Myeloma: Firstline Phase III Trials in Multiple Myeloma
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, MD1,
Susanna Jacobus, MS2,*,
Natalie Callander, MD3,
Rafael Fonseca, MD4,
David Vesole, MD, PhD5,
Michael Williams, MD6,
Rafat Abonour, MD7,
David Siegel, MD8 and
Philip Greipp, MD1
1 Mayo Clinic, Rochester, MN, USA; 2 Dana Farber Cancer Institute, Boston, MA, USA; 3 University of Wisconsin, Madison, WI, USA; 4 Mayo Clinic, Scottsdale, AZ, USA; 5 St. Vincents Comprehensive Cancer Center, New York, NY, USA; 6 University of Virginia, Charlottesville, VA, USA; 7 Indiana University Medical Center, Indianapolis, IN, USA and 8 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) innewly diagnosed myeloma (MM).
Methods: Pts with untreated, symptomatic MM were eligible. Ptsin the RD arm (Arm A) received lenalidomide 25 mg/day PO days1–21 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 responserate at 4 months, with the null hypothesis being that the responserates in the two 2 arms are equivalent. Planned sample sizewas 196 eligible pts per arm with one-sided 0.10 Type I and0.05 Type II error rate. All analysis were performed on an intentto treat basis. An independent DMC recommended release of studyresults.
Results: 445 pts (median age, 65 yrs) were accrued; 223 randomizedto RD, 222 to Rd. Median follow-up time is 17 months. Arms werewell balanced for age, gender, stage, bone lesions, hemoglobin,beta-2 microglobulin, performance status, bone marrow plasmacells, and M protein levels at baseline. Major grade 3 or highertoxicities, including DVT/PE and infections, were significantlyhigher in the high dose dex arm (see Table). Overall survival(OS) at the second pre-planned interim analysis was significantlysuperior with lenalidomide plus low dose dex, P<0.001; oneyear survival 96% (Rd) versus 87% (RD). The 18 month survivalrate is 91% versus 80%, respectively. OS differences in favorof the low dose dex arm were seen in pts <65 (P=0.022; oneyear rate 97% vs 92%) as well as pts 65 and older (P=0.002;one year rate 94% vs 83%), respectively. Sixty-one patientshave died; 42 in the RD arm and 16 in Rd arm. The cause of deathhas been verified by detailed chart review in 38 patients. Of29 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 beavailable at the time of the meeting.
Conclusions: Lenalidomide plus low-dose dexamethasone (Rd) isassociated with superior OS compared to lenalidomide plus high-dosedexamethasone (RD) in newly diagnosed MM. The increased mortalityin Arm A is due to disease progression (myeloma deaths) as wellas increased toxicity. This study has major implications forthe use of high-dose dexamethasone in the treatment of newlydiagnosed MM.
Major Grade 3 or Higher Adverse Events
Arm A %
Anygrade 3 or higher non-hematologic
Any grade4 or higher non-hematologic
Deaths in first4 months
Disclosure:Research Funding: S. Vincent Rajkumar - Researchsupport, Celgene Corporation. Off Label Use: Lenalidomide -newly diagnosed myeloma.