Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma.

PURPOSE: The efficacy of low-dose thalidomide (THAL) plus dexamethasone (DEX) has been evaluated in myeloma. The clinical outcome of patients treated with THAL-DEX was compared with that of a control group treated with conventional chemotherapy (CC). EXPERIMENTAL DESIGN: A total of 120 relapsed/refractory patients to one (52%), or two or more(48%) lines of chemotherapy were treated with THAL 100mg/day (continuous) and DEX 40 mg (days 1-4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. Clinical characteristics were homogeneous in the two groups. RESULTS: In patients treated after one line of chemotherapy, THAL-DEX significantly improved outcome. Median progression-free survival (PFS) was superior in THAL-DEX group versus CC group (17 months versus 11 months, P = 0.0024). The median survival for THAL-DEX patients has not to been reached, but the probabilities of survival at 3 years were 60% after THAL-DEX and 26% after CC (P = 0.0016). The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy, was similar. In the THAL-DEX group, the medianPFS was 11 months compared to 9 months in the CC group (P = NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL-DEX and CC). CONCLUSIONS: As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.

Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant.

OBJECTIVES: High-dose therapy followed by autologous transplant (AT) is the effective induction treatment for newly diagnosed multiple myeloma (MM) patients. The best salvage therapy has not been defined; treatment options include thalidomide plus dexamethasone (TD), AT and conventional chemotherapy (CC). The aim of the study was to define the best treatment option for patients relapsing after AT. PATIENTS AND METHODS: We compared the outcome of 90 MM patients treated at diagnosis with AT and then salvaged with TD (43 patients), AT (28 patients) or CC (19 patients). The major prognostic factors, the median times between diagnosis and start of salvage treatment and the progression-free survival (PFS) from diagnosis were similar among the three groups. RESULTS: The response rate was higher after salvage AT and after TD, and lower after CC (P < 0.001). TD significantly prolonged PFS from first relapse (P < 0.0001). Median PFS was 20.3 months after TD, 9 months after AT, and 4.5 months after CC. Overall survival (OS) from first relapse was significantly improved by TD (median OS 55.5 months) but not by AT (15 months) or CC (27.5 months) (P = 0.008). Multivariate analysis indicated that TD and age were the only independent risk factors associated with improved outcome. CONCLUSION: TD improved PFS and OS in myeloma patients relapsing after AT.

Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.

BACKGROUND: Thalidomide is an immunomodulatory drug with strong antimyeloma activity. It is an effective treatment for multiple myeloma at disease recurrence and at diagnosis, both as a single agent and in combination with steroids or chemotherapy. No data are available on the association of thalidomide with oral melphalan and prednisone, still considered the standard treatment for elderly patients. METHODS: The feasibility and efficacy of the combination of melphalan, prednisone, and thalidomide (MPT) have been valuated in 49 newly diagnosed patients with multiple myeloma. RESULTS: According to European Bone Marrow Transplantation/ International Bone Marrow Transplantation Registry (EBMT/IBMTR) criteria, 18% of patients achieved immunofixation-negative complete disease remission (CR), 6% achieved immunofixation-positive near CR, 4% achieved a very good partial response, and 45% achieved a partial response, with a 50-89% reduction in monoclonal paraprotein. Six percent did not respond and 10% showed progressive disease. The median time to maximum response was 4 months. The Kaplan-Meier estimates of event-free survival and overall survival at 2 years were 64% and 91%, respectively. The major acute adverse events (National Cancer Institute Common Toxicity Criteria Grade III-IV) included thrombosis (20%), infections (12%), constipation (6%), and hematologic (22%) and neurologic (8%) toxicities. One patient died of pulmonary thromboembolism. CONCLUSIONS: These data suggested that MPT induced rapid and durable tumor responses with CR rates similar to those observed after autologous transplantation. Administration of prophylactic anticoagulant was required to prevent thromboembolism. MPT merits further investigation in randomized clinical trials.

Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome.

