Lower-dose dexamethasone can be used to treat newly diagnosed myeloma

22 Oct 2009

High-dose dexamethasone is a mainstay of therapy for multiple myeloma. However, a study published in The Lancet Oncology concludes that lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma; and is thus a viable treatment option for these patients. The Article is written by Professor S Vincent Rajkumar, Mayo Clinic, Rochester, MN, USA, and colleagues on behalf of the Eastern Cooperative Oncology Group (ECOG), USA.

In this randomised controlled trial, patients with untreated, symptomatic myeloma were assigned to receive lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles, assessed with European Group for Blood and Bone Marrow Transplant criteria.

The researchers found that 79% of 214 patients receiving high-dose therapy and 68% of 205 patients on low-dose therapy had complete or partial response within four cycles. However, at the second interim analysis at 1 year, overall survival was 96% in the low-dose dexamethasone group compared with 87% in the high-dose group. As a result, the trial was stopped and patients on high dose therapy were crossed over to low-dose therapy. 117 (52%) patients on the high-dose regimen had grade 3 or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available. 12 (5%) of 222 on high dose and one (<1%) of 220 on low-dose dexamethasone died in the first four months. The three most common grade three or higher toxicities were deep-vein thrombosis-57 (26%) of 223 versus 27 (12%) of 220; infections including pneumonia-35 (16%) of 223 versus 20 (9%) of 220; and fatigue-33 (15%) of 223 versus 20 (9%) of 220, respectively.

The authors say: "High-dose dexamethasone in a community-setting seems more toxic than low-dose dexamethasone, with more early deaths in the first 4 months, increased risk of thromboembolic complications, and higher overall risk of serious adverseevents, particularly in patients older than 65 years."

They conclude: "This trial...shows that low-dose dexamethasone in conjunction with lenalidomide is an active regimen for newly diagnosed myeloma with acceptable toxicity and low early mortality."

They add*: "The results of this trial show that the use of high-dose dexamethasone is not needed for the most part in the context of new active agents for myeloma, and as a result almost all current phase 3 trials have adopted low-dose dexamethasone as the standard in combination regimens."

In an accompanying Reflection and Reaction comment, Professor Antonio Palumbo and Dr Francesca Gay, Divisione di Ematologia dell'Universita di Torino, Turin , Italy say: "The high efficacy and good tolerability of lenalidomide plus low-dose dexamethasone as initial therapy for myeloma has thus been established."

They conclude: "Further randomised phase 3 studies, comparing this regimen with current standards of care such as melphalan-prednisone-thalidomide or melphalan-prednisone-bortezomib, are still needed to verify whether lenalidomide plus low-dose dexamethasone can become a new standard of care for patients with myeloma, and whether the optimal therapeutic strategy should be long-term treatment with lenalidomide and steroids or short-term treatment followed by consolidation with autologous transplantation."