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118 Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Post-Hoc Analysis of Sustained Undetectable Measurable Residual Disease (MRD)

Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Autologous Transplantation: Clinical and Epidemiological: Multiple Myeloma and CHIP
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Plasma Cell Disorders, Diseases, Therapies, therapy sequence, Lymphoid Malignancies, Minimal Residual Disease
Saturday, December 10, 2022: 10:15 AM

Maria-Victoria Mateos, MD1, Joaquín Martínez-López, MD, PhD2*, Paula Rodríguez-Otero, MD, PhD3*, Jesús San-Miguel, MD, PhD4, Veronica Gonzalez-Calle, MD, PhD1*, Marta Sonia Gonzalez, MD5*, Albert Oriol, MD6*, Norma C. Gutierrez1*, Rafael Rios, MD, PhD7*, Laura Rosinol Dachs8*, Miguel Angel Alvarez, MD9*, Joan Bargay, MD, PhD10*, Ana Pilar Gonzalez, PhD11*, Fernando Escalante, MD12*, Adrian Alegre, MD, PhD13, Belén Iñigo, MD14*, Javier de la Rubia, MD15*, Ana Isabel Teruel, MD16*, Felipe De Arriba, PhD17*, Luis Palomera, MD, PhD18*, Miguel-Teodoro Hernández, MD, PhD19*, Javier Lopez Jimenez, MD, PhD20*, Marta Reinoso Segura21*, Aránzazu García Mateo, PhD22*, Enrique M. Ocio1, Joan Bladé, MD, PhD8*, Juan-José Lahuerta, MD, PhD23*, María Teresa Cedena, MD, PhD24*, Noemi Puig, MD, PhD25 and Bruno Paiva26*

1Hospital Universitario de Salamanca,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
2Department of Hematology, Hospital Universitario 12 de Octubre; Instituto de Investigación Sanitaria Hospital Universitario 12 de Octubre i+12,H12O-CNIO Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain
3Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain
4Clínica Universidad de Navarra, CCUN, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC, Pamplona, Spain
5Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain
6Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
7Hospital Universitario Virgen de las Nieves de Granada, Instituto de Investigación Biosanitaria IBS GRANADA, Granada, Spain
8Amyloidosis and Myeloma Unit, Hospital Clínic, Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Hospital Universitario Reina Sofia, Cordoba, Spain
10Department of Hematology, Son Llatzer University Hospital/ IdISBa, Palma de Mallorca, Spain
11Hospital Central de Asturias, Oviedo, Spain
12Hematology Department, Hospital Universitario de León, León, Spain
13Univeritary Hospital La Princesa, Madrid, Madrid, Spain
14Hematology, Hospital Universitario Clínico San Carlos, Madrid, Spain
15Hematology Department, University Hospital La Fe, Valencia, Spain
16Hospital Clínico Universitario de Valencia, VALENCIA, ESP
17Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
18Hospital Clínico U. "Lozano Blesa". Instituto Investigación Sanitaria Aragón, Zaragoza, Spain
19Hospital Universitario de Canarias, Universidad de La Laguna, Tenerife, Spain
20Hematology and Hemotherapy Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
21Instituto de Biomedicina de Sevilla (IBiS), UGC-Hematología, Hospital Universitario Virgen del Rocío/ CSIC/ CIBERONC, Universidad de Sevilla, Sevilla, Spain
22Hospital General de Segovia, Segovia, Spain
23Hospital Universitario 12 de Octubre; Instituto de Investigación Sanitaria Hospital Universitario 12 de Octubre i+12,H12O-CNIO Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain
24Hospital Universitario 12 de Octubre, CNIO, Madrid, Spain
25Hospital Universitario de Salamanca Hematología. Instituto de investigación biomédica de Salamanca (IBSAL), Salamanca, Spain
26Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain

Introduction: SMM is an asymptomatic plasma cell disorder with heterogeneous clinical behavior and once R-based regimens have shown to be effective in high-risk SMM patients, our next step was to perform this phase 2 trial, but aiming at abrogating the risk of progression through an intensive treatment regimen with the end point of achieving sustained MRD negativity (MRD-ve) at 3 and 5 years after ASCT.

Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 years), younger than 70 years and transplant candidates were included. Induction therapy consisted of six 4-weeks cycles of KRd in which carfilzomib (K) was given at dose of 36 mg/m2 twice per week plus lenalidomide (R) at dose of 25 mg on days 1-21 and dexamethasone (d) 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 years. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after ASCT and MRD-ve rate maintained at 3 and 5 years after ASCT. Because of the COVID-19 pandemic, the MRD evaluation 3 years after ASCT was done in less patients than expected and we amended the protocol to evaluate sustained MRD-ve rate at 4 and 5 years. Patients experiencing biological progression (biochemical or MRD conversion from -ve to +ve) after stopping maintenance had the opportunity of receiving rescue therapy with daratumumab in combination with pomalidomide and dexamethasone (DPd).

Results: Between June 2015 and June 2017, 90 high-risk SMM pts (31 with ultra high-risk) were recruited and 70 pts (78%) completed the scheduled treatment. After a median f/u of 65.8m, 94% of patients remain alive and progression-free: 6 pts progressed to MM and 7 pts died. Thirty-one patients biologically progressed (biochemical progression or conversion from MRD-ve to +ve) and the biological PFS at 5 years is 72%.

In the ITT population, MRD-ve rates at 10-5 were observed in 40% of pts after induction, 63% after HDT-ASCT, 68% after consolidation and 52% after maintenance therapy. Forty-seven patients were in MRD-ve at the end of maintenance and 23 maintained it 2 years after stopping maintenance indicating that the sustained MRD-ve 2 years after stopping maintenance (4 years after ASCT) was 25.6%. The same analysis was done with the sensitivity threshold of 10-6 and the MRD-ve rates were 27%, 43%, 57%, 43% after induction, ASCT, consolidation and maintenance, respectively. Thirty-nine patients were in MRD-ve at the end of maintenance and the sustained MRD-ve 4 years after ASCT was 23% (21 patients).

Conclusions: Twenty-three percent of high-risk SMM treated with this curative strategy maintained MRD-ve 4 years after ASCT and 2 years after finalizing the treatment protocol. Progression to MM as well as biochemical progression were driven by the persistence of MRD at the end of maintenance and by lack of sustained MRD-ve 4 years after ASCT (2 years after the end of maintenance).

Disclosures: Mateos: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: 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. Rodríguez-Otero: Regeneron: Speakers Bureau; Amgen: Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Speakers Bureau. San-Miguel: Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Gonzalez-Calle: Janssen, Pfizer, Bristol-Myers Squibb/Celgene, GlaxoSmithKline: Honoraria, Speakers Bureau; Janssen: Consultancy. Oriol: GlaxoSmithKline: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau. Rios: Becton-Dickinson, Celgene, GSK, Janssen, Sanofi, Binding Site: Consultancy. Rosinol Dachs: Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; BMS-Celgene: Honoraria; Janssen: Honoraria. Escalante: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alegre: Janssen, BMS-Celgene, Amgen, Sanofi,GSK, Grifols, Pfizer, Abbvie, Novartis, Oncopeptide, Takeda: Consultancy. de la Rubia: Bristol Myers Squibb: Honoraria; Janssen: Honoraria; Ablynx/Sanofi: Honoraria; Pfizer: Honoraria; GSK: Honoraria. De Arriba: Amgen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau. Hernández: Sanofi, -amgen, Janssen, Celgene (BMS): Honoraria, Other: Advisory board; Roche, GSK: Other: Advisory board. Ocio: Amgen, BMS/Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; GSK: Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy; Pfizer: Consultancy, Honoraria; Janssen, Takeda: Speakers Bureau; Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, Takeda: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Puig: Celgene, Janssen, Amgen andTakeda: Research Funding; Amgen, Celgene, Takeda and The Binding Site: Honoraria; Amgen, Celgene, Janssen and Takeda: Consultancy; Celgene: Honoraria, Speakers Bureau. Paiva: EngMab: Research Funding; GSK: Honoraria, Research Funding; Amgen: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Adaptive: Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche Glycart AG: Honoraria, Research Funding; Gliead: Honoraria; Oncopeptides: Honoraria.

*signifies non-member of ASH