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3030 Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Saurabh Zanwar, M.B.B.S., M.D.1, Jennifer Le-Rademacher, Ph.D.2*, Eric Durot3*, Shirley D'Sa4*, Jithma Prasad Abeykoon, MD5, Patrizia Mondello, MD, PhD, MSc6, Shaji Kunnathu Kumar, MD6, Shayna R Sarosiek7, Jonas Paludo, MD8, Saurabh Chhabra, MD9*, Joselle Cook, MBBS8, Ricardo Parrondo, MD10, Angela Dispenzieri, MD8, Wilson I. Gonsalves, MD11, Eli Muchtar, MD12, Sikander Ailawadhi13, Robert Kyle, MD14, Vincent Rajkumar, MD8*, Alain Jacques Delmer, MD15*, Rafael Fonseca, MD9, Morie A. Gertz, MD16, Steven P. Treon, MD, PhD, FRCP17, Stephen M Ansell, MD, PhD6, Jorge J. Castillo, MD18 and Prshant Kapoor, MD1

1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN
3CHU Reims, Reims Cedex, France
4Department of Haematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
5Mayo Clinic, Boston, MN
6Division of Hematology, Mayo Clinic, Rochester, MN
7Dana-Farber Cancer Institute, Bing Center for Waldenström Macroglobulinemia, Boston, MA
8Mayo Clinic, Rochester, MN
9Mayo Clinic, Phoenix, AZ
10Mayo Clinic, Jacksonville, FL
11Division of Hematology, Mayo School of Graduate Medical Education, Rochester, MN
12Mayo Clinic, Rochester, Minnesota, Rochester, MN
13Mayo Clinic Florida, Jacksonville, FL
14Mayo Clinic, Stabile 6-28, Rochester, MN
15Hôpital Robert Debré CHU de Reims, Reims Cedex, -, FRA
16Department of Medicine, Division of Hematology,, Mayo Clinic, Rochester, MN
17Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
18Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA

Background: Waldenström Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous outcomes. The recently developed, Revised International Prognostic Scoring System for WM (rIPSS-WM) did not examine the prognostic impact of MYD88L265P, a somatic alteration present in most patients with WM. Moreover, rIPSS-WM could only be partially validated in an external cohort. Here, we report the performance of rIPSS-WM and propose a refined prognostic model with external validation.

Methods: We reviewed medical records of treatment-naïve patients with active WM consecutively seen at Mayo Clinic, Rochester (MCR) between 01/01/1996 and 12/31/2017. We applied the rIPSS-WM model in patients with data available for all required parameters, including age, serum beta-2 microglobulin (β2M), serum lactate dehydrogenase (LDH) and serum albumin at diagnosis to assess the prognostic utility of this model. We then identified the dichotomized clinical and laboratory parameters prognostic for overall survival (OS) by univariate analyses (UVA) in our cohort. The significant parameters were analyzed to independently predict OS in a multivariable analysis (MVA) and to create a prognostic model, which was subsequently validated in an independent multi-institutional cohort.

