Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease

Abstract

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. We conducted a phase 2 trial in 76 eligible patients with SMM, combining thalidomide (THAL, 200 mg/d) with monthly pamidronate. In the first 2 years, THAL dose reduction was required in 86% and drug was discontinued in 50%. Within 4 years, 63% improved, including 25% qualifying for partial response (PR); by then, 34 patients had progressed and 17 required salvage therapy. Unexpectedly, attaining PR status was associated with a shorter time to salvage therapy for disease progression (P < .001), perhaps reflecting greater drug sensitivity of more aggressive disease. Low beta-2-microglobulin levels less than 2 mg/L were independently associated with superior overall and event-free survival. Four-year survival and event-free survival estimates of 91% and 60%, respectively, together with a median postsalvage therapy survival of more than 5 years justify the conduct of a prospective randomized clinical trial to determine the clinical value of preemptive therapy in SMM. Trial registered at http://www.clinicaltrials.gov under identifier NCT00083382.

Figure 1

Kaplan-Meier plots of clinical outcomes in patients with smoldering myeloma receiving preemptive thalidomide therapy. (A) Cumulative incidence of patients experiencing disease progression and of patients receiving salvage therapy. Patients who experienced disease progression at any time after enrollment (including those removed from protocol) are included. Patients who died without disease progression are censored. At 4 years from enrollment, 34% have progressed and 17% have received salvage therapy for progressive myeloma. (B) Cumulative proportions of patients achieving various response levels. Included are all responses that occurred between the time of enrollment and the date of salvage therapy or the date of last contact for patients not requiring salvage therapy. Four years from study entry, 63% achieved at least 25% myeloma protein reduction (improvement, IMP); 25% qualified for having attained partial remission (PR), including 12% with near-complete remission (n-CR) and 5% with complete remission (CR). (C) Postlandmark event-free survival according to the level of response achieved within 9 months of starting thalidomide therapy. Patients attaining at least PR status had an inferior event-free survival to those achieving improvement or no improvement status; no difference was apparent between the latter 2 categories. P values are as follows: curve a versus curve b, P = .015; curve a versus curve c, P = .040; and curve b versus curve c, P = .655. (D) Cumulative proportions of patients receiving salvage therapy for myeloma progression, according to response level achieved with preceding thalidomide preemptive intervention. Patients who had attained at least PR status on thalidomide for SMM started salvage therapy for disease progression sooner and ultimately in higher proportions than those who had either not responded (no improvement) or qualified for improvement only after preemptive intervention with thalidomide. P values are as follows: curve a versus curve b, P < .001; curve a versus curve c, P < .001; and curve b versus curve c, P = .926.