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2142 Curativestategy (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
Session: 731. Clinical Autologous Transplantation: Results: Poster I
Hematology Disease Topics & Pathways:
Diseases, smoldering myeloma, Plasma Cell Disorders, Lymphoid Malignancies
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Maria-Victoria Mateos, MD, PhD1, Joaquin Martínez-López, MD, PhD2*, Paula Rodriguez Otero3*, Enrique M. Ocio, MD4*, Marta Sonia Gonzalez, MD5*, Albert Oriol, MD6*, Norma C. Gutierrez, MD, PhD7*, Bruno Paiva, PhD8*, Rafael Rios, MD, PhD9*, Laura Rosinol, MD, PhD10*, Miguel Angel Alvarez, MD11*, Maria Jose Calasanz, BSc, PhD12*, Joan Bargay, MD, PhD13*, Ana Pilar Gonzalez, PhD14*, Adrián Alegre, MD15, Fernando Escalante, MD16*, Rafael Martínez17*, Noemi Puig, MD, PhD18*, Javier De La Rubia, MD19*, Ana Isabel Teruel, Medical Doctor20*, María Teresa Cedena21*, Felipe De Arriba, PhD22*, Luis Palomera, MD, PhD23*, Miguel T Hernández, MD, PhD24*, Javier Lopez Jimenez, MD, PhD25*, Jesús Martín26*, Esther Piensa27*, Aránzazu García Mateo, PhD28*, Veronica Gonzalez De La Calle, MD, PhD29*, Joan Bladé, MD, PhD30, Juan Jose Lahuerta, MD, PhD31* and Jesus F San-Miguel, MD, PhD32

1University Hospital of Salamanca/IBSAL, Salamanca, Spain
2Hospital Doce de Octubre, CIBERONC, Madrid, Spain
3Clínica Universidad de Navarra, Pamplona, Spain
4University Hospital of Salamanca (IBSAL) & Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain
5Hospital Universitario de Santiago, Santiago de Compostela, Spain
6Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
7Hospital Universitario De Salamanca, Salamanca, ESP
8Applied Medical Research Center (CIMA), Clinica Universidad De Navarra, Pamplona, Navarra, Spain
9Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain
10Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, IDIBAPS, Josep Carreras Research Institute, Hospital 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 Quirón Madrid, Madrid, Spain
16Hospital de León, León, Spain
17Hospital Clínico San Carlos, Madrid, Spain
18Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain
19Hematology Department, Universidad Católica de Valencia Hospital Dr. Peset, Valencia, Spain
20Hospital Clínico Universitario de Valencia, VALENCIA, ESP
21Hospital Universitario 12 de Octubre, Madrid, Spain
22Hospital Morales Meseguer, Murcia, Spain
23Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
24Department of Hematology, Hospital Universitario de Canarias, La Laguna, Spain
25Hematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
26Hospital Universitario Virgen del Rocío, Sevilla, Spain
27Hospital de Mataró, Barcelona, Spain
28Hospital General de Segovia, Segovia, Spain
29Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
30Amyloidosis and Myeloma Unit, Hospital Clínic, Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
31Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain
32Clinica Universidad de Navarra, Pamplona, Spain

Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017).

Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD –ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT.

Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (>50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice 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/m2followed by 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 at dose of 20 mg weekly for up to 2 yrs

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

The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD –ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM.

Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed 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 patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing.

After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment.

Conclusions: Although longer follow-up is required, this “curative strategy for high risk SMM” continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%.

Disclosures: Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, 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; Amgen: 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero: Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio: AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios: Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia: Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo: Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé: Janssen: Honoraria. Lahuerta: Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel: Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

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