrow and cardiac reserve of the patients in the conventional-dose group with no concomitant benefit, resulting in worse survival. This possibility is supported by the paradoxically greater differences in overall survival than in event-free survival, which implies that survival after relapse was better in the high-dose group than in the conventional-dose group. Indeed, the authors note that two-year survival after salvage therapy was 35 percent in the high-dose group and 25 percent in the conventional-dose group. Had the patients in the conventional-dose group received only melphalan and prednisone, perhaps they would have fared better.
1 ReferencesCarl D. Atkins, M.D.
South Shore Hematology–Oncology Associates, Rockville Centre, NY 115701
Attal M ,Harousseau J-L ,Stoppa A-M , et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-97
Full Text | Web of Science | Medline
To the Editor:
Attal et al. report that high-dose chemotherapy combined with autologous bone marrow transplantation improves the response rate, event-free survival, and overall survival in patients with multiple myeloma. However, their conclusion seems premature. From the overall-survival curves in their Figure 2, it is obvious that the survival of the patients in both treatment groups was almost identical during the actual period of observation, or two years; a difference appears only later, when the curves are based more on projections than on observations. The pattern of the survival curves resembles that found in an interim analysis of a myeloma trial by the Finnish Leukaemia Group,1 but when the remaining Finnish patients had been observed for four years, the survival curves for both groups were identical — that is, the difference favoring combination chemotherapy had disappeared.2
We would be very interested in seeing the French data after two more years of follow-up.
2 ReferencesTiina M. Oivanen, M.D.
Tampere University Hospital, FIN 36280 Pikonlinna, FinlandIlmari P. Palva, M.D., Ph.D.
Finnish Leukaemia Group, FIN 33950 Pirkkala, Finland1
Finnish Leukaemia Group. Comparison of melphalan and prednisone with five-drug combination MOCCA for multiple myeloma. Presented at the 16th Nordic Meeting of Hematology, Tampere, Finland, 1985. abstract.
2
Finnish Leukaemia Group
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Author/Editor Response
The authors reply:
To the Editor: Dr. Atkins suggests that “imbalance in the beta2-microglobulin level” could be responsible for the better survival in the high-dose group. This statement is not supported by our data. No significant difference was observed for beta2-microglobulin between either the mean values (P = 0.3) or the medians (3.5 vs. 3.4 mg per liter). For overall survival, the difference between treatment groups had a P value of 0.06 in the multivariate analysis (not much different from the value in the univariate analysis, but not significant). This low level of significance could be related to the intention-to-treat analysis: the difference in overall survival between groups had a P value of 0.03 in the multivariate analysis in which only the patients less than 60 years old were studied (and 82 percent of those in the high-dose group underwent transplantation). The 95 percent confidence intervals are given in each figure for each time point (15, 30, 45, and 60 months), together with the probabilities of survival. The difference in survival is unlikely to “have been due to a detrimental effect in the conventional-dose group,” as Dr. Atkins suggests. The median survival of the patients in that group was 37.4 months. This value is within the range of values reported in published trials1 (in which either melphalan–prednisone or combination chemotherapy was administered) of patients with aggressive myeloma (Durie–Salmon stages II and III; mean beta2-microglobulin level, 5 mg per liter). Atkins's concern about worse survival after relapse in the conventional-dose group is not supported by our findings. There was no significant difference between the treatment groups (P = 0.3).
We agree with Drs. Oivanen and Palva about long-term follow-up. Our study began in 1990, enrollment ended in 1993, and the results were reported in 1996 with a median follow-up of 39 months among the surviving patients. At that time, the differences in event-free and overall survival were as shown in Figure 1, 2, and 3. The analysis of the first 100 patients enrolled in the study may give information on actual long-term results. With a median follow-up of four years, the actual four-year overall survival rates were 62 percent (95 percent confidence interval, 46 to 75 percent) in the high-dose group and 26 percent (95 percent confidence interval, 14 to 42 percent) in the conventional-dose group (P<0.001).
1 ReferencesMichel Attal, M.D.
Hôpital Purpan, 31059 Toulouse, FranceJean-Luc Harousseau, M.D.
Régis Bataille, M.D.
Hôtel Dieu, 44035 Nantes, France1
Gregory WM ,Richards MA ,Malpas JS . Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 1992;10:334-342
Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
B Wirk. (2011) Renal failure in multiple myeloma: a medical emergency. Bone Marrow Transplantation 46:6, 771-783
CrossRef2
M. Attal, P. Moreau, H. Avet-Loiseau, J.-L. Harousseau. (2007) Stem Cell Transplantation in Multiple Myeloma. Hematology 2007:1, 311-316
CrossRef3
Heinz Gisslinger, Mathias Kees. (2003) Therapy strategies for multiple myeloma: current status. Wiener Klinische Wochenschrift 115:13-14, 451-461
CrossRef
