A Phase II Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma

Multiple myeloma is ranked second in hematological malignancies in the United States (Munshi et al., 2001). Because no curable option exists, patients with early stage disease are typically observed without treatment until the disease progresses or symptoms appear.

The majority of patients will respond to initial chemotherapy, however, all treated patients repeatedly relapse with shorter remissions following each subsequent course of chemotherapy (Rajkumar et al., 2002a). Regimens most commonly used for initial therapy include melphalan and prednisone (MP), which induce remission in approximately 50% of patients (Alexanian et al., 1969), VAD-vincristine, adriamycin and dexamethasone with response rates in the 50% range (Salmon et al., 1994; Barlogie et al., 1984; Alexanian et al., 1986), dexamethasone pulses, and more recently introduced combinations of thalidomide with dexamethasone (Rajkumar et al., 2002b; Weber et al., 2003). All these regimens have comparable response rates. With the exception of the recent report, which showed a superior response rate to the combination of thalidomide with dexamethasone versus dexamethasone pulses (Rajkumar et al., 2004), multiple other comparative studies did not show superiority of any of these regimens for overall survival. Complete responses to any of these regimens are observed infrequently (< 5%). Patients who complete initial therapy, usually proceed to high dose chemotherapy with autologous stem cell transplant support. Alternatively, patients may be placed on maintenance regimen or can be observed. Except for one study with alternate day high dose of Prednisone (Berenson et al., 2002), no convincing evidence exists that maintenance impacts the natural history of the disease (Kyle, 2002; The Myeloma Trialists' Collaborative Group, 2001).

High dose chemotherapy has been used as consolidation in multiple myeloma by a number of investigators (Barlogie et al., 1986; Cunningham et al., 1994; Harousseau et al., 1995). A randomized trial conducted by French Myeloma Intergroup (IFM 90) provided evidence that treatment with high dose chemotherapy and autologous stem cell transplant (ASCT) after initial therapy results in significantly longer event-free survival (median 28 vs. 18 months) and overall survival (57 vs. 42 months) if compared to conventional chemotherapy (Attal et al., 1996). The benefit of auto transplantation was seen in patients of all ages (Siegel et al., 1999). More recently, similar results were reported from a large randomized study in Great Britain (Childs et al., 2003). Based on these studies, in patients eligible for transplant, consolidation of initial therapy with high dose therapy followed by ASCT is considered a standard of care (NCCN Guidelines 2004). However, ASCT is not curative even in patients who achieve complete response (CR), which is observed in 20-30% of patients who completed ASCT. Contamination of autologous stem cell collection with malignant myeloma cells may play some role. In support of this notion, syngeneic bone marrow transplants showed better and more durable outcomes than those seen with ASCT (Gahrton et al., 1999). Another reason for failure of autologous stem cell transplant is ineffective eradication of myeloma clone with high dose chemotherapy. In an effort to provide more effective elimination of malignant clones, some investigators developed intensified treatment regimens. Improved results have been reported using Total Therapy, which involves a sequence of treatments, including tandem ASCT (Barlogie et al., 1999, Barlogie at al., 2004). The notion that intensification of therapy improves outcomes has been validated in a recent randomized study, which showed that consolidation of initial therapy with tandem autologous stem cell transplant was superior than consolidation with single autologous stem cell transplant as measured by an improved duration of responses and overall survival (Attal at al, 2003). In contrast to ASCT, allogeneic stem cell transplantation can provide stem cell products free of malignant cells, as well as the benefit of graft-versus-myeloma effect.

However, very high 1-year mortality (30-60%) was reported in early allogeneic bone marrow transplant studies, with disease free survival in only 15-30% of patients and no superior survival if compared to ASCT (Bensinger et al., 1996; Bjorkstrand et al., 1996; Barlogie et al., 1995). More recent studies, including allogeneic transplants with nonmyeloablative conditioning regimens, provide more encouraging results (Reynolds et al., 2001; Badros et al., 2002). Recently, a combined treatment with ASCT followed by a non-myeloablative allogeneic stem cell transplant showed very promising outcomes and improved, although still significant toxicity, with CR rates in 55-60% range (Kroger et al., 2002; Maloney et al., 2003). It is too early to determine whether improved responses using this approach will result in an increased survival.

Emerging data suggest that achieving CR or near CR (nCR) will result in more durable remission and longer survival. Recent analysis of long term outcomes of patients treated on randomized French study IMG90 clearly indicates that the longest survivors are those patients who achieve at least very good partial response or complete response (Harousseau, 2003). At 7 years, 60% of patients were alive in a group, which achieved CR or near CR. In contrast, in a group of patients who achieved > PR but less than CR or near CR only 30% were alive and among patients who had less than PR none were alive. Similar results have bee recently reported for patients who underwent allogeneic stem cell transplant (Corradini et al., 2003). It is not clear whether CR in response to initial therapy and prior to transplant may have similar impact on overall outcomes. Regardless of specific transplant approach, survival curves do not plateau and all patients are expected to relapse, regardless of method of intensification therapy, possibly due to persistence of residual population of chemotherapy-resistant clonogenic myeloma cells.