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1951 Integrating Chromosomal 1 Abnormalities into the Definition of High-Risk Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry

Program: Oral and Poster Abstracts
Session: 653. Multiple Myeloma: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Plasma Cell Disorders, Clinical Research, Diseases, Real-world evidence, Lymphoid Malignancies, Registries
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Kenneth J C Lim, MBBS1,2,3, Cameron Wellard, BSc (Hons), PhD4*, Elizabeth Moore, PhD, MPH, PgradDip (Nurs Crit Care)4*, Betty Gration, BMBCh5*, Bradley Augustson, MBBS, FRACP, FRCPA6*, Peter Mollee, FRACP, MBBS, MSc, FRCPA7,8, Jennifer Zhang, PhD9*, Nicole Wong Doo, MBBS, MD, FRACP, FRCPA10,11, Sabine Ringkowski, MD12, Adam Bryant, MBBS(Hon), PhD, FRACP, FRCPA12,13*, Slavisa Ninkovic, MBBS14,15,16, Nada Hamad, MBBS, MSc, BSc17,18,19, Georgia McCaughan, MBBS, MMed20,21*, Shaji Kumar, MD22, Andrew Spencer, MBBS23,24* and Hang Quach, MD, FRACP, FRCPA, MBBS25,26

1Hematology, St Vincent's Hospital Melbourne, Brunswick, Australia
2Division of Hematology,, Mayo Clinic Rochester, Rochester, MN
3Victorian Cancer Cytogenetic Service, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia
4School of Public Health and Preventative Medicine, Monash University, Melbourne, VIC, Australia
5Haematology, St Vincent's Hospital Sydney, Sydney, Australia
6Sir Charles Gairdner Hospital and Linear Clinical Research, Perth, Western Australia, Australia
7Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
8Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia
9Concord Repatriation General Hospital, Sydney, Australia
10Department of Haematology, Concord Hospital, University of Sydney, Concord, NSW, AUS
11Concord Clinical School, Faculty of Medicine and Health, University of Sydney, Australia, Concord, NSW, Australia
12Hematology, Liverpool Hospital, Liverpool, NSW, AUS
13Liverpool Hospital, Sydney, Australia
14Faculty of Medicine, University of Melbourne, Melbourne, Australia
15Haematology, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia
16Victorian Cancer Cytogenetics Service, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia
17Haematology Department, The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, NSW, Australia
18School of Clinical Medicine, Faculty of Medicine and Health, The University of New South Wales, Sydney, NSW, Australia
19School of Medicine, University of Notre Dame, Sydney, Australia
20School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
21Department of Haematology, St. Vincent's Hospital, Sydney, Australia
22Division of Hematology, Mayo Clinic, Rochester, MN
23Department of Malignant Haematology & Stem Cell Transplantation, The Alfred Hospital, Melbourne, Australia
24School of Translational Medicine, Alfred Health-Monash University, Melbourne, VIC, Australia
25Department of Haematology, St Vincent’s Hospital Melbourne, Victoria, Australia, Melbourne, VIC, Australia
26University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia

Aim:

The definition of high-risk (HR) in Multiple Myeloma (MM) is ever evolving with the discovery of new genomic abnormalities and increasing therapeutic options. There are various stratification models incorporating laboratory and genetic features with different definitions of high-risk and varied emphasis on individual risk factors. Recognized high-risk cytogenetic abnormalities (HRCA) include t(4;14), t(14;16), t(14;20), del(17p) with recent inclusion of del(1p) and gain/amplification (amp) of 1q (+1q) . In addition to del(17p), the presence of biallelic del(1p) and ≥2 HRCAs (“double-” or “triple-hit”) appear to confer poorer outcomes. A new definition proposed by the International Myeloma society (IMS) defines HR as the presence of del(17p) and/or TP53 mutation; an IgH translocation - t(4;14), t(4;16) or t(14;20) along with +1q and/or del(1p); monoallelic del(1p32) along with +1q; bi-allelic del(1p32); or β2 microglobulin ≥5.5 with normal creatinine (<1.2mg/dL). Herein, we report real-world outcomes on these HRCAs and the new IMS consensus definition of HR MM.

