Lenalidomide Maintenance After Stem-Cell Transplantation For Multiple Myeloma: Follow-Up Analysis Of The IFM 2005-02 Trial

Abstract

Methods and Patients This randomized, placebo-controlled, phase 3 trial investigated the efficacy of lenalidomide (LEN) maintenance after transplantation for multiple myeloma. Patients, under 65 years of age, with non-progressive disease after a first-line autologous stem-cell transplant (ASCT) were randomized to receive maintenance with placebo or LEN (10 to 15 mg/d) until disease progression or unacceptable toxic effects. From July 2006 to August 2008, 614 patients were randomized. In January 2011, the DSMB recommended to stop LEN due to the increased incidence of second primary malignancies (SPMs). The median duration of maintenance treatment with LEN was 2 years (IQ range= 1-3). We previously reported this trial with a median follow-up of 45 months (Attal et al, N Engl J Med 2012). Results As of May 2013, median follow-up was 70 months from diagnosis and 60 months from randomization. LEN maintenance improved the 5-year progression-free survival (PFS) post randomization: 42%, versus 18% with placebo (p<0.0001), respectively. Overall, 403 patients had disease progression and 364 have started a second line therapy. The median 2nd PFS for the treated patients (time from progression in first-line to the second progression or last follow-up or death) was 10 months within the LEN arm versus 18 months within the placebo arm (p<0.0001), respectively. The median 2nd PFS in the LEN and placebo groups were 9 and 8 months (NS) for patients treated with a bortezomib-based regimen, 8 months and 18 months (p<0.01) for patients treated with an IMiD-based regimen, 14 months and 28 months (p=0.03) for patients treated with a regimen without new agents or with a second line ASCT, respectively. The 5-year post randomization overall survival (OS) was similar in the 2 groups: 68% in the LEN group versus 67% in the placebo group (HR=1). In the multivariate analysis, the OS was significantly related to age (p=0.001), International Staging System (p=0.03), and poor cytogenetics (t(4;14) or chromosome 17 deletion; p=0.008). The median survival after the first progression was 29 months in the LEN group versus 48 months in the placebo group (p< 0.0001). An increased incidence of SPMs was observed in the LEN group: 44 SPMs (hematologic: 20, non-hematologic: 24) in 35 patients were reported in the LEN group versus 28 SPMs (hematologic: 6, non-hematologic: 22) in 20 patients in the placebo group. The incidence of SPMs (excluding non melanoma skin cancers) was 2.3 per 100 patient-years in the LEN group versus 1.3 in the placebo group (p=0.03). Conclusion This new analysis confirms that lenalidomide is an effective treatment to prolong PFS after transplantation for multiple myeloma patients. However, this impressive benefit is not currently associated with an improved overall survival, due to a shorter survival after the first progression. Disclosures: Attal: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE THERAPY WITH CARFILZOMIB IN MULTIPLE MYELOMA. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Hulin:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.

Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice

“…The use of thalidomide as a treatment for morning sickness in the 1950s resulted in the birth of more than 10 000 children with phocomelia and other characteristic malformations, as well as an unknown but likely high number of miscarriages. 1,2 Since that time, thalidomide and its derivatives, lenalidomide and pomalidomide, have demonstrated clinical efficacy in B-cell malignancies, including multiple myeloma, [3][4][5][6][7] mantle cell lymphoma, 8 and chronic lymphocytic leukemia. 9,10 In addition, lenalidomide has striking activity in myelodysplastic syndrome (MDS) with somatic deletion of the long arm of one copy of chromosome 5 (del(5q)), and complete cytogenetic remission is seen in ;50% of del(5q) MDS patients.…”

The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma

“…The incidence of SPMs (excluding non‐melanoma skin cancers) was 2.3 per 100 patient‐years in the lenalidomide group vs. 1.3 in the placebo group ( P = 0.03). Although in this latest analysis of the IFM 2005‐02 trial, it was confirmed that lenalidomide treatment is effective in prolonging PFS after transplantation, this benefit was not associated with improved OS, as a result of shorter survival after the first progression .…”

“…The immunomodulatory activity of lenalidomide may be responsible for its maintenance effect . So far, lenalidomide maintenance therapy after ASCT has been studied in two randomized, phase 3 trials: the CALGB‐100104 (Cancer and Leukemia Group B) trial in North America and the IFM 2005‐02 trial in France .…”

“…At the last ASH Annual Meeting in December 2013, Attal et al . reported updated results of the IFM 2005‐02 study. After a median follow‐up period of 70 months from MM diagnosis, lenalidomide maintenance treatment was found to have significantly improved 5‐year PFS vs. placebo (42% vs. 18%, P < 0.0001).…”

Current Status of Maintenance Therapy in Multiple Myeloma

“…In the IFM 05-02 study, patients having received previous induction therapy with either vincristine, doxorubicin, plus dexamethasone or bortezomib plus dexamethasone (VD) followed by one or two AHSCT were treated with two cycles of lenalidomide consolidation therapy and were, thereafter, randomized to lenalidomide maintenance (LM) ( of the significantly shorter time from first to second relapse/progression observed for patients randomized to LM (10 versus 18 months for the placebo group). 42,43 The Cancer and Leukemia Group B (CALGB) designed a similar study was 46 months for the lenalidomide group and 27 months for the placebo group. The 3-year PFS was 66 % for the lenalidomide group and 39 % for the placebo group.…”