Results: We identified 889 patients with active WM at MCR, with a median follow-up of 8.2 [95% confidence interval (CI): 7.5-9] years. The estimated median OS for this cohort was 10.6 (95%CI: 9.7-11.4) years. Patients with available data in this cohort for the validation of rIPSS-WM (n=241) were risk stratified into very low (n=46), low (n=64), intermediate (n=58), high (n=46) and very-high risk groups (n=27) per rIPSS-WM, with the respective 5-year OS rates of 96%, 76%, 72%, 77% and 32%, demonstrating overlapping survival curves for the low, intermediate and the high-risk groups. Because rIPSS-WM could not be validated, we used the data from the MCR cohort and identified age at diagnosis of active WM, LDH >upper limit of normal (ULN), β2M >3µg/mL and albumin <3.5g/dL as statistically significant prognostic markers for OS on UVA. Notably, the presence of MYD88L265P did not impact OS [median 11.4 years (95%CI: 10.1-not reached (NR) for MYD88L265P genotype (n=231) versus 10 years (95% CI: 8.1-NR) for MYD88WT genotype (n=65); p=0.33]. On MVA, LDH >ULN (HR 2.34), serum albumin <3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and >75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin <3.5 g/dL and age group 66-75 years and similarly, 2 points each for age >75 years and serum LDH >ULN per their impact on OS. Patients with the composite scores of 0, 1 and 2 were categorized as low risk, low- intermediate risk and intermediate risk, respectively. Due to similar OS for the scores of 3 to 5, these were combined to form the high-risk group of our proposed model: Modified Staging System for WM (MSS-WM). The median OS was 14.6 years [95%CI: 9.1 years-NR] for low-risk (score 0, n=71, 21%), 11.2 years (95% CI: 9.1-15.2 years) for low-intermediate risk (score 1, n=110, 32%), 8.1 years (95% CI: 6.4-12.2) for intermediate risk (score 2, n=81, 24%) and 5.5 years (95 % CI: 3.9-11 years) for the high-risk group (score ≥3, n=79, 23%); p<0.0001. In this derivation cohort, the 5-year OS rate was 93%, 82%, 69% and 55% and 10-year OS rate was 60%, 53%, 45% and 30% for the low, low-intermediate, intermediate, and high-risk cohort, respectively (Figure 1A). We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p<0.0001). We then used data from an independent series of 335 treatment-naïve symptomatic patients from academic institutions (n=5) across the US and Europe for external validation of the MSS-WM model. The median follow-up for the validation cohort was 6.3 years (95% CI: 5.5-7.2 years). The 5-year OS was 93%, 90%, 75% and 57% and the estimated 10-year OS was 91%, 80%, 64% and 35% for the low risk (n= 86, 26%), low-intermediate (n=107, 32%), intermediate (n=86, 26%) and high-risk (n=59, 18%) cohorts, respectively (p<0.0001, Figure 1B).

Conclusions: Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients’ age, serum albumin and serum LDH at diagnosis.

Disclosures: D'Sa: BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria; Kite: Honoraria. Sarosiek: Cellectar: Consultancy, Research Funding; Beigene: Honoraria, Research Funding; ADC Therapeutics: Research Funding. Paludo: Karyopharm: Research Funding; Biofourmis: Research Funding; AbbVie: Consultancy. Dispenzieri: Alnylam, Bristol-Myers Squibb, Janssen, Pfizer, Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides, Sorento: Consultancy. Muchtar: Protego: Consultancy. Ailawadhi: AbbVie, Amgen, Ascentage, BMS, Cellectar, GSK, Janssen, Pharmacyclics, Sanofi: Research Funding; Beigene, BMS, Cellectar, GSK, Janssen, Pfizer, Regeneron, Sanofi, Takeda: Consultancy. Fonseca: Takeda: Consultancy; Janssen: Consultancy; Binding Site: Consultancy; Millenium: Consultancy; AZBio: Membership on an entity's Board of Directors or advisory committees; BMS (Celgene): Consultancy; Antegene: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; FISH: Patents & Royalties: FISH; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Regeneron: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Merck: Consultancy; Kite: Consultancy; Juno: Consultancy; Bayer: Consultancy; Aztrazenica: Consultancy; AMGEN: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Gertz: Juno Pharmaceutics, and Sorrento Therapeutics: Other: Meetings; Ionis/Akcea, Prothena, Sanofi, Janssen, Aptitude Healthgrants, Ashfield, Physicians Education Resource, Research to Practice, Johnson & Johnson, and Celgene: Consultancy; AbbVie: Other: Data Safety Monitoring board; i3HEalth: Other: For development of educational material. Treon: BeiGene: Consultancy, Research Funding; Eli Lilly: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Bristoll Myers Squibb: Consultancy, Research Funding. Ansell: ADC Therapeutics, Affimed, Bristol-Myers Squibb Company, Pfizer Inc, Regeneron Pharmaceuticals Inc, Seagen Inc, Takeda Pharmaceuticals USA Inc.: Other: Contracted Research. Castillo: Mustang Bio: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Cellectar: Consultancy, Research Funding; Kite: Consultancy; Abbvie: Consultancy, Research Funding. Kapoor: GSK: Consultancy, Research Funding; Amgen: Research Funding; Regeneron: Research Funding; BMS: Research Funding; Loxo: Research Funding; Ichnos: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; GSK: Consultancy; Beigene: Consultancy; Pharmacyclics: Consultancy; X4 Pharmaceuticals: Consultancy; Casma: Consultancy; AbbVie: Consultancy; Sanofi: Consultancy; Karyopharm: Consultancy.

*signifies non-member of ASH