Cyclooxygenase 2 (COX-2) is an inflammation-associated enzyme involved in the pathogenesis of many solid tumors, but little is known about its presence and role in hematologic neoplasms. Multiple myeloma (MM) is known to involve a deregulated cytokine network with secretion of inflammatory mediators. We thus decided to investigate the involvement of COX-2 in this neoplasm. Western blotting (WB) was used to evaluate 142 bone marrow (BM) specimens, including MM and monoclonal gammopathy of undetermined significance (MGUS). Selected cases under-went further evaluation by WB on purified CD138(+) cells, immunohistochemistry (IC), and real-time polymerase chain reaction (PCR) for mRNA expression. COX-2 was expressed in 11% (2 of 18) of MGUS specimens, 31% (29 of 94) of MM at diagnosis, and 47% (14 of 30) of MM with relapsed/refractory disease. COX-2 positivity was associated with a poor outcome in terms of progression-free (18 vs 36 months; P < .001) and overall survival (28 vs 52 months; P < .05). Real-time PCR showed COX-2 mRNA overexpression. IC and cell separation studies demonstrated COX-2 expression to be restricted to malignant plasma cells. This is the first report of the presence and prognostic role of COX-2 expression in MM. Future studies will assess COX-2 involvement in other hematologic tumors and its potential use as a therapeutic or chemo-preventive target in onco-hematology.

New drugs for treatment of multiple myeloma.

Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into the biology of MM have identified molecular mechanisms that hold promise as therapeutic targets. Laboratory and preclinical studies have shown that intracellular regulatory proteins and functional interactions between MM cells and the bone-marrow microenvironment have a pivotal role in the growth, survival, drug resistance, and malignant progression of MM cells. New agents associated with molecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results. Here, we discuss the mechanisms of action of these new rational drugs and the preliminary clinical outcomes of a new treatment regimen for MM.

Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma.

BACKGROUND AND OBJECTIVES: Since optimal collection of peripheral blood progenitor cells (PBPC) remains crucial for high-dose therapy in patients with multiple myeloma (MM) in relapse phase or refractory to chemotherapy, we evaluated several variables that may influence mobilization. DESIGN AND METHODS: Eighty-nine patients who underwent a standard mobilization procedure with cyclophosphamide (3 g/m2) and growth factors entered the study. A composite collection totalling at least 2x106 CD34+/kg was defined as a sufficient yield: 59 patients achieved an adequate collection. A reliable factor to predict adequate yields was prior therapy: an adequate collection was obtained in 92% of patients treated with conventional non-alkylating therapy (VAD-based regimens), in 56% treated with oral melphalan and in 23% who had received intravenous melphalan. RESULTS: The three groups were similar for most clinical features. After adjustment for several potential confounders, the probability of an adequate PBPC collection remained higher in the group treated with non-alkylating agents, with an odds ratio (OR) of 6.14 (95% confidence interval, CI=1.34, 28.13) and lower in those treated with intravenous melphalan (OR=0.08; CI=0.01-0.61), when compared to the group treated with oral melphalan. Among the other prognostic factors (stage, percentage of bone marrow plasma cells, b2-microglobulin, labeling index, isotype, monoclonal component, Bence-Jones proteinuria) evaluated at diagnosis, there was no clear association with progenitor cell yield. INTERPRETATION AND CONCLUSIONS: In conclusion, patients who are potential candidates for high-dose therapy with PBPC support should not receive conventional alkylating therapy, even orally. Alternatively, progenitor cells should be collected early in the course of MM.

Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial.

High-dose therapy is an effective standard treatment for multiple myeloma patients. Evidence that intermediate-dose therapy improves survival is limited. At diagnosis, about 70% of patients are older than 65. Intermediate-dose regimen is very well tolerated in older patients. In a multicenter study, 194 patients were randomized to receive at diagnosis either conventional chemotherapy (6 courses of oral melphalan and prednisone [MP]) or intermediate-dose therapy (2 courses of melphalan at 100 mg/m(2) [MEL100]) with stem cell support. Response rate was higher after MEL100. Near-complete remission (nCR) was 6% after MP and 25% after MEL100 (P = .0002). At 3 years, MEL100 increased event-free survival (EFS) from 16% to 37% and overall survival (OS) from 62% to 77% (P < .001). Similar results were observed in patients aged 65 to 70: nCR was 8% after MP and 25% after MEL100 (P = .05); at 3 years, MEL100 improved EFS from 18% to 31% (P = .01) and OS from 58% to 73% (P = .01). Patients aged 65 to 70 had a median OS of 37.2 months (MP) versus 58 months (MEL100). Intermediate-dose melphalan improves response rate, EFS, and OS in myeloma patients, specifically in those aged 65 to 70. It constitutes a more effective first-line regimen than standard treatment for elderly patients.