Multicenter, Randomized, Open-Label, Phase III Trial of Lenalidomide-Dexamethasone (Len/dex) Vs Therapeutic Abstention in Smoldering Multiple Myeloma at High Risk of Progression to Symptomatic MM: Results of the First Interim Analysis.

Abstract 614

Smoldering MM (sMM) is a plasma cell (PC) disorder defined by the presence of ≥10% of PC and/or a serum M-component (MC) ≥3g/dl without end-organ damage. Recent studies have identified a subgroup of sMM at high risk of progression to active MM (>50% at 2 y): patients with both PC ≥10% & MC ≥3g/dl (Kyle R. NEJM 2007) or ≥95% aberrant PC (aPC) by immunophenotyping (Pérez E. Blood 2007) or abnormal FLCs (Dispenzieri A. Blood 2008). Standard of care for sMM is monitoring without treatment until disease progression. Several small studies have explored the value of early treatment with either conventional agents (melphalan/prednisone) or novel drugs (thalidomide, interleukin-1b), with no clear benefit. It should be noted that these trials didn't focus on high-risk sMM.

In this phase III trial we investigated whether early treatment prolongs the time to progression (TTP) in sMM patients at high risk of progression to active MM. Patients were randomized to receive Len-dex versus no treatment. The high risk population was defined by the presence of both PC ≥10% and MC ≥3g/dl or if only one criterion was present, patients must have a proportion of aPC within the total PCBM compartment by immunophenotyping of ≥95% plus immunoparesis. 120 patients are planned to be recruited. The 60 patients randomized to the Len-dex arm receive 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) (induction phase); subsequently maintenance with Lenalidomide at dose of 10 mg on days 1-21 every two months administered until disease progression.

Between October 2006 and June 2008, 80 patients were randomized. In this interim analysis, we present the first 40 patients recruited. According to baseline characteristics, both groups were well balanced.

In an ITT analysis (n=40), based on IMWG criteria, the overall response rate was 90%, including 53% PR, 21% VGPR, 11% CR and 5% sCR. If we select the group of 16 patients who completed the nine cycles, the ORR was 100%, including 27% VGPR, 13% CR and 7% sCR. After a median follow-up of 16 months (range:12-20), no disease progression was observed in the Len-dex arm, while 8 patients progressed to active MM in the therapeutic abstention arm with a median TTP from inclusion in the trial of 17.5 months (p<0.002). It should be noted that 6 of these 8 patients developed bone lesions as a symptom of active MM.

As far as toxicity is concerned, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 2 patients G3 asthenia, 1 pt G3 diarrhea and 3 patients G3 DVT. Serious AEs occurred in 5 patients, 3 of these were dexamethasone-related (GI bleeding, delirium and glaucoma) and 2 were lenalidomide-related (two infections). Two SAEs lead to early discontinuation of the treatment (infection and delirium), and another 2 additional patients discontinued at pt's request. Four patients needed to reduce lenalidomide from 25 to 15 mg due to non-hematological AEs (asthenia (2), diarrhea (1) and GI bleeding (1).

In conclusion, these preliminary results show that in sMM patients at high-risk for progression to active MM, delayed treatment is associated with early progression (median time 17.5 months) with bone disease, while so far Len-dex has been able not only to prolong the TTP (without any progression so far) but also to induce CRs with a manageable and acceptable toxicity profile.