Method:

We retrospectively reviewed newly diagnosed MM patients from the Australian and New Zealand Myeloma and Related Diseases Registry across 4 Australian states. Patients with FISH and/or SNP microarray testing for IgH translocations, 1q21 (CKS1B), del(1p32) (CDKN2C) and del(17p) (TP53) were identified. Positive threshold was 30%. We used Kaplan-Meier methods to compare progression free survival (PFS) and overall survival (OS) between groups and first performed univariate analysis (UA) for each HRCA. We next analyzed patients with gain1q vs amp1q and monoallelic vs biallelic del(1p). In the final analysis, two risk groups were formed: cases meeting the new IMS-defined HR criteria were considered IMS-HR and the rest were considered standard risk (IMS-SR). Indeterminate cases with missing variables that could influence risk classification were excluded.

Results:

Of 839 newly diagnosed patients (pts) included, 31% had ISS (International staging system) stage 3 disease. High-risk IgH translocations t(4;14) and t(14;16) were present in 8% and 4%. Secondary HRCAs del(17p), del(1p), gain1q and amp1q were present in 9%, 14%, 30% and 11% respectively. In this cohort, 41% received ASCT. Of the transplant eligible pts, 41% received triplet therapy (PI, IMiD and corticosteroid) and 57% received PI-based induction. Of the transplant ineligible pts, 31% received triplet therapy, 47% PI-based and 19% IMiD-based therapy. Frontline Anti-CD38 antibody use was <1%. Median follow up was 35 months[m] (IQR 18-60).

On UA, the risk of progression and/or death was increased with ISS III vs I, amp1q, del(17p), t(14;16), del(1p) and gain1q in descending order by hazard ratio. The risk remained significant in ISS III, del(17p), amp1q and gain1q after multi-variate analysis (MVA). The risk of death was increased with ISS III vs I, del(17p), amp1q, del(1p) and t(14;16), ISS II vs I in descending order by hazard ratio. After MVA, the risk remained significant for ISS stage III, del(17p), amp1q and t(14;16).

Of the 117 pts with del(1p32), 108 had monoallelic and 9 had biallelic loss. Pts with biallelic del(1p32) had an inferior PFS (median 16.3 vs 23.2m, p<0.001) and OS (median 24.8m vs NR, p<0.001) compared to those with monoallelic del(1p32). In pts with 1q+, pts with amp1q had an inferior PFS (median 16.3 vs 27.5m, p<0.001) and OS (median 37.0m vs NR, p<0.001) vs pts with gain1q.

Based on the new definition of HR myeloma - 385 pts met the criteria for IMS-HR and 216 for IMS-SR. There were 238 indeterminate cases due to missing data. The IMS-HR group had an inferior PFS (median 20.2 vs 39.7m, p<0.001) and OS (median 44.2m vs NR, p<0.001) when compared to IMS-SR. Noting that the IMS-HR group had a higher median age, poorer performance status and lower rates of ASCT use, adjusted analysis for these variables still showed an inferior PFS (aHR 1.68; 95% CI 1.30-2.16, p<0.001) and OS [aHR 1.72; 95% CI 1.21-2.44, p=0.002).

Conclusion:

ISS III, del(17p), amp1q are the strongest predictor of OS and PFS. Differentiating between monoallelic vs biallelic del(132p) and gain vs amp1q21 has important prognostic value. The IMS- HR definition which takes into account del(1p), “double-“ and “triple-hit” disease predicts for a group of patients with a PFS of ~20 months and inferior OS, and provides a standardized approach to risk stratification in MM.

Disclosures: Lim: Sanofi: Research Funding. Mollee: Antengene: Research Funding, Speakers Bureau; Janssen, Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. McCaughan: Pfizer: Honoraria; Janssen: Honoraria; Antengene: Research Funding. Kumar: MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Other: Independent review committee participation; Sanofi: Research Funding; Roche: Research Funding. Spencer: F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Quach: Roche: Consultancy; Johnson & Johnson: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Research Funding.

*signifies non-member of ASH