Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial

Abstract

Purpose This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

“…8,14 More patients experienced grade 3 or 4 neutropenia with MPT (45%) than with Rd continuous (30%) or Rd18 (26%). Grade 3 or 4 infections were observed in a greater proportion of patients treated with Rd continuous (32%) than with Rd18 (22%) or MPT (17%).…”

“…Other second-line treatment, n/n (%) § 41/299 (14) 49/377 (13) 33/381 (9) CR, n (%) 0 4 (8) 1 (3) VGPR, n (%) 2 (5) 1 (2) 3 (9) PR or better, n (%) 6 (15) 19 ( thalidomide, which are often associated with more hematologic and neurological toxicity, may have had inferior outcomes with bortezomib due to lower bone marrow reserves and residual symptoms of peripheral neuropathy. 16,17 Regardless of the second or subsequent lines of therapy they received, however, patients in the Rd continuous and Rd18 arms had higher median OS and better outcomes after second-line treatment compared with patients in the MPT arm.…”

Long-lasting Responses to Immunomodulatory Drugs (IMIDs) in Combination with Dexamethasone in Multiple Myeloma; Identification of Exceptional Responders at any Treatment Line

“…In addition, they can be easily and relatively safely [13] administered per os, continuously [14], in an outpatient basis rendering them very attractive. Long term benefit of IMIDs/dexamethasone treatment in myeloma has been previously evaluated, although it mostly concerned lenalidomide/ dexamethazone induction [13][14][15] or second line treatment [16]. One step further, Vu T, et al [10] presented a series of 33 out of 240 (14%) patients that received lenalidomide/dexamethasone as first line and remained in remission for 6 years (72 months) or more.…”

Developments in the Field of Myeloma in the Last Decade

“…Current recommendations are, lenalidomide-dexamethasone for patients with adequate renal functions, non-aggressive disease, presence of peripheral neuropathy due to any cause, and away from well-equipped medical facilities as initial therapy till the achievement of a best response or plateau phase. This is followed by low-dose lenalidomide maintenance for a limited period of 18-24 months or until the disease progresses [13]. In others with renal impairment, aggressive disease, extramedullary disease and close to a medical facility should receive bortezomib based regimens like, doublet of bortezomib ?…”