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489 Reevaluating the IMWG Multiple Myeloma Complete Response Criterion in the Era of Mass Spectrometry: A Critical Analysis

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Multiple Myeloma: Clinical and Epidemiological: Cellular and Molecular Profiling of Multiple Myeloma: Implications for Clinical Practice
Hematology Disease Topics & Pathways:
Measurable Residual Disease
Sunday, December 8, 2024: 10:00 AM

Noemi Puig, PhD1,2, Cristina Agullo2*, Bruno Paiva, PhD3,4,5,6*, María T Cedena7*, Laura Rosiñol Dachs8,9,10*, Teresa Contreras11*, Joaquín Martínez-Lopez12,13*, Albert Oriol14,15*, María-Jesús Blanchard, MD, PhD16,17*, Rafael Rios Tamayo, MD, PhD18*, Ana Maria Sureda Balari, MD, PhD19,20,21,22,23,24,25,26,27, Miguel Teodoro Hernández Garcia, MD, PhD28*, Javier de la Rubia29,30*, Valentin Cabanas Perianes, MD, PhD31*, Felipe De Arriba, MD, PhD32*, Luis Palomera, MD, PhD33*, Maria Belen Inigo Rodriguez34*, Veronica Gonzalez-Calle, MD, PhD2,4,35,36*, Enrique M Ocio, MD, PhD37*, Sergio Castro2*, Joan Bargay38*, Joan Bladé, MD, PhD39,40*, Jesús F. San-Miguel, MD, PhD41,42, Juan-Jose Lahuerta Palacios, MD, PhD43,44* and Maria- Victoria Mateos45,46,47,48

1Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
2Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
3Cancer Center Clinica Universidad de Navarra (CCUN)., Pamplona, Spain
4Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Madrid, Spain
5Department of Hematology, Centre for Applied Medical Research, Cancer Center Clinica Universidad de Navarra, University of Navarra, IdiSNA, CIBERONC, Pamplona, Spain
6Clinica Universidad de Navarra (CCUN), Center for Applied Medical Research (CIMA), IDISNA, CIBER-ONC, Pamplona, Spain
7University Hospital 12 de octubre, Madrid, Spain
8Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain
9Hematology Department, Hospital Clinic de Barcelona and Insitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
10Hospital Clinic of Barcelona, Barcelona, Spain
11Biochemistry Department, University Hospital of Salamanca, Salamanca, ESP
12Hospital Universitario 12 de octubre, Universidad Complutense, CNIO, Madrid, Spain
13University of Complutense, Hospital 12 de Octubre, Madrid, Spain
14Catalan Institute of Oncology and Josep Carreras Institute, Hospital Germans Trias i Pujol, Badalona, Spain
15Institut Josep Carreras and Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain
16Hematology, Hospital Universitario Ramón y Cajal, Madrid, Spain
17Hematology, Hospital Universitario Ramon y Cajal, Madrid, Spain
18Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, ESP
19Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC), Spain, Spain
20Hematology, Institut Català d'Oncologia-Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
21Institut Catala d’Oncologia, Barcelona, Spain
22Biomedical Research Institute, Universitat de Barcelona, Barcelona, Spain
23Blood Cell Barcelona Hematology Institute, Barcelona, Spain
24Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC), Madrid, Spain
25EBMT Lymphoma Working Party, Paris, France
26for the Lymphoma Working Party of the EBMT, Barcelona, Spain
27Institut Català d'Oncologia-Hospital Duran i Reynals, Hospitalet del Llobregat, Spain
28Hospital Universitario de Canarias, La Laguna, ESP
29Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
30Hospital Universitario y Politécnico La Fe, Valencia, Spain
31Hematology, IMIB-Virgen de la Arrixaca University Hospital, University of Murcia, El Palmar, Murcia, Spain
32Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
33Hospital Clinico Universitario Lozano Blesa, Instituto Investigacion Sanitaria Aragon, Zaragoza, Spain
34HOSPITAL CLINICO SAN CARLOS, MADRID, Spain
35Haematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca (IBSAL), CIBERONC and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain
36University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), CIBERONC, Salamanca, Salamanca, ESP
37Hospital Universitario Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
38Hematology Department, Hospital Universitario Son Llàtzer. IdIsBa., Palma de Mallorca, Spain
39Amyloidosis and Multiple Myeloma Unit, Department of Hematology, IDIBAPS, Hospital Clinic, Spain, Barcelona, Spain
40Hospital Clinic, IDIBAPS, Barcelona, Spain
41Hematology and Cell Therapy Department. Clinica Universidad de Navarra, Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
42Clínica Universidad de Navarra, CIMA, IDISNA, CIBER-ONC (CB16/12/00369), Pamplona, Spain
43Hematology, Hospital Universitario 12 de Octubre, Imas12, CIBERONC, Madrid, Spain
44Hospital Universitario 12 de Octubre, CIBER-ONC CB16/12/00369, CNIO, Madrid, Spain
45Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain, Salamanca, Spain
46Hospital Universitario de Salamanca, Salamanca, Spain
47Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca, Salamanca, Spain
48University of Salamanca, Department of Medicine, Salamanca, Spain

