PANGEA / PANGEA-2 Trial

[Slide 1] Mayo clinic model identified 3 risk factors for progression I - - My - annourmal - # Risk factors: 18th ANY Annual Newting # Non IgG subtype M-spike >1.5g/dL Abnormal free # Light chain ratio - N - = " " 20 year risk of progression: 5% (low risk), 21% (low-int), 37% (high-int) and 58% (high) with 0-3 risk factors, respectively Rajkumar a M. Mood 3005 Stanford University 66th ASH® Annual Meeting and Exposition --- [Slide 2] Pangea model Can be used for MGUS and Birth ASH Annual lisaning SMM Includes 4 variables Serum FLC ratio M-spike Creatinine Age Option of adding hemaglobin measurements over time Bone marrow biopsy optional Cower et M. LIMOR PAZA Stanford University 66th ASH® Annual Meeting and Exposition

[Slide 1] Acknowledgments Ghobrial lab & clinical research team, data science CHU team @DFCI LA Ligue ANGERS Ligue contre le cancer and the University Hospital of CONTRE LE CANCER CENTRE HOSPITALIER UNIVERSITAIRE Angers Our collaborators: NAVARRENUS UNIVERSITAS RSITAS Universidad UNIVERSITÄT HEIDELBERG de Navarra ZUKUNFT University College London (UK) SEIT 1386 University of Athens (Greece) University of Heidelberg (Germany) UCL National and Kapodistrian University of Navarra (Spain) UNIVERSITY OF ATHENS 12 Dana-Farber Cancer Institute --- [Slide 2] Static model Conclusion Detection of progression Tumor growth Next steps: Dynamic model Inclusion of new validation cohorts Early detection Validation of models integrating FISH results Time Take-home messages: Time We developed the PANGEA 2.0 trajectory model which will soon be available as an easy-to-use online calculator to predict progression risk in SMM By observing trajectories, PANGEA 2.0 can detect earlier patterns of progression and stratify patients more accurately Trained on >1000 patients and validated on >1000 patients in a multicenter cohort with longitudinal follow-up PANGEA 2.0 still performs robustly when prior results are unknown Dana-Farber Cancer Institute 11

