Rapid Control of Previously Untreated Multiple Myeloma with Bortezomib-Thalidomide-Dexamethasone Followed by Early Intensive Therapy.

With the combination of thalidomide - dexamethasone (TD), we had induced disease remission in 62% of 132 newly diagnosed patients with multiple myeloma (MM) usually with preventable or manageable side effects (constipation, insomnia, edema). With added bortezomib, the 3-drug combination (VTD) had induced remission in 55% of patients with myeloma resistant to standard therapies, twice the frequency of 28% observed with bortezomib alone (Zangari et al, 2003). Between 7/03 - 5/05, we prescribed VTD for 36 consecutive, previously untreated patients. Median age was 60 (33–80), median B2M 4.2 mg/L (1.4–19), median Hgb 10.2 g/dl (6.8–15.5), creatinine > 2.0 mg/dl in 19%. Initial dose of thalidomide was 100 mg each evening, increased every 7 days to maximum of 200 mg in accordance with tolerance; dexamethasone was given in a dose of 20 mg/m2 for 4 days beginning on days 1, 9 and 17. Bortezomib was given IV twice weekly for 4 infusions in 3 different doses after one patient inadvertently received 1.9 mg/m2 without side effects and rapid onset of complete remission; 15 patients received 1.3 mg/m2, 11 patients were given 1.5 mg/m2 and 10 patients received > 1.6 mg/m2. As prophylaxis of deep vein thrombosis, all received therapeutic doses of low-molecular weight heparin or coumadin to maintain INR between 2.0–3.0. Applying strict criteria of response (>75% reduction serum myeloma protein and/or 99% reduction Bence Jones protein), disease remission was observed in 28 patients (78%) including 7 patients with complete remission (19%); with prior standard criteria (>50% reduction serum myeloma protein and/or >90% reduction Bence Jones protein excretion), the response rate was 92%. Response rates by either criteria were 30% higher than those observed previously among similar patients treated with TD (p 1.5 mg/m2 were similar to those with 1.3 mg/m2, suggesting no added value with a dose higher than 1.3 mg/m2. Remissions were confirmed within 1.5 months in all responding patients so that no more than 2 cycles of therapy were necessary before intensification or maintenance, thus avoiding potential side effects and cost of more therapy. Side effects were often preventable, but otherwise were mild and reversible; deep vein thrombosis occurred in 2 patients, short-term neuropathy of grade 3 degree in 3 patients, serious non-neutropenic infections in 3 patients and orthostatic hypotension in 1 patient. Median nadir of neutrophil count was 2930/μl (range 500 – 8200); median nadir of platelet count was 130,000/μl (range 28,000–268,000). After median 4 months, intensive therapy supported by autologous blood stem cells was given to 22 patients without serious complications; primary resistant disease became responsive in 4 of 6 patients, partial remission was converted to complete in 3 of 13 patients, and 3 patients were intensified in CR. Consequently, the myeloma was in remission in 89% of all patients by strict criteria including 31% with complete remission. This experience supported a limited program of bortezomib-thalidomide-dexamethasone, followed by early intensive therapy, as an effective and safe primary treatment for newly diagnosed patients with multiple myeloma.