Introduction:

In multiple myeloma (MM), "Complete Response" (CR) is defined by the IMWG as negative immunofixation (IFE) on the serum and urine, disappearance of any soft tissue plasmacytomas, and less than 5% plasma cells (PC) in the bone marrow (BM). However, 24-hour urine collections and BM examinations can be challenging and uncomfortable for patients (pts), leading to noncompliance in routine clinical practice. The Spanish Myeloma Group already showed the limited value of urine IFE for defining CR. In this study, we aimed to evaluate the value of BM examinations in pts with suspected CR based on negative IFE results in serum (sIFE) and to explore the utility of mass spectrometry (MS) as a marrow sparing, single serological marker to determine a potentially mass-spec based CR category.

Methods:

We analyzed a total of 1050 paired serum and BM samples obtained from 380 newly diagnosed transplant eligible MM pts enrolled in the GEM12MENOS65, GEM14MAIN, and GEM-CESAR clinical trials. Samples were obtained at four predefined time points: post-induction, after ASCT, post-consolidation and after 2 years of maintenance. Serum samples were analyzed using Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads in the EXENT® Analyzer (The Binding Site, part of Thermo Fisher Scientific) and SPEP/IFE, carried out as per each center protocol. First-pull bone marrow aspirations were used for morphological assessment with May-Grümwald-Giemsa staining. PC counts were obtained from a 200-cell differential count, using conventional bright-field microscopy. The treatment schemas and dosing of the three trials have been previously described.

Results:

First, we pooled together the results of all samples (including all time points and independently of the conventional response achieved by the pts) and analyzed the individual clinical value of the two main factors defining CR (i.e., PC counting [<5% vs 5%] and sIFE [positive vs negative]). Results showed that PC counting and sIFE status were not able differentiate two groups of pts with different median progression-free survival (mPFS). In contrast, MS status effectively separated two groups with different mPFS (MS negative not reached [NR] vs MS positive 5.55 years; p<0.0001; HR. 0.5674 [95% CI: 0.46 – 0.69]).

Focusing only in the 426 samples (from 189 pts) with “suspected CR” based solely on sIFE negative results, we observed a trend towards inferior PFS in the 18 samples (from 15 pts) with 5% PC (mPFS: <5%PCs NR vs ≥5%PCs 5.42 years; p=0.1884). However, a highly significant reduction in mPFS was observed among these cases with a sIFE negative but positive for MS (mPFS: MS- negative NR vs MS positive 4.98 years; p=0.0002; HR. 0.52 [95%CI 0.37 – 0.74]). Further, analysis of the combined results of PC counting and MS (among sIFE negative cases) showed that only 8 out of the 408 cases had 5%PC and were MS negative, being all of them also MRD negative by NGF. Therefore, the negative predictive value of MS using the results of PC counting among sIFE negative cases was of 97% (95%-99%, p=0.0184). Among sIFE positive cases, MS discriminated 2 subgroups with different mPFS (NR in negative cases vs 5.96 years in positive cases) although not reaching statistical significance.

