Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.
Autologous stem cell transplant is considered the standard of care for patients with advanced symptomatic multiple myeloma. Despite prolongation of progression-free survival (PFS) and overall survival (OS) with autologous stem cell transplant, the disease remains incurable and most patients relapse within a few years of transplant. Efforts to improve outcome included intensification of induction therapy, incorporation of novel therapeutic agents into induction and transplant regimens, tandem transplantation and maintenance therapy following transplantation. The use of maintenance therapy post autologous stem cell transplant when the tumor burden is reduced was initially studied using α-interferon. This approach was shown to exert anti-myeloma activity but was associated with significant toxicities and no statistical difference in OS in a randomized study.1 Thalidomide is an active anti-myeloma agent with multiple effects including direct inhibition of myeloma cell growth and survival, direct stimulation of the cellular immune system, modulation of integrins compromising the adhesive interactions between the myeloma cells and bone marrow stroma and anti- angiogenic effects.2, 3, 4 Thalidomide has shown significant activity in patients with multiple myeloma both as frontline therapy and salvage therapy for patients with relapsed disease.5, 6 We conducted a phase II study to evaluate the tolerability and efficacy of thalidomide as maintenance therapy following autologous stem cell transplant.
Patients and methods
Between May 2001 and January 2004, 29 patients with stage II and III multiple myeloma were enrolled at our center on this phase II trial. The study was approved by the Institutional Review Board at City of Hope Comprehensive Cancer Center and voluntary written informed consent was obtained from all patients. Patients received priming chemotherapy with cyclophosphamide with or without taxol as previously described.7 Autologous peripheral stem cells were harvested according to standard procedures at City of Hope Comprehensive Cancer Center. All but one patient underwent single-cycle autologous peripheral blood stem cell transplant using high-dose melphalan 200 mg/m2. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day, provided that they did not have any greater than grade I residual toxicity related to transplant. Thalidomide dose was intended to be escalated by 50 mg every week to a target dose of 400 mg daily. Thalidomide was continued until disease progression or up to 6 months after achieving CR for a maximum total duration of 18 months following transplant. Vitamin B6 at 50 mg a day and monthly bisphosphonate therapy were given post transplant. Median age of patients at enrollment was 57 (range 49–70). Median β2 microglobulin at enrollment was 1.72 mg/l (range 1.01–3.68). Cytogenetic data were available in all but three patients, six of whom had chromosome 13 abnormality. In three patients, chromosome 13 abnormality was detected by standard cytogenetic study with or without flourescence in situ hybridization (FISH) and in three patients it was detected by FISH only. Two patients had plasma cell leukemia at presentation. Nine patients had received thalidomide alone or in a combination with dexamethasone or chemotherapy before transplant. At enrollment, none of the patients were in CR, and 20 patients were in partial remission (PR). Two patients had progressive disease, six patients had stable disease and one patient was in near CR. Patient's characteristics are outlined in Table 1. All toxicities related to thalidomide were graded according to the National Cancer Institute Common Toxicity Criteria (version 2).
The primary objectives were to assess the feasibility and toxicities of thalidomide maintenance therapy following autologous peripheral stem cell transplantation and to evaluate the CR rate. The secondary objectives were to evaluate OS and PFS. Overall survival and PFS were calculated from date of transplant. Standard Kaplan–Meier and Cox regression methods were applied for survival analysis, Fisher's exact test was used for evaluating the relationship between categorical variables and logistic regression was used to evaluate the effect of dose on response rate. All statistics were carried out using SAS/STAT and S-Plus software. All significant testings were two-sided.
Complete remission was defined as absence of serum and urinary M component with negative immunofixation that was maintained for a minimum of 6 weeks and bone marrow less than 5% plasma cells using modified EBMT (Blade) criteria.8 Patients who met all other criteria for CR and had only positive immunofixation were considered in near CR. The separation of positive immunofixation group from those in PR was based on the observation that patients may have positive immunofixation intermittently and positive immunofixation does not necessarily lead to recurrence. Partial remission was defined as ⩾50% reduction in serum M protein, ⩾90% reduction in 24 h urinary light chain excretion and ⩾50% reduction in bone marrow plasma cells. Progressive disease was defined as a greater than 25% increase in the level of serum M protein.
Thalidomide tolerability and dose
Median follow-up for surviving patients was 27.7 months. One patient did not undergo transplant because of disease progression after priming chemotherapy and subsequently died of progressive myeloma. One patient declined maintenance thalidomide after transplant. One patient received dexamethasone in addition to thalidomide inadvertently, as maintenance treatment. The median tolerated dose of thalidomide was 200 mg a day (range 0–400 mg). The median duration of thalidomide maintenance therapy was 11 months (range 0.5–18 months). Only five patients reached and were maintained at the target dose of 400 mg a day. Eleven patients in the CR group completed 6 months of thalidomide, whereas three in the non-CR group completed 18 months of thalidomide. Twenty-three out of 27 patients required thalidomide dose reduction because of toxicities with a median of two dose reductions (range 1–6); 12 patients stopped and subsequently restarted thalidomide, and five patients discontinued thalidomide permanently because of toxicities. The median tolerated dose in previously thalidomide treated patients was 200 mg, similar to patients who did not receive thalidomide pre-transplant.
There was no treatment-related mortality. Fourteen patients developed peripheral neuropathy (eight patients grade I, four patients grade II and two patients grade III). One patient experienced grade III ataxia, one patient developed grade III dizziness and two patients experienced grade III fatigue. One 65-year-old patient experienced transient aphasia and dyslexia post transplant while on thalidomide. Extensive evaluation including brain computed tomography scan, carotid Doppler study and MR angiogram was non-diagnostic. This patient had mildly elevated cholesterol level. A diagnosis of transient ischemic attack (TIA) was made and thalidomide was discontinued. No patient received prophylaxis for deep vein thrombosis (DVT) while on thalidomide. Three patients had DVT before transplant, and no new case of DVT occurred post transplant. One patient experienced grade III lymphopenia, one patient grade III anemia and one patient developed grade III neutropenia. Ten patients experienced constipation and six patients had skin rash, all of which were grade I or II (Table 2).
Patients were evaluated for response after transplant before starting thalidomide. Five patients were in CR, four patients were in near CR, 10 patients were in PR and seven patients had stable disease. One patient had progressive disease. Data were not available in one patient. One patient did not receive transplant and was not included in the analysis. At 6 months post transplant, 10 patients achieved CR, three near CR with overall CR and near CR rates of 45%. Seven patients achieved PR. Five patients had stable disease and three patients had progressive disease (Table 3). There was a trend toward thalidomide dose and achievement of CR and near CR with 66% CR and near CR rates on thalidomide ⩾200 mg/day vs 33% CR and near CR rates on thalidomide <200 mg/day (P=0.1).
Overall survival and progression-free survival
Estimated OS was 83% and PFS was 49% at 2 years (Figure 1). Seventeen patients progressed. Six patients died of progressive disease, including the two patients who had plasma cell leukemia at presentation. One patient was diagnosed with bladder cancer after transplant and died of bladder cancer and progressive multiple myeloma. One patient developed myelodysplastic syndrome one and a half years after transplant. This patient is alive and free of myeloma. Overall survival and PFS were not different in patients who had received thalidomide before transplant as compared to patients who did not. There was a correlation between chromosome 13 abnormality and PFS and OS, with 2-year PFS of 70% in patients without chromosome 13 abnormality vs 16% in patients with chromosome 13 abnormality (P<0.01), and 2-year overall survival of 100% in patients without chromosome 13 abnormality vs 50% in patients with chromosome 13 abnormality (P=0.01). There was no statistically significant correlation between β2 microglobulin level and PFS and overall OS. Among patients who relapsed on maintenance therapy, only three patients were treated with new targeted therapies (two patients received bortezomib and one received the tyrosine kinase inhibitor SCIO-469). Other patients received dexamethasone, radiation therapy or chemotherapy. The median post relapse survival was 18 months.
