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Dr. Rajkumar - A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, Minnesota
Member, IMF Board of Scientific Advisors

"Although the response rates may have been higher with high dose dexamethasone, this did not translate into better time to progression or response duration or progression-free survival. In fact, all of the long term markers...were all in favor of lenalidomide and low dose dexamethasone."
Dr. Vincent Rajkumar

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A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group. Session Type: Oral Session

S. Vincent Rajkumar, Susanna Jacobus, Natalie Callander, Rafael Fonseca, David Vesole, Michael Williams, Rafat Abonour, David Siegel, Philip Greipp Mayo Clinic, Rochester, MN, USA; Dana Farber Cancer Institute, Boston, MA, USA; University of Wisconsin, Madison, WI, USA; Mayo Clinic, Scottsdale, AZ, USA; St. Vincents Comprehensive Cancer Center, New York, NY, USA; University of Virginia, Charlottesville, VA, USA; Indiana University Medical Center, Indianapolis, IN, USA; Hackensack University Medical Center, Hackensack, NJ, USA

Aim: A phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1-21 every 28 days plus dex 40 mg days 1-4, 9-12, and 17-20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was response rate at 4 months, with the null hypothesis being that the response rates in the two 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. All analysis were performed on an intent to treat basis. An independent DMC recommended release of study results. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 17 months. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities, including DVT/PE and infections, were significantly higher in the high dose dex arm (see Table). Overall survival (OS) at the second pre-planned interim analysis was significantly superior with lenalidomide plus low dose dex, P<0.001; one year survival 96% (Rd) versus 87% (RD). The 18 month survival rate is 91% versus 80%, respectively. OS differences in favor of the low dose dex arm were seen in pts <65 (P=0.022; one year rate 97% vs 92%) as well as pts 65 and older (P=0.002; one year rate 94% vs 83%), respectively. Sixty-one patients have died; 42 in the RD arm and 16 in Rd arm. The cause of death has been verified by detailed chart review in 38 patients. Of 29 verified deaths in the RD arm, 13 were due to disease progression, 6 thrombosis/embolism, 3 infection, 3 cardiac ischemia, 1 stroke, and 1 respiratory failure. Of 9 verified deaths in the Rd arm, 5 were due to disease progression, 2 infection, 1 thrombosis/embolism, and 1 cardiac arrest. Response rate data are expected to be available at the time of the meeting. Conclusions: Lenalidomide plus low-dose dexamethasone (Rd) is associated with superior OS compared to lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM. The increased mortality in Arm A is due to disease progression (myeloma deaths) as well as increased toxicity. This study has major implications for the use of high-dose dexamethasone in the treatment of newly diagnosed MM.

Major Grade 3 or Higher Adverse Events
Toxicity Arm A % Arm B % P value
Neutropenia 10 19 0.01
DVT/PE 25 9 <0.001
Infections 16 6 <0.001
Any grade 3 or higher non-hematologic 49 32 <0.001
Any grade 4 or higher non-hematologic 20 9 <0.001
Deaths in first 4 months 5 0.5 0.006

Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007

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