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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
María-Victoria Mateos
University Hospital of Salamanca
Salamanca, Spain

María-Victoria Mateos1*, Lucía López-Corral1*, Miguel Hernández2*, Pilar Giraldo, PhD3, Javier De La Rubia4*, Felipe de Arriba5*, Laura Rosiñol6*, Juan-Jose Lahuerta7*, Luis Palomera8*, Joan Bargay9*, Albert Oriol10*, Felipe Prosper, MD11, Jose Garcia-Laraña12*, Eduardo Olavarría13*, Maria Luz Martino14*, Ana-Isabel Teruel15*, Jose Hernández16*, Graça Esteves17*, Jose Mario Mariz18*, Fernando Leal-da-Costa, MD19, Adrian Alegre20, Jose-Luis Guzman21*, Ana López de la Guía22*, Nuria Quintana23*, Jose Baquero24*, Jose Luis García24* and Jesús F. San Miguel Sr., MD, PhD25

1University Hospital of Salamanca, Salamanca, Spain
2Hospital Universitario de Canarias, Tenerife, Spain
4Hospital La Fe, Valencia, Spain
5Hospital Morales Messeguer, Murcia, Spain
6Hospital Clínic, Barcelona, Spain
7Hematology, Hospital 12 de Octubre, Madrid, Spain
8Hospital Lozano Blesa, Zaragoza, Spain
9On behalf of CETLAM Cooperative Group, Palma de Mallorca, Spain
10Clinical Hematology, ICO-Hospital Germans Trias i Pujol and PETHEMA Group, Badalona, Spain
11Dept. of Medicine Hematology & Cell Therapy Prog., Clinica Universitaria de Navarra, Pamplona, Spain
12Hospital Ramón y Cajal, Madrid, Spain
13Hospital de Navarra, Pamplona, Spain
14Hospital Virgen del Rocío, Sevilla, Spain
15Hospital Clinico Universitario de Valencia, Valencia
16Hospital General de Segovia, Segovia, Spain
17Hospital de Santa Maria, Lisboa, Portugal
18Department of Hematooncology, Portuguese Institute of Oncology, Porto, Portugal
19UTM/Hematologia, Instituto Portugues De Oncologia, Lisbon, Portugal
20Hospital Universitario de La Princesa, Madrid, Spain
21Hospital de Jerez, Jerez de la Frontera, Spain
22Hospital La Paz, Madrid, Spain
23Celgene Corporation, Madrid
24Celgene Corporation, Madrid, Spain
25Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain

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), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (>50% at 2 years): >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 close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn’t focus on high-risk patients.

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 progresión (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 aberrants 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 (ammended in May 2010 into monthly).

The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn’t meet inclusion criteria). This second interim analysis was planned when all patients were recruited.  

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 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%.

After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), 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 10 out of these 21 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).

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 developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection.

In conclusion, this second interim 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: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time.

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