No abstract

IntroductionOver the last decade, major advances in the treatment of multiple myeloma (MM) have been reported with the use of autologous stem-cell transplantation [1][2][3][4] and, more recently, of novel agents targeting the tumor clone and the bone marrow microenvironment. 5 In this setting, thalidomide represents a new treatment paradigm because of its alternative mechanisms of action that include disruption of myeloma-bone marrow stromal cell interactions, inhibition of cytokine secretion, and immunomodulatory effects. The observation that increased bone marrow angiogenesis correlates with advanced phases of MM, 6 along with the welldocumented in vitro antiangiogenic activity of thalidomide, 7 led to the investigational use of this agent in patients with advanced and refractory MM. 8 Response rates in the 30% range initially reported by Singhal et al 8 were extended and confirmed by other groups (for a review, see Cavenagh and Oakervee 9 and Dimopoulos et al 10 ). Subsequent combination of thalidomide with dexamethasone increased the rate of response up to 50% to 55%, 11,12 suggesting a synergism between these agents and providing the rationale for their use as primary therapy for patients with symptomatic MM. Results of 3 phase-2 studies with thalidomide-dexamethasone (Thal-Dex) in preparation for subsequent autologous transplantation 13-15 and a randomized comparison of Thal-Dex with dexamethasone alone 16 were promising in terms of response rate and collection of adequate quantities of peripheral blood stem cells (PBSCs). Based on these data, Thal-Dex has been proposed, and is currently accepted at many centers, as a front-line treatment option for patients with symptomatic MM, particularly if it is planned to offer subsequent high-dose therapy with autologous transplantation. However, no comparative study of Thal-Dex with vincristinedoxorubicin-dexamethasone (VAD), the reference treatment used so far to reduce tumor cell mass before autologous transplantation, has been reported. To address this issue, we performed a retrospective matched case-control analysis of 200 patients with symptomatic MM who were primarily treated with Thal-Dex (n ϭ 100) or VAD (n ϭ 100) in preparation for autologous stem-cell transplantation as part of 2 consecutive studies conducted from 1996 to 2004. Table 1; the 2 groups were comparable with respect to the major presenting variables known to potentially affect clinical outcome. Both studies were approved by local ethical committees of participating centers. Informed consent was provided according to the Declaration of Helsinki. Patients, materials, and methods Patients and criteria of matching Study design and treatment regimensBy design of both studies, Thal-Dex and VAD were planned to be administered for 4 months in an attempt to reduce tumor cell mass before collection of PBSCs and subsequent autologous transplantation. Details on treatment regimens were given elsewhere. 4,15 Briefly, thalidomide was given orally at the starting dose of 100 mg/d for 14 days and then increa...

Patients in complete clinical remission after myeloablative allogeneic stem cell transplantation (allo-SCT) were enrolled in a longitudinal study to assess the predictive value of molecular monitoring. Using polymerase chain reaction (PCR) for immunoglobulin gene rearrangements it was possible to generate a clonespecific molecular marker in 48 of 70 patients. Of these 48 patients, 16 (33%) attained durable PCR-negativity after transplantation, whereas 13 (27%) remained persistently PCR-positive and 19 (40%) showed a mixed pattern. The cumulative risk of relapse at 5 years was 0% for PCR-negative patients, 33% for PCRmixed patients, and 100% for PCR-positive patients. Within the group studied it was not possible to identify any clinical feature predictive of durable PCR-negativity. We believe that these findings could prompt the design of prospective studies to evaluate if the treatment of molecular disease can extend remission duration and survival.

MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.