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467 Impact of Chromosome 1 Abnormalities Among Patients with Newly Diagnosed Multiple Myeloma: A Subgroup Analysis from the Endurance (ECOG-ACRIN E1A11) Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials; treatment of NDMM and amyloidosis patients
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, Clinical Research, Plasma Cell Disorders, Clinically Relevant, Diseases, Lymphoid Malignancies, Study Population
Sunday, December 12, 2021: 1:00 PM

Timothy M. Schmidt, MD1, Prashant Kapoor, MD2, Susanna Joan Jacobus, MSc3*, Zihan Wei, MS3*, Adam D Cohen, MD4, Rafael Fonseca5, Natalie S. Callander, MD1, Sagar Lonial, MD, FACP6, S Vincent Rajkumar, MD2* and Shaji K Kumar, MD2

1Carbone Cancer Center, University of Wisconsin, Madison, WI
2Division of Hematology, Mayo Clinic, Rochester, MN
3Dana Farber Cancer Institute, Boston, MA
4University of Pennsylvania Abramson Cancer Center, Philadelphia, PA
5Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ
6Emory University School of Medicine, Atlanta, GA

Background: Extra copies of the long arm of chromosome 1 (+1q) and deletion of its short arm (del1p) are associated with high risk features in multiple myeloma (MM), but the prognostic impact of +1q and/or del1p among pts with conventionally defined standard risk cytogenetics is unclear. Whether treatment with carfilzomib (K) may be more effective than bortezomib (V), in combination with lenalidomide (R) and dexamethasone (d), among pts with chromosome 1 abnormalities (C1A) is also unknown.

Methods: We performed a post hoc analysis of the E1A11 trial, in which pts without del17p, t(14;16), t(14;20), high LDH, or plasma cell leukemia and not intended for upfront transplant were randomized to receive KRd versus VRd induction, followed by indefinite or 2-year R maintenance. Among pts with +1q, copy number (CN) was quantified, with gain1q defined as 3 copies and amplification (amp1q) defined as ≥4 copies of 1q. Ultra high risk (UHR) MM was defined as ≥2 of the following: +1q, del1p, and t(4;14), whereas only one of these comprised single hit (SH).

Results: Of 1087 total pts, 912 were tested for +1q at diagnosis and 310 of these (34%) had +1q. CN was known for 280 pts, of which 212 (76%) had gain1q and 68 (24%) had amp1q. There were no differences in treatment arm allocation or demographics between pts with and without +1q or by CN. Pts with +1q, compared to those without +1q, were more likely to present with ISS Stage 3, hemoglobin <10g/dL, abnormal karyotype, del(1p), -13, t(4;14), and absence of t(11;14). Del1p was evaluated in 774 pts and identified in 69 (8.9%) pts at diagnosis. Pts with del1p were more likely to have ISS Stage 3, ECOG performance status >0, +1q, and absence of t(11;14).

Median follow up was 30.1 months (mo) for PFS and 41.3 mo for OS. In the overall study population, as shown in Figure 1, pts with +1q, compared to pts without +1q, had significantly worse progression-free survival (PFS) (median 29.1mo vs 41.9mo, HR 1.54, p<0.001) and overall survival (OS) (3y OS 78.4% vs 86.9%, HR 1.38, p=0.035). There was no significant difference in PFS between patients with amp1q and gain1q (median PFS 24.4mo vs 29.2mo, HR 1.24, p=0.275) or OS (3y-OS 68.9% vs 80.7%, HR 1.36, p=0.259). Pts with del1p, compared with no del1p, had significantly worse PFS (median 28.8mo vs 38.6mo, HR = 1.49, p=0.042) and OS (3y OS 74.1% vs 85%, HR 2.03, p=0.003). Additional “hits” resulted in inferior outcomes. Median PFS for pts without +1q, del1p or t(4;14), compared to pts with SH or UHR was 47.9mo, 32.6mo, and 19.7mo, respectively (SH HR 1.41, p=0.014; UHR HR 2.42, p<0.001), and 3y OS rates were 89.2%, 79.5%, and 68.6%, respectively (SH HR 1.66, p=0.01, UHR HR 2.54, p<0.001).

Outcomes were also evaluated by induction arm. Best responses to VRd and KRd were similar for pts with and without +1q, as well as those with and without del1p. PFS of pts with +1q was significantly worse for both arms (VRd HR 1.51, p=0.011; KRd HR 1.63, p=0.002), and a trend towards worse OS was also seen in both arms (VRd HR 1.47, p=0.069; KRd HR 1.34, p=0.185). Pts with gain1q had inferior PFS in both arms (VRd HR 1.59, p=0.012; KRd HR 1.41, p=0.051). OS rates with gain1q were inferior in the VRd arm (HR 1.78, p=0.014) but not KRd (HR 1.02, p=0.93). In contrast, pts with amp1q had inferior outcomes with KRd (PFS HR 2.37, p<0.001; OS HR 2.43, p=0.008) but not with VRd (PFS HR 1.43, p=0.186; OS HR 1.29, p=0.48). Impact on PFS for pts with del1p was similar for both VRd (HR 1.49, p=0.173) and KRd arms (HR 1.52, p=0.118). However, pts with del1p treated with VRd had inferior OS (HR 3.3, p<0.001), whereas those treated with KRd had no difference in OS compared to no del1p (HR = 1.1, p=0.818). The adverse impact of UHR on PFS compared to no hit was similar for VRd (HR 2.21, p=0.009) and KRd (HR 2.74, p<0.001), but regarding OS, UHR was far more detrimental in the VRd arm (HR 5.24, p<0.001) than KRd (HR 1.33, p=0.516). Direct comparisons of KRd to VRd by C1A are found in Table 1.

Conclusions: Gain1q, amp1q, and del1p confer inferior PFS among pts with otherwise standard risk features treated with standard triplet induction therapies without upfront transplant. While acknowledging the limitations of a post hoc subgroup analysis and the need for additional follow up, KRd may overcome the negative OS impact among pts with gain1q and del1p, but not among pts with amp1q. Pts with +1q and del1p should be considered to have high risk MM and considered for enrollment in clinical trials using novel strategies aimed at improving outcomes in high risk pts.

Disclosures: Schmidt: Sanofi: Consultancy; Janssen: Consultancy. Kapoor: Pharmacyclics: Consultancy; Amgen: Research Funding; Sanofi: Consultancy; Ichnos Sciences: Research Funding; Karyopharm: Research Funding; Regeneron Pharmaceuticals: Research Funding; Cellectar: Consultancy; BeiGene: Consultancy; Karyopharm: Consultancy; Glaxo SmithKline: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Cohen: Janssen: Consultancy; AstraZeneca: Consultancy; BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda: Consultancy; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy. Fonseca: Mayo Clinic in Arizona: Current Employment; Sanofi: Consultancy; Pharmacyclics: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Lonial: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Carsgen: Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: 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; Sanofi: Research Funding.

*signifies non-member of ASH