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402 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

Clinical Autologous Transplantation: Results
Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Clinical Autologous Transplantation: Results: Novel Conditioning & Maintenance Approaches
Sunday, December 10, 2017: 10:45 AM
Bldg C, Lvl 1, C101 Aud (Georgia World Congress Center)

Maria-Victoria Mateos, MD, PhD1, Joaquin Martinez Lopez2*, Paula Rodriguez-Otero, MD, PhD3*, Enrique M Ocio, MD4*, Marta Sonia Gonzalez, MD5*, Albert Oriol, MD6*, Norma Gutierrez, MD, PhD7*, Bruno Paiva, PhD8*, Rafael Rios9*, Laura Rosinol, MD, PhD10*, Miguel Angel Alvarez, MD11*, Maria Jose Calasanz, BSc, PhD12*, Joan Bargay, MD, PhD13*, Ana Pilar Gonzalez, PhD14*, Fernando Escalante, Dr.15*, Rafael Martínez16*, Noemi Puig, MD, PhD17*, Javier de la Rubia, MD18*, Ana Isabel Teruel, MD19*, Maria Teresa Teresa Cedena Romero20*, Felipe De Arriba, PhD21*, Luis Palomera22*, Miguel T Hernández23*, Javier Lopez Jimenez24*, Jesús Martín25*, Esther Piensa26*, Aránzazu García-Mateo27*, Veronica González17*, Joan Blade, MD28, Juan Jose Lahuerta29* and Jesus F. San Miguel, MD30

1University Hospital of Salamanca, Salamanca, Spain
2Hospital Universitario 12 de Octubre, Madrid, Spain
3University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain
4Hospital Clinico Universitario de Salamanca, Salamanca, Spain
5Hospital Universitario de Santiago, Santiago de Compostela, Spain
6ICO Badalona, Hospital Germans Trias i Pujol, Badalona, Spain
7IBSAL, University Hospital of Salamanca, Salamanca, Spain
8Universidad de Navarra, Pamplona, Spain
9Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain
10Hospital Clinic i Provincial, Barcelona, Spain
11Hospital Universitario Reina Sofia, Cordoba, Spain
12Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain
13Hospital Sont LLatzer, Palma de Mallorca, Spain
14Hospital Central de Asturias, Oviedo, Spain
15Hospital Universitario de León, León, Spain
16Hospital Clínico San Carlos, Madrid, Spain
17IBSAL, Hospital Universitario de Salamanca, Salamanca, Spain
18Hematology Department, Universidad Católica de Valencia Hospital Dr. Peset, Valencia, Spain
19Hospital Clinico Universitario de Valencia, Valencia, Spain
20Hospital 12 de Octubre, Madrid, Spain
21Hospital Morales Meseguer, Murcia, Spain
22Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
23Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
24Hospital Ramon y Cajal, Madrid, Spain
25Hospital Universitario Virgen del Rocío, Sevilla, Spain
26Hospital de Mataró, Barcelona, Spain
27Hospital General de Segovia, Segovia, Spain
28Servicio de Onco-Hematología, Hospital Clínica de Barcelona, Barcelona, Spain
29Department of Hematology, Hospital 12 de Octubre, Madrid, Spain
30Centro de Investigación Médica Aplicada, University of Navarra, Clinica Universidad de Navarra, Pamplona, Spain

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 if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping of 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.

Disclosures: Mateos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero: Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Ocio: BMS: Honoraria; Mundipharma: Research Funding; Pharmamar: Honoraria; Array Pharmaceuticals: Research Funding; Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Paiva: EngMab: Research Funding; Amgen: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosinol: Janssen: Honoraria; Celgene: Honoraria. de la Rubia: Janssen: Other: Honoraria; Celgene: Other: Honoraria; Amgen: Other: Honoraria. Blade: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. San Miguel: MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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