Long Term Follow-up on the Tretament of High Risk Smoldering Myeloma with Lenalidomide Plus Low Dose Dex (Rd) (phase III spanish trial): Persistent Benefit in Overall Survival
Authors: Mateos Maria-Victoria , Hernandez Miguel T , Giraldo Pilar , De La Rubia Javier , de Arriba Felipe , López-Corral Lucía , Rosiñol Laura , Paiva Bruno , Palomera Luis , Bargay Joan , Oriol Albert , Prosper Felipe , López Javier , Olavarría Eduardo , Quintana Nuria , García Jose Luis , Blade Joan , Lahuerta Juan José , San Miguel Jesus F. 
Published: November 2019

Abstract
Background: SMM is a plasma cell (PC) disorder defined by the presence of at least 10% of PC and/or a serum M-component (MC) at least 3g/dl without end-organ damage. Due to the nature of the disease, SMM pts at high risk of progression to active MM (> 50% at 2 yrs) have been identified using different criteria: bone marrow infiltration by > 10% of PCs & MC > 3g/dl (Kyle,NEJM 2007), or > 95% aberrant PC (aPC) by immunophenotyping plus immunoparesis (Pérez, Blood 2007), or abnormal FLCs (Dispenzieri,Blood 2008). The current standard of care for SMM is watchful waiting until disease progression. Although several small randomized studies have explored the value of early treatment with either conventional agents (melphalan/prednisone) or thalidomide, bisphosphonates, they showed no significant benefit. It should be noted that these trials did not focus on high-risk SMM. In 2007, the Spanish Myeloma Group initiated a randomized, phase III trial comparing lenalidomide (R) + low-dose dexamethasone (Rd) vs observation in high-risk SMM pts. After a median follow-up of 40 months, early treatment with Rd showed to be superior in terms of time to progression to active disease and overall survival (OS) (Mateos, NEJM 2014). Here we present an update after long-term median follow-up of 5 years.
Pts and Methods: 119 pts with high-risk SMM were enrolled and randomized to Rd vs. observation. Pts in the treatment group received an induction regimen (lenalidomide 25 mg/day on days 1 to 21 plus dexamethasone 20 mg/day on days 1 to 4 and 12 to 15, at 4-week intervals for nine cycles) followed by a maintenance regimen (lenalidomide 10 mg/day on days 1 to 21 of each 28-day cycle). Maintenance therapy was initially given until disease progression, but an amendment limited the total treatment duration (induction plus maintenance) to 2 years, and the addition of dexamethasone (20 mg on days 1 to 4 of each cycle) for pts who developed asymptomatic biological progression during maintenance (>25% of increase in monoclonal component with no symptoms). The primary endpoint was time to progression to symptomatic disease (TTP), secondary endpoints included OS, response, and safety.
Results: After a median follow-up of 64 months (range: 49-81), progression to symptomatic disease occurred in 23% of pts with Rd vs. 85% for the pts in the observation arm. Long term follow-up with early Rd treatment continues to show a significant benefit in TTP to active disease vs. watchful waiting (median TTP not reached vs. 21 months, HR= 6.21; 95% CI: 3.1-12.7, p<0.0001). During maintenance therapy, 24 pts in the Rd arm experienced asymptomatic biological progression and low-dose dexamethasone was added in 18 pts. With a median follow-up of 50 months from biological progression, disease remains under control in 10 out of these 18 pts and they continue on therapy with lenalidomide plus dexamethasone at low doses. Pts who progressed to symptomatic disease and required to start systemic therapy were also followed for survival, and the percentage of pts who remain alive at 5 years after progression to active disease is 83% in the Rd vs. 58% in the observation arm.
OS continues to be significantly longer with Rd vs. with the observation arm: 93% of the pts who received early treatment with Rd remain alive vs. 67% in the watchful waiting arm, (HR= 4.35, 95% CI 1.5-13.0, p=0.008). Only four pts died in the Rd arm, whilst 17 deaths occurred in the observation arm. In the Rd arm, only one patient’s death was considered treatment-related (pneumonia); disease progression was the cause of death in two pts and bronchoaspiration as consequence of surgery-related complication in the fourth pt. In the observation arm, disease progression was the most frequent cause of death, in 76% of the pts.
As far as toxicity is concerned, no new second primary malignancy (SPM) occurred: four SPM were reported in 4 of the 62 pts with Rd (6%) and in 1 of the 63 pts in the observation group (2%).
Conclusions: After long-term follow-up, Rd in high risk SMM pts as early treatment with Rd continued to show a significant reduction of not only in the risk of progression to active disease but also the risk of death. In addition, the long post relapse survival observed among pts who received early treatment with Rd and subsequently progressed to symptomatic disease indicate that this strategy does not induce more resistant clones.

Disclosures
Mateos: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide as first-line combination therapy for AL amyloidosis.. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. Blade:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria.