Progressively Intensified Chemotherapy: A Phase II Trial in Patients with Multiple Myeloma.

Background: A number of randomized and non-randomized studies have demonstrated the efficacy of the high-dose therapy with stem cell rescue. The efficacies of these treatment modalities were mainly related to the degree of myeloablation and destruction of the bone marrow microenvironment. We decided to evaluate the efficacy and toxicities of a progressively intensified chemotherapy followed by stem cell rescue in patients with multiple myeloma.

Methods: Between 1997 and 2000 twenty-eight patients (median age, 51years; range 38–70) consecutively enrolled in this study. Patients received VAD combination chemotherapy as induction regimen. Blood progenitor cells were collected following two cycles of cyclophosphamide, etoposide and granulocyte-colony stimulating factor (G-CSF). The chemotherapy intensified by giving melphalan at a dose of 140 mg/m²and mitoxantrone at a dose of 60 mg/m² on day -7of 1^st myeloablation followed by stem cell rescue on day 0. Between 56–94 days following 1^st transplant patients received 2^nd intensification by Melphalan at a dose of 200 mg/m² on day -3 of 2^nd myeloablation followed by stem cell rescue on day 0. After recovery from 2^nd intensification patients received Interferon-alfa2b and prednison as maintenance therapy for 18 months.

Results: After induction there was 7%(2) complete response (CR), 72%(20) partial response and in 21%(6) their disease progressed (PD). Following escalation with cyclophosphamide and etoposide the CR rate was 21%(6), with 86%(24) overall response. After dose intensification with melphalan, mitoxantrone and 1^st stem cell rescue the CR increased to 61%(17) with 89%(25) overall response. Following 2^nd dose intensification with melphalan and stem cell rescue the CR increased to 68%(18) and overall response reached to 90%(24) Most non-hematologic toxicities were in the range of grade 0–2. Mucositis and diarrhea were the most severe toxicities associated with 1^st and 2^nd intensification. After median duration of follow up of 66.67 months the survival probability was 56.47% with 95 percent confidence interval of 42.65% and 70.29%.

Conclusion: Our study suggests that combination of cyclophosphamide with etoposide could induce remission in significant number of patients prior to aphresis and by decreasing tumor burden could reduce stem-cell contamination (in vivo purging). Also mitoxantrone in addition to melphalan as a standard preparative regimen could result in high rates of complete remission and overall response, which could be translated in to better overall survival.