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

Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Clinical Autologous Transplantation: Results: Autologous Stem Cell Transplantation: Lymphoma and Plasma Cell Disorders
Hematology Disease Topics & Pathways:
therapy sequence, Biological, Diseases, Adult, survivorship, Non-Biological, Therapies, Combinations, chemotherapy, Study Population, Clinically relevant, Myeloid Malignancies, Quality Improvement , transplantation
Monday, December 9, 2019: 2:45 PM
W311ABCD, Level 3 (Orange County Convention Center)

Maria-Victoria Mateos1, Joaquin Martinez-Lopez, MD, PhD2*, Paula Rodriguez Otero3*, Veronica Gonzalez-Calle4*, Marta Sonia Gonzalez, MD5*, Albert Oriol, MD6*, Norma C. Gutierrez, MD, PhD7*, Bruno Paiva, PhD8*, Rafael Ríos Tamayo9*, Laura Rosinol Dachs10*, Miguel Angel Alvarez, MD11*, Maria Jose Calasanz, PhD, BSc12*, Joan Bargay, MD, PhD13*, Ana Pilar Gonzalez, PhD14*, Adrián Alegre Amor, MD15*, Fernando Escalante, MD16*, Belén Iñigo17*, Noemi Puig, MD, PhD18*, Javier De La Rubia19*, Ana Isabel Teruel, Medical Doctor20*, Maria Teresa Cedena Romero, MD, PhD21*, Felipe De Arriba, PhD22*, Luis Palomera, MD, PhD23*, Miguel T Hernández24*, Javier Lopez Jimenez, MD25*, Jesús Martín26*, Aránzazu García Mateo, PhD27*, Enrique M. Ocio28*, Joan Bladé, MD29*, Juan Jose Lahuerta, MD, PhD30* and Jesus San-Miguel, MD, PhD31

1Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca, Salamanca, Spain
2H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research Center, Madrid, Spain
3Clínica Universidad de Navarra, Pamplona, Spain
4Departamento De HematologíA, Hospital Universitario De Salamanca (HUSAL),, Salamanca, ESP
5Hospital Universitario de Santiago, Santiago de Compostela, Spain
6Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
7Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
8Centro de Investigación Médica Aplicada, University of Navarra, Clínica Universidad de Navarra, CIBERONC, IDISNA, Pamplona, Spain
9Unidad de Hematología y Hemoterapia. Hospital Universitario Virgen de las Nieves,, Granada, Spain
10University of Barcelona, Barcelona, Spain
11Hospital Universitario Reina Sofia, Cordoba, Spain
12Scientific co-Director of CIMA LAB Diagnostics, CIMA Lab Diagnostics, University of Navarra, Pamplona, Spain
13Hospital Sont LLatzer, Palma de Mallorca, Spain
14Hospital Central de Asturias, Oviedo, Spain
15Hospital Universitario La Princesa, Madrid, Spain
16Hospital de León, León, Spain
17Hospital Clínico San Carlos, Madrid, Spain
18Hospital Universitario de Salamanca Hematología. Instituto de investigación biomédica de Salamanca (IBSAL), Salamanca, Spain
19Hematology Department, Internal Medicine, School of Medicine and Dentistry, Catholic University of Valencia and Hospital Doctor Peset, Valencia, Spain
20Hospital Clínico Universitario de Valencia, VALENCIA, ESP
21Hospital 12 de Octubre, Madrid, Spain
22Hospital Morales Meseguer, Murcia, Spain
23Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
24Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
25Hospital Ramon y Cajal, Madrid, Spain
26Hospital Virgen del Rocío, Sevilla, Spain
27Hospital General de Segovia, Segovia, Spain
28University Hospital of Salamanca (IBSAL) & Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain
29Hospital Clínica de Barcelona - Servicio de Onco-Hematología, Barcelona, Spain
30Hospital Doce de Octubre, CIBERONC, Madrid, Spain
31Hematology Department, Clínica Universidad De Navarra, Pamplona, Spain

Introduction: SMM is an asymptomatic and heterogeneous plasma cell disorder. Both Spanish Myeloma and ECOG Groups have demonstrated that pts at high risk of progression to active MM benefit from early treatment with R-based regimens. Our next step was to design this phase 2, single arm trial, focusing on the same population, but with the potential goal of cure, defined by sustained minimal residual disease negativity (MRD-ve) at 5 years after HDT-ASCT.

Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo) or if only one criterion was present, pts must >95% of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish). 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 at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after induction and ASCT and our aim was to increase the MRD –ve rate from 34% (reported in NDMM pts after VTD and ASCT) to at least 50%.

Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM.

On February 4th, 2019, 71 pts were already receiving maintenance treatment; 7 pts had finalized the treatment and there were 11 early discontinuations (4 biochemical relapses during maintenance, 2 Informed Consent refusal, 3 adverse events and two deaths). After a median follow-up of 32 months (8-128), 93% of pts remain alive and free of progression and 98% of them alive.

In the intent-to-treat pts’ population, after induction, the ≥CR rate was 41% and increased to 59% after HDT-ASCT and to 70% after consolidation. In the same analysis, MRD-ve rate was observed in 30% of pts after induction, 52% after HDT-ASCT and 57% after consolidation. If we focus on the 83 pts who completed induction, HDT-ASCT and consolidation, the ≥CR/undetectable MRD rates were 42%/31%, 64%/56% and 76%/63% after each step, respectively.

Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Maintenance treatment is ongoing and one patient had to discontinue due to a second primary malignancy (lung cancer) and other due to sustained thrombocytopenia.

Conclusions: The primary end point of the trial was met, and 56% of the pts who completed induction and HDT-ASCT achieved MRD-ve. This “curative strategy for high risk SMM” continues being encouraging and 93% of pts remain alive and progression-free at 30 months and 98% of pts alive.

Disclosures: Mateos: GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Oriol: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rosinol Dachs: Janssen, Celgene, Amgen and Takeda: Honoraria. Amor: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Puig: Takeda: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria. De La Rubia: AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. De Arriba: Takeda: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lopez Jimenez: GILEAD SCIENCES: Honoraria, Other: Education funding. Ocio: Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Research Funding; AbbVie: Consultancy; Sanofi: Research Funding; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pharmamar: Consultancy. Bladé: Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel: Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

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