We then combined the results of PC counting and sIFE, therefore dividing the global cohort in samples in CR (<5%PC and sIFE negative) vs <CR cases (5%PC and/or sIFE positive). No significant differences in PFS between the CR and < CR groups defined as above were observed. In contrast, when we examined the impact of MS in pts in CR, we found out that the MS status effectively segregated two groups with different mPFS. Importantly, MS was able to identify a subgroup of cases with a significantly inferior outcome (mPFS: MS negative NR vs MS positive 4.98 years; p=0.0009; HR 0.55 [95% CI: 0.38 – 0.78]).

Conclusion: Our study suggests that MS surpasses the clinical value of the CR category and the limitations of PC counting and sIFE, and thus supports the consideration of a new, MS-based, category of treatment response in pts with MM. Also, our results show that performing a BM aspiration in cases with “suspected CR” would only be justified if the analysis of MRD is planned, given the limited added value of PC counting.

Disclosures: Puig: Pfizer, Sanofi, Amgen, BMS-Celgene, Janssen, and Takeda: Consultancy; Pfizer, Sanofi, Amgen, BMS, Janssen, Takeda, and The Binding Site: Honoraria. Agullo: The Binding Site: Honoraria. Paiva: Adaptive, Amgen, Becton Dickinson, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis, Roche, Sanofi and Takeda: Honoraria; Aztra Zeneca, Bristol Myers Squibb/Celgene, EngMab, Roche, Sanofi, and Takeda: Research Funding; Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda: Consultancy. Rosiñol Dachs: BMS, Takeda, Pfizer, Menarini: Honoraria; GSK: Honoraria, Other: Honoraria for lectures; Amgen: Honoraria, Other: Educational lectures; Sanofi: Honoraria, Other: Honoraria for lectures; Janssen Pharmaceutica: Honoraria, Other: Honoraria for lectures and meeting travel support. Contreras: The Binding Site: Honoraria. Martínez-Lopez: Incity: Research Funding; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Oriol: Sanofi: Honoraria, Speakers Bureau; Pfizer, Amgen, Oncopeptides: Honoraria; GSK: Honoraria, Speakers Bureau; Bristol Myers Squibb/Celgene: Honoraria, Speakers Bureau; Johnson & Johnson, Janssen: Honoraria, Speakers Bureau. Rios Tamayo: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sureda Balari: Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; BMS/Celgene: Consultancy; Sanofi: Consultancy. de la Rubia: GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria; Takeda: Research Funding; Janssen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Menarini: Honoraria; Sanofi: Speakers Bureau; Oncopharm: Honoraria. De Arriba: Sanofi: Consultancy, Honoraria, Other: advisory board; Takeda: Consultancy, Honoraria; GlaxoSmithKline (GSK): Consultancy, Honoraria, Other: advisory board; Janssen‐Cilag: Consultancy, Honoraria, Other: advisory board; Amgen: Consultancy, Honoraria, Other: advisory board; Bristol‐Myers Squibb (BMS)/Celgene: Consultancy, Honoraria, Other: advisory board. Gonzalez-Calle: Janssen, GSK, Pfizer, BMS: Consultancy, Other: Travel and accommodation, Speakers Bureau. Ocio: Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Johnson & Johnson - Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Regeneron: Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Bladé: Celgene/Bristol Myers Squibb: Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; Janssen: Other: Honoraria for lectures; Sanofi: Other: Honoraria for lectures. San-Miguel: Takeda: Other: Advisory board; Novartis: Other; MSD: Other: Advisory board; Karyopharm: Other: Advisory board; Janssen-Cilag: Other: Advisory board; Haemalogix: Other: Advisory board; GlaxoSmithKline: Other: Advisory board; Celgene: Other: Advisory board; Bristol Myers Squibb: Other: Advisory board; Amgen: Consultancy, Other: Advisory Board ; Abbvie: Consultancy, Other: Advisory Board; Regeneron: Other: Advisory board; Roche: Other: Advisory board; Sanofi: Other: Advisory board; SecuraBio: Other: Advisory board. Lahuerta Palacios: BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Mateos: Amgen, Takeda, Regeneron: Honoraria; BMS/Celgene, Janssen-Cilag, Sanofi, Abbvie, Stemline, Oncopeptides, GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH