Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment
Authors: Mateos María-Victoria , López-Corral Lucía , Hernández Miguel , Giraldo Pilar , De La Rubia Javier , de Arriba Felipe , Rosiñol Laura , Lahuerta Juan José , Palomera Luis , Bargay Joan , Oriol Albert , Prosper Felipe , López Javier , Olavarría Eduardo , Martino Maria Luz , Teruel Ana-Isabel , Hernández Jose Mariano , Esteves Graça , Mariz Jose Mario JS , Leal-da-Costa Fernando , Alegre Adrian , Guzman Jose-Luis , Guía Ana López de la , Baquero Jose , Quintana Nuria , García Jose Luis , Miguel JesÃ°s F. San 
Published: October 2019

Abstract
Abstract 991
Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease.
In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis.
Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly).
The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria).
According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%.
After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03).
As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist.
In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time.

Disclosures:
Mateos: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Baquero:Celgene: Employment. Quintana:Celgene: Employment. García:Celgene: Employment.