Myeloma and Lymphoma: Initial Therapy and Therapeutic Sequencing in Multiple Myeloma

Posted by James

Speaker: Paul Richardson, Dana-Farber Cancer Institute, Boston, Massachusetts

Lenalidomide/Dexamethasone. The combination of lenalidomide and dexamethasone is effective for newly diagnosed MM. It demonstrated a 91% overall objective response with a complete response in 6% of the patients. An ongoing study of lenalidomide and dexamethasone (at a lower dose) is in progress to establish better tolerability than that found in the previous standard dosing study. Results to date indicate that lenalidomide/dexamethasone provides high anti-cancer responses when it is used as an initial therapy.

A phase 3 study of lenalidomide 25 mg/day plus dexa-methasone 40 mg/day versus dexamethasone plus placebo was conducted in the U.S., Canada, Europe, Israel, and Australia. The primary endpoints were time to tumor progression (TTP), overall survival, myeloma response rate, and safety. The combination therapy showed a high rate of response and clinical remission and a TTP of 15 months, versus five months with dexamethasone plus placebo.
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Common adverse drug events (ADEs) included neutro-penia, thrombocytopenia, anemia, and deep vein thrombosis (DVT) or pulmonary embolism. It was concluded that len-alidomide 25 mg plus high-dose dexamethasone significantly prolonged the TTP (P < .0001). The combination was well tolerated with predictable and manageable side effects.

Bortezomib versus Dexamethasone. Bortezomib, a small-molecule boronic acid dipeptide reversible proteasome inhibitor, prevents interactions of MM cells with bone marrow stromal cells and the secretion of cytokines, including IL-6, VEGF, and insulin growth factor-1 (IGF-1). In a large phase 3 study, Assessment of Proteasome Inhibition for Extending Remissions (APEX), bortezomib demonstrated superior efficacy to high-dose dexamethasone in relapsed MM. There was a significant TTP benefit (P < .0001), with a 78% increase in the median TTP. There was also a response rate advantage (P < .0001) (38% vs. 18%), clinical remission, and partial remission, and clinical remission plus partial remission with bortezomib (13%) versus dexamethasone (2%).

Bortezomib/Lenalidomide. In a combination study of bortezomib/lenalidomide in MM patients, the beneficial effects were found to be additive and synergistic. The bortezomib dose was 1-1.3 mg/m² IV. The oral dose of lenalidomide was 5-10 mg each day. The remission rate (clinical + partial + minimal) was 91%. There were no discontinuations or serious ADEs through the first three cohorts. The results were encouraging, and another 10 patients will be enrolled at the maximum tolerated dose. Future investigations will include phase 2 trials of relapsed and refractory MM and newly diagnosed MM. canadian antibiotics

Thalidomide/Dexamethasone. Several clinical studies have compared the thalidomide/dexamethasone combination with dexamethasone alone in MM patients. Superior response rates were found with the combination in newly diagnosed MM, but the combination was associated with higher toxicity than dexamethasone alone. There was also a need for DVT prophylaxis with the drug combination. The higher response rates of thalidomide/dexamethasone must be weighed against increased toxicity for individual patients.