Recurrent multiple myeloma remains the major cause of death after autologous stem cell transplantation. Maintenance treatment with active anti-myeloma agents post transplant may successfully eliminate minimal residual disease and further delay disease recurrence and potentially extend survival. Thalidomide, the first drug in the class of immunomodulatory drugs, has a broad spectrum of activities in multiple myeloma. Its oral route of administration with minimal myelosuppressive effects makes it an attractive agent for maintenance therapy post autologous transplant. Our results demonstrate that the early use of thalidomide post transplant is feasible and safe. The majority of patients were able to tolerate thalidomide at a median daily dose of 200 mg. Only five patients could be maintained on 400 mg of thalidomide daily. A study by the NCI group of Canada using a combination of thalidomide and prednisone post transplant found a daily dose of 200 mg of thalidomide as the tolerable maintenance therapy in the post transplant setting.9 Similar to our results, they reported CR and near CR rates of 38% at 1 year. They also reported a 7.5% incidence of DVT. In contrast, we did not observe any new cases of DVT on thalidomide. One patient experienced TIA while on thalidomide. This 65-year-old patient had mildly elevated cholesterol as a known risk factor for TIA. Although most of thromboembolic events reported on thalidomide are venous, there are few reports of arterial thrombotic events including cerebrovascular accident and TIA on thalidomide.10 Risk factors for development of thromboembolism in multiple myeloma patients treated with thalidomide are new diagnosis with high tumor burden at the time of therapy, and concomitant doxorubicin and steroid therapy.11 Whether or not patients should receive prophylactic anticoagulation post autologous stem cell transplant while on maintenance thalidomide is not clear and requires further study. We observed a trend between thalidomide daily dose ⩾200 mg and achievement of CR and near CR. However, possibly due to the small sample size in the study, the P-value did not reach statistical significance. Although thalidomide and its analogues may act by a direct dose-dependent effect on myeloma cell line and in multiple myeloma patients,2, 12, 13 clinical use of high-dose thalidomide is limited by increased toxicities as was observed in this study. Furthermore, durable responses with low-dose thalidomide, as low as 50–100 mg a day, have also been reported.14, 15 Our results also suggest that the potential benefit of thalidomide might be influenced by the underlying biological parameters such as presence of chromosome 13 abnormality. Because of the design of our study to start thalidomide early post transplant in a state of minimal residual disease, it is difficult to address the contribution of thalidomide to complete remission rate and it is also possible that our results could be related to delayed response from transplant. A study by the MD Anderson group utilized the combination of thalidomide and dexamethasone in 21 patients with disease in stable PR at a median of 7 months after autologous transplant. They reported a 57% response rate with 19% CR rate suggestive of further cytoreduction with maintenance thalidomide.16 Furthermore, a recent randomized study by the French group (IFM99) presented in an abstract form reported improvement in PFS with maintenance thalidomide post tandem autologous stem cell transplant with a 3-year PFS of 56% as compared to 34% in the observation arm and 37% in the pamidronate arm, although with no difference in OS as of yet.17 A study by the Arkansas group also reported an increase in CR rate and 5-year EFS with the addition of thalidomide to tandem autologous transplant plan throughout (Total Therapy II), with no difference in OS. They reported shorter survival from relapse in patients who received thalidomide.18 This shorter post relapse survival was traced to high amplification of chromosome 1q21, which was more often present on thalidomide arm. In our study, we observed a post relapse median survival of 18 months, which compares favorably to post relapse survival of 13 months on the thalidomide-containing arm of the Arkansas group. It must be noted that the shorter post relapse survival may be related to the fact that relapse occurs later on maintenance thalidomide, as OS was similar in the two treatment arms in Total Therapy II. Based on our study design, thalidomide was continued for up to 6 months after achieving CR for a maximum duration of 18 months. The median duration of maintenance thalidomide was 11 months in our study, suggesting that many patients achieved CR early on and did not require long-term therapy. In a recent report by the UK group presented in an abstract form, they observed an improvement in PFS in patients who received more than 12 months of thalidomide therapy post transplant.19 It is possible that a longer duration of maintenance thalidomide post transplant can further improve PFS. An ongoing phase III study by the Clinical Transplant Network (CTN) Group is also evaluating the role of maintenance thalidomide and dexamethasone in patients following tandem autologous stem cell transplant. In conclusion, thalidomide at a dose of 200 mg a day is safe and tolerable as maintenance therapy after autologous stem cell transplant with acceptable toxicities. Further studies investigating the potential role of newer anti-myeloma agents such as Imids or bortezomib either alone or in combination with dexamethasone in the post transplant setting are warranted, especially in patients with adverse prognostic features such as chromosome 13 abnormality.
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