Timing of High-Dose Therapy For Myeloma

ABSTRACT & COMMENTARY

Synopsis: Multiple myeloma remains an incurable illness, even with high-dose chemotherapy and autologous or allogeneic transplantation. However, high-dose therapy has definitely enhanced overall survival, extending median survival from less than three years to greater than five years in most series.

Source: Fermand JP, et al. Blood 1998;92:3131-3136.

The median survival for patients with multiple myeloma treated with conventional dose chemotherapy remains less than three years. However, treatment with high-dose therapy (HDT) with autologous stem cell support has been shown in a number of phase II trials to enhance survival to five years or more.1-3 One of the many questions that remains is when is the appropriate time to use HDT? Should it be used as initial therapy or should it be reserved until a patient has become refractory to conventional chemotherapy? The French "Myelome Autograffe" group set out in 1990 to address this question. This report details that clinical investigation.

Two hundred two previously untreated myeloma patients were entered on a multicenter sequential randomized trial to assess the optimal timing of HDT and peripheral blood stem cell autotransplantation. Eligibility criteria included age younger than 56 years, symptomatic disease (not stage I by the Durie and Salmon classification), no more than one prior cycle of cytotoxic chemotherapy, and the absence of severe liver, kidney, or heart disease. Eligible patients (n = 185) were randomly assigned to receive HDT and PBSC autotransplantation (early HDT, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treatment, in case of primary resistance to CCT or at relapse in responders. In all cases, PBSC were collected before randomization, after mobilization by chemotherapy. In both groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisilone. Data were analyzed on an intent-to-treat basis using a sequential design.

At a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late HDT group. Survival curves were not significantly different. The average time without symptoms, treatment, and treatment toxicity (TWiSTT) was 27.8 months for the early HDT group and 22.3 months for the late HDT group.

COMMENTARY

For younger patients with multiple myeloma, HDT with autologous stem cell transplant has been clearly demonstrated to provide survival advantages. There are some data suggesting that older patients would also benefit from this approach,4 but firm conclusions are not yet possible in the older subgroup. For selected individuals, sequential HDT (i.e., two autologous transplants) may offer even greater overall survival.5 In contrast, allogeneic transplant, which offers some theoretical advantages (including a possible graft vs. tumor effect) remains associated with unacceptable toxicity and relatively high procedure-associated deaths.6

This report provides useful information for the practicing oncologist. Depending upon the availability of stem cell harvesting and transplantation facilities, it appears perfectly reasonable to embark upon standard chemotherapy approaches for myeloma patients of any age. Once the patient is stable, arrangements can be made for "rescue" HDT and PBSC autotransplant. However, it should be remembered that in this study, stem cell harvest was performed in all patients before treatment. The possibility that prolonged alkylating agent therapy during the initial treatment could diminish stem cell proliferative potential and possibly even result in genetic damage resulting in leukemia cannot be overlooked. Today, in contrast to the procedures of eight years ago, the use of GM-CSF to mobilize stem cells would probably reduce the first concern, but the leukemia potential remains.

An additional argument for early HDT can be made from the quality-of-life perspective. Although the differences were modest, TWiSTT was approximately 22 weeks (5½ months) longer for those receiving early HDT. This marks a real advantage in a disease that is typically associated with poor quality of life.

Thus, HDT, early or late, is associated with a median survival of more than five years. Early transplantation may be favored because it entails less chemotherapy and less overall time with toxicity. However, clinicians should be aware that if early transplantation is not possible, HDT may still be used later when the disease has become refractory to first-line, conventional approaches, or upon relapse after initial remission.

References

1. Bensinger WI, et al. Bone Marrow Transplant 1996; 18:527-531.

2. Barlogie B, et al. Blood 1986;67:1298-1301.

3. Fermand JP, et al. Blood 1989;73:20-23.

4. Vesole D, et al. Blood 1994;84:535a.

5. Vesole D, et al. Blood 1994;84:950-956.

6. Bensinger WI, et al. Hematol Oncol Clin North Am 1997;11:147-157.