[Slide 1] Risk Stratification of Smoldering in Multiple Improved Myeloma Using Trajectory Data A Multicenter Study in 2,203 Participants the PANGEA 2.0 Model: Floris Chabrun1234 Daniel Schwartz1+, Martin-Sanchez⁶, Susanna Rosalinda Termini⁶, Thomas Hielscher⁷, Annie Cowan1, Federico G El-Khoury¹, S Gentile1,5+, Tulika R Gupta¹, Jacqueline Perry1, Jean-Baptiste Alberge¹,², Ferrari1, Samuel Noelia Michael Freeman³, A Timonian¹, Robert Redd', David Cordas dos Santos¹, David J Lee1,2,8, Elizabeth Lightbody1,2, Hadley Barr¹, Priya Kaur1, Katelyn Downey1, Collado Gisbert5, Esperanza Vidhi Patel1, Patrick Costello¹, Catherine Tobia1, Romanos Sklavenitis-Pistofidis12, Habib Phan¹, Maya Patel¹, Jennifer Lamb1, Nana Ama Boadi-Acheampong¹, Selina J Chavda9, Louise Ainley⁹, Foteini Theodorakakou®, Sally Despina Fotiou¹⁰, Christine Ivy Liacos¹⁰, Nikolaos Kanellias¹⁰, Elizabeth K O'Donnell1,2, Catherine R Marinac1,2, Gad Getz¹⁸, Omar Nadeem12,8, Thomas Hielscher¹¹, Johannes Waldschmidt¹, Martin Kortüm¹¹, Marietou Binta Thiam12, Salomon Manier¹², Elias K Mai', Mareike Hampel, Marc Raab⁷, Niccolo Bolli13, Kwee Yong⁹, Efstathios Kastritis¹⁰, Meletios A Dimopoulos¹⁰, Jesus San Miguel⁶, Bruno Paiva⁵*, Lorenzo Trippa¹*, Irene M Ghobrial12* Dana Farber Cancer Institute, Boston, MA, Harvard Medical School, Boston, MA, The Broad Institute, Cambridge, MA, Laboratory of Biochemistry and Molecular Biology, University Hospital of Angers, University of Angers, Angers, France, Sapienza University of Rome, Rome, Italy, University of Navarra, Pamplona, Spain, University of Heidelberg, Heidelberg, Germany, Massachusetts General Hospital, Boston, MA, University College London, London, UK, University of Athens, Athens, Greece, "University Hospital of Würzburg, Würzburg, Germany, University Hospital of Lille, France, University of Milan, Milano, Italy December 9ª, 2024 Dana-Farber Cancer Institute 66th --- [Slide 2] Trajectory changes allow detecting earlier patterns of progression M-Protein FLC ratio BMPC% 2.0 60 21 1.9 18 40 1.8 15 1.7 20 1.6 12 1.5 0 9 Progression to MM Biomarker / risk score value Creatinine Hemoglobin Age No trajectory change detected 3.5 16 58 3.0 15 Trajectory change detected 2.5 14 57 2.0 13 56 1.5 12 1.0 11 55 PANGEA Traj. No BM PANGEA Traj. BM Rolling 20/2/20 2-year risk 2-year risk 2-year risk 1.00 1.00 1.00 0.75 0.75 0.75 0.50 0.50 0.50 0.25 0.25 0.25 0.00 0.00 0.00 0 1 2 3 Dana-Farber Cancer Institute 0 1 2 3 0 1 2 3 6 Years since baseline visit 3 --- [Slide 3] >2000 patients followed for SMM using SLiM-CRAB criteria¹ Validation Cohort 3 Validation Cohort 2 Validation Cohort 1 Universidad Training Cohort UNIVERSITÄT de Navarra HEIDELBERG National and Kapodistrian ZUKUNF Dana-Farber UCL UNIVERSITY OF ATHENS SEIT 1386 Cancer Institute 240 447 485(105 & 380) 59 (25%) 1,031 140 (31%) cohort size (total: 2,203) 159 (33%) 231 (22%) 1.6 (0.7 2.7) rogressed to MM (total: 589) 3.4 (1.4 6.3) 2.4(0.7 5.7) 3.7 (1.8 7.1) 6.0 (4.0 2.7) llow up (years) 5.5 (3.4 8.5) 3.9 (3.0 6.2) erval between visits (months) 6.0 (3.7 7.6) 63.8(54.0 72.9) 60.0 (52.0 67.0) 66.0 (58.0 - 74.3) at initial diagnosis (years) 61.7 (53.3 69.0) 278/206 (58/42%) 196/122 (44/56%) 122/118 (51/49%) 504/527 (49/51%) (Female/Male) 26 (3%) 17 (4%) an back or African American 86 (8%) 19 (4%) 882 (86%) 429 (88%) 66th / ana-Farber Cancer Institute 1. Rajkumar et al. Lancet Oncol. 2014 Nov;15(12):e538-548. 4 --- [Slide 4] PANGEA 2.0 identifies patients at higher risk 20/2/20 PANGEA 2.0 BM 20/2/20 Risk Low Intermediate High PANGEA20 BM Risk Low intermediate High 1.00 1.00 0.90 0.90 0.75 0.75 Training cohort/BM Survival probability 0.50 Survival probability 0.50 0.25 0.25 0.00 0.00 0 2 5 10 0 2 5 10 Time Time PANGEA 20 BM Risk Low Intermediate High 20/2/20 Risk Low intermediate High 1.00 1.00 0.90 0.90 Validation cohort 1/BM 0.75 0.75 Survival probability 0.50 0.25 Survival probability 0.50 0.25 0.00 0.00 0 2 5 10 0 Time 2 5 10 Time PANGEA 2.0 BM 2-year progression rate 20/2/20 Low Int. High Training cohort Low Int. 3.3% High 16.7% 59.4% Validation cohort 1 5.4% 20.7% 2.0% 7.8% 43.3% 66t 46.6% 1.1% 18.3% 26,7% 10

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