Curative Strategy for High-Risk Smoldering Myeloma (GEM-CESAR): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Introduction: Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder that includes patients with different risk of progression to Multiple Myeloma (MM). The Spanish Myeloma Group demonstrated that early treatment with Rd versus observation in SMM at high risk (HR) of progression resulted into a significant benefit in terms of progression to MM and overall survival. Our next step was to design this phase 2 trial with the potential goal of cure, defined by a sustained minimal residual disease (MRD) negativity for at least 5 years (yr).

Methods: In this phase 2 single-arm trial, 90 SMM patients (pts) at high-risk of progression (>50% at 2 yr), younger than 70 yr and transplant candidates were included. The HR was defined by the presence of both bone marrow plasma cells (PCs)≥ 10% and serum M-protein ≥3g/dL (Mayo) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCs bone marrow compartment by immunophenotypingof 95% plus immunoparesis (Spanish). Asymptomatic MM patients with any of the three biomarkers that currently define active MM were allowed to be included, because the design of the trial was done before the publication (Lancet Oncol 2014). Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m² twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone (dex) at dose of 40 mg weekly. Melphalan at dose of 200 mg/m² followed by autologous stem-cell transplant (ASCT) was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex 20 mg weekly for up to 2 yr. MRD was evaluated by next-generation flow cytometry after induction, ASCT, consolidation and annually thereafter.

Results: the 90 planned patients were recruited between June 2015 and June 2017. Although 126 patients signed the informed consent (IC), there were 36 screening failures, including 21 (17%) pts due to the detection of lytic lesions by PET-CT or MRI (the most frequent exclusion criteria). The median age of the whole series was 59 yr. All pts were at HR according to the Mayo and/or Spanish models, including 28 pts (31%) that shared at least one of the new MM biomarkers (MDE).

Forty-three patients have completed the 6 induction cycles and are evaluable for response: the ORR was 98% including 46% of ≥CR (37% sCR and 9% CR) and 37% of VGPR. MRD by NGF was evaluated in 34 out of these 43 pts and was negative in 13 (38%). Twenty-nine patients have received ASCT and were evaluable at 3 months: the ORR was 100% including ≥CR in 69% of the patients (65% sCR and 3% CR) and VGPR rate in 21%. MRD was negative in 17 out of these 29 patients (58%). Nineteen patients have completed the two planned consolidation cycles and 85% of them are in ≥CR, including sCR in 74%, CR in 11% and VGPR in 16%.

As far as toxicity during induction is concerned, , G3-4 neutropenia and thrombocytopenia were reported in 4 (4%) and 2 pts (2%), respectively. G3-4 infections were the most frequent non-hematological adverse events (AE), observed in 9 pts (10%), followed by skin rash in 7 pts (8%). With regard to cardiovascular events, 1patient reported atrial fibrillation and another cardiac failure, both of G1, and 2 patients reported G2 arterial hypertension. In all but one of the pts, peripheral blood stem cell collection was successful, with a median number of CD34⁺ cells collected of 6,79 x 10⁶/Kg. Engraftment occurred in all patients and the median number of CD34⁺ infused was 3.29 x 10⁶/Kg. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash.

After a median f/u of 13 months (1-108), 98% of patients remain free of progression and alive. Three patients early discontinued: one withdrew the IC; and two treatment unrelated deaths, one during induction due to a massive ischemic stroke and the other one because of refractory disease after induction. No discontinuations due to related-AE have been reported.

Conclusions: Although longer follow-up is required, this "curative strategy for high-risk SMM" seems to be encouraging. The depth of response improved along with the duration of treatment, achieving up to 85% of ≥CR in patients who completed induction, ASCT and consolidation, with an acceptable safety profile. Interestingly, novel imaging techniques at screening allowed us to identify up to 17% of MM that would have been considered SMM with the conventional criteria.