Continuous induction with lenalidomide/dexamethasone versus autologous stem cell transplantation in newly diagnosed multiple myeloma: a case for response-adapted approach

Abstract

Although upfront autologous stem cell transplantation (ASCT) generally improves progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM), the overall survival (OS) benefit and optimal timing of ASCT are not well established. Patients with early response may be able to safely continue induction and avoid ASCT without compromised outcomes. We report an extended follow-up analysis of a phase 2 trial that randomized transplant-eligible patients with NDMM who responded to induction (50/65 patients) to continued induction or ASCT; median follow-up was 8.0 years. Patients had similar 8-year PFS (55% vs. 43%), 8-year OS (83% vs. 72%), and rates of at least very good partial response (72% vs. 84%) whether continuing induction of lenalidomide and dexamethasone (Ld arm) or receiving ASCT (Ld + ASCT arm) (p = 0.5). Notably, over 50% of patients receiving continuous Ld had PFS of 5-10 years. These results suggest the need for prospective trials incorporating response-adapted therapeutic approaches to NDMM.STATEMENT OF PRIOR PRESENTATIONPresented in abstract form (interim analysis) at the 56th annual meeting of the American Society of Hematology (San Francisco, CA, 6 December 2014) and at the 57th annual meeting of the American Society of Hematology (Orlando, FL, 3 December 2015).

Keywords: Multiple myeloma; continuous induction; lenalidomide; response-adapted therapy; stem cell transplantation.

Fig 1.. Treatment schema.

Patients received Ld induction (lenalidomide 25 mg daily on days 1–21 plus dexamethasone 40 mg once weekly during each 28-day-cycle) for 4 cycles. Patients in the Ld+ASCT arm received, starting 3 months post ASCT, L maintenance (lenalidomide 10 mg daily on days 1–28 of a 28-day cycle, escalated to 15 mg daily after 3 cycles if tolerated). Patients in the continued Ld arm received continuous Ld (continuous lenalidomide at the last tolerated dose until progression or toxicity plus dexamethasone 20 mg weekly for 1 year). ASCT, autologous stem cell transplantation; β₂M, beta-2 microglobulin; FISH, fluorescence in-situ hybridization; L, lenalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld+ASCT, Ld induction followed by early ASCT; NDMM, newly diagnosed multiple myeloma; PD, progressive disease; PR, partial response; R, randomization; SD, stable disease.

Fig 2.. CONSORT diagram of clinical trial enrollment and treatment.

ASCT, autologous stem cell transplantation; L, lenalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld+ASCT, Ld induction followed by early ASCT; PD, progressive disease; PR, partial response; SD, stable disease.

Fig 3.. Survival analyses.

(A) Progression-free survival and (B) overall survival (Kaplan-Meier analysis) of all randomized patients, the intention-to-treat population (n = 50). (C) Overall survival and progression-free survival from the start of treatment of all patients who initiated Ld induction (N = 65). Ld, lenalidomide plus low-dose dexamethasone; Ld+ASCT, Ld induction followed by early ASCT; No., number; OS, overall survival; PFS, progression-free survival.