title: A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.
abstract: Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.
authors.affiliation: University of Melbourne and Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Miles.Prince@petermac.org
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.forename: Andrew
authors.initials: A
authors.lastname: Roberts
authors.forename: Vinod
authors.initials: V
authors.lastname: Ganju
authors.forename: Craig
authors.initials: C
authors.lastname: Underhill
authors.forename: John
authors.initials: J
authors.lastname: Catalano
authors.forename: Richard
authors.initials: R
authors.lastname: Bell
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: David
authors.initials: D
authors.lastname: Westerman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Simmons
authors.forename: Kate
authors.initials: K
authors.lastname: Lillie
authors.forename: Alvin D
authors.initials: AD
authors.lastname: Milner
authors.forename: Juliana Di
authors.initials: JD
authors.lastname: Iulio
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Zeldis
authors.forename: Robert
authors.initials: R
authors.lastname: Ramsay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D011720:Pyrazoles / Q000008:administration & dosage*; D012008:Recurrence; D012306:Risk; D013449:Sulfonamides / Q000008:administration & dosage*; D013792:Thalidomide / Q000008:administration & dosage* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D001613:beta 2-Microglobulin; D013792:Thalidomide; D000068579:Celecoxib