Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

Abstract

Summary Background High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide. Methods Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to 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 non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475. Findings 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1·75, 80% CI 1·30–2·32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high-dose group (p=0·0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three 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 (p=0·0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0·003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0·0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0·04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0·08), respectively. Interpretation 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.

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

“…The LD dex selected for this study corresponds to that typically used when given weekly in combination with other agents. The use of LD dex was established in combination with lenalidomide in a study that demonstrated superior safety and improved outcomes when compared with high‐dose dex (Rajkumar et al , 2010). An interim analysis was built into the study, if the enrolment targets were met after the pre‐specified Simon 2‐stage expansion criteria.…”

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

“…Rd which combines lenalidomide with a lower dose of dexamethasone (40 mg once weekly) is an active regimen in newly diagnosed myeloma, and has less toxicity and better OS than lenalidomide plus high dose dexamethasone [49]. Stem cell collection with granulocyte colony-stimulating factor (G-CSF) alone may be impaired when Rd is used as induction therapy [50].…”

ESRD due to Multiple Myeloma in the United States, 2001–2010

“…1 In this regard, the therapeutic approach to earlier-stage multiple myeloma has changed substantially in recent decades. [2][3][4][5][6][7][8][9][10][11] However, the current belief is that even with aggressive therapy, the risk of progression to ESRD is high, recovery of renal function is low, and survival time on dialysis therapy is very short. 12 As the detection and treatment of multiple myeloma continues to evolve, it seems natural to question whether reductions in associated ESRD have occurred, and if so, among which demographic subgroups.…”