Drug combination effective against multiple myeloma: NEJM study shows lenalidomide-dexamethasone slows disease

Abstract

Pairing a new thalidomide derivative with a steroid slows progress ofmultiple myeloma, an incurable bone marrow cancer, and prolongs thelives of patients who have relapsed from previous treatment,researchers reported in the Nov. 22, 2007 New England Journal ofMedicine.In the study conducted at 44 centers in the United States and Canada,353 patients with myeloma received either a combination oflenalidomide (Revlimid) and the steroid dexamethasone ordexamethasone plus a placebo."Those taking the lenalidomide combination had a median time todisease progression of 11.1 months compared with 4.7 months in theplacebo-dexamethasone group and an improved median overall survivaltime of 29.6 months compared with 20.2 months," says lead authorDonna Weber, M.D., associate professor in the Department of LymphomaandMyeloma at The University of Texas M. D. Anderson Cancer Center.The results were impressive enough that in December of 2005 anindependent interim data analysis resulted in the trial being haltedearly so those on placebo-dexamethasone could also benefit from theaddition of lenalidomide.The collaborative study by North American Multiple Myeloma StudyInvestigators, and an international trial also reported in the NewEngland Journal of Medicine, led to the approval of lenalidomide anddexamethasone for previously treated patients by the U.S. Food andDrug Administration in 2006."These trials highlight how large-scale cooperation in a team effortby myeloma investigators can quickly confirm benefits and introducenew active agents for patients with this disease," Weber says. "Wealso owe a debt to the willing patients who participated in thisstudy."Multiple myeloma is caused by formation of abnormal plasma cells, atype of white blood cell, in the bone marrow. These cells multiplyrapidly, crowding out normal red and white blood cells and platelets.Tumors starting in the bone marrow may cause pain, and weaken bonespredisposing them to fracture. In the United States about 20,000people are diagnosed with multiple myeloma annually, and about 11,000succumb to the disease each year.Thalidomide, a breakthrough drug for multiple myeloma, is producedand marketed by Celgene Corporation as Thalomid. The companychemically altered thalidomide to make lenalidomide, knowncommercially as Revlimid, in hopes of reducing side effects andimproving efficacy against the disease. The drugs attack both themalignant cells and the cellular environment that nurtures them.Of 177 patients who received the lenalidomide combination therapy,108 (61%) had complete, near-complete or partial responses to themedication compared with 35 patients out of 176 (19.9%) in theplacebo-dexamethasone group.An analysis by Michael Wang, M.D., assistant professor in theDepartment of Lymphoma and Myeloma at M. D. Anderson, found 56.8% ofpatients who had prior treatment with thalidomide before receivingthe lenalidomide combination had a response, compared with 64.1% withno previous thalidomide treatment. "That suggests that the drugsdiffer enough to get a separate response, not just a refinement ofside effects," Weber says.The superior results for the combination also held up among patientspreviously treated with another new drug, bortezomib, a proteasomeinhibitor known commercially as Velcade and marketed by MillenniumPharmaceuticals.Combinations of drugs are important in ongoing treatment as apatient's disease becomes resistant to one therapy. "It's great thatthis research gave us a new drug," Weber says, "But what we also findwith new drugs is that they work well with older therapies, whichgives us many combinations to offer our patients."Lenalidomide is being tested as a front-line therapy and incombination with other medications in a variety of clinical trials.Overall, 85.3% of those receiving the combination therapy experiencedside effects compared with 73.1% of the placebo-dexamethasone group.Some of the side effects were serious enough to cause 19.8% of thecombination group and 10.2% of the placebo group to quit the trial.Major side effects from the combination were suppression of patients'white blood cells, making them vulnerable to infection, and formationof blood clots. In most cases, these side effects were countered bydecreasing the lenalidomide dose, or administering antibiotics oranticoagulants.One of the major side effects of thalidomide - significant nerve painand numbness in the limbs known as peripheral neuropathy - was nearlyabsent in the lenalidomide group.The research was funded by Celgene. Weber and Wang have receivedgrant funds and lecture fees from Celgene. These relationships aremanaged in accordance with M. D. Anderson's conflict-of-interestpolicies.Co-authors with Weber and Wang are Christine Chen, M.D., PrincessMargaret Hospital in Toronto; Ruben Niesvizky, M.D., Weill CornellMedical College; Andrew Belch, M.D., Cross Cancer Institute,Edmonton, Alberta; Edward Stadtmauer, M.D., University ofPennsylvania Cancer Center; David Siegel, M.D., The Cancer Center atHackensack University Medical Center; Ivan Borrello, M.D., JohnsHopkins; S. Vincent Rajkumar, M.D., Mayo Clinic Cancer Center;Asher Alban Chanan-Khan, M.D., Roswell Park Cancer Institute; SagarLonial, M.D., Emory University; and Zhinuan Yu, Ph.D., John Patin,Marta Olesnyckyj, Jerome B. Zeldis, M.D., Ph.D., and Robert D.Knight, M.D., all of Celgene in Summit, N.J.