Combining Plasma Cell Leukemia-like Status with the Second Revision of the International Staging System Improves Risk Classification

Introduction Newly diagnosed multiple myeloma (NDMM) is characterized by a highly variable clinical course, with an overall survival (OS) ranging from less than 3 years to over 10 years. While patients with standard risk disease have benefited significantly from the introduction of novel agents, it remains unclear what the best upfront treatment strategy is for those with high-risk disease. As a result, risk-adapted trial designs (e.g., the MUKnine b OPTIMUM study, NCT03188172) are becoming more common in NDMM and are driving research efforts to improve the identification of high-risk disease.

High-risk NDMM can be identified with the recently published Second Revision of the International Staging System (R2-ISS), which combines several conventional risk markers including tumor burden and cytogenetic aberrations that generally reflect increased proliferation and resistance to apoptosis (D'Agostino et al. - J Clin Oncol 2022). We have recently shown that NDMM with high levels of circulating tumor cells can be identified based on a plasma cell leukemia-like (PCL-like) transcriptome that reflects aggressive disease, which is different from the high-risk biology that is recognized by conventional risk models (Hofste op Bruinink et al. - J Clin Oncol 2022). Hence, we hypothesized that combining PCL-like status with the R2-ISS classification would improve prognostic accuracy.

Methods Baseline characteristics including serum β2 microglobulin, albumin, lactate dehydrogenase and high-risk cytogenetic markers including deletion of chromosome 17p, t(4;14) and gain/amplification of chromosome 1q were collected from NDMM patients enrolled in the HOVON-65/GMMG-HD4 (EudraCT 2004-000944-26), HOVON-87/NMSG-18 (EudraCT 2007-004007-34), MRC-IX (ISRCTN68454111), Total Therapy 2 (NCT00083551), Total Therapy 3 (A: NCT00081939 and B: NCT00572169) and MMRF CoMMpass studies (NCT01454297) and used to determine the R2-ISS classification. Transcriptomic profiles were generated from CD138-enriched bone marrow tumor cells and used to calculate PCL-like status. For progression-free survival (PFS), an event was defined as either progressive disease or death from any cause. For OS, an event was defined as death from any cause. Hazard ratios (HRs) for PCL-like status, the R2-ISS classification or a combination thereof were estimated using a Cox proportional hazards model stratified by study cohort and corrected for age ≤ 65 years. Two-sided P values < 0.05 were considered statistically significant.

Results For a total of 976 NDMM patients of known age, both the R2-ISS classification and PCL-like status could be determined, with a median follow-up time of 53 months. 31% of patients were classified as R2-ISS low (R2-ISS I), 31% as R2-ISS low-intermediate (R2-ISS II), 33% as R2-ISS intermediate-high (R2-ISS III) and 5% as R2-ISS high (R2-ISS IV), whereas 9% were classified as PCL-like MM and 91% as not PCL-like MM (i.e., intramedullary MM, i-MM). PCL-like status was associated with both an inferior PFS (HR, 1.8; 95% confidence interval (CI), 1.4 to 2.3; P = 0.001) and OS (HR, 2.2; 95% CI, 1.7 to 2.9; P < 0.001). This also applied to the R2-ISS classification when comparing R2-ISS IV to R2-ISS I, II and III (HR for PFS, 2.5; 95% CI, 1.9 to 3.4; P < 0.001 and HR for OS, 3.0; 95% CI, 2.2 to 4.2; P < 0.001).

PCL-like status retained its prognostic significance in a multivariate model when combined with the R2-ISS classification, both in terms of PFS (HR, 1.8; 95% CI, 1.4 to 2.4; P = 0.001) and OS (HR, 2.2; 95% CI, 1.6 to 2.9; P < 0.001). Of note, 1% of NDMM patients were both classified as PCL-like MM and R2-ISS IV, which translated into a median PFS of 4 months (95% CI, 3 months to not reached) and a median OS of 7 months (95% CI, 4 months to not reached). Patients with PCL-like MM and R2-ISS III (3%) had a comparable median OS to those with i-MM and R2-ISS IV (4%) (35 and 30 months, respectively).

Conclusions 1. PCL-like status has independent prognostic value in the context of the R2-ISS classification in NDMM.

2. The presence of both PCL-like MM and R2-ISS IV may confer exceptionally high risk in NDMM, with a median OS of only 7 months.

3. NDMM patients with PCL-like MM and R2-ISS III have a comparable OS to those with i-MM and R2-ISS IV, comprising a median OS of 35 and 30 months, respectively.

Kuiper:SkylineDx: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: SKY92 gene classifier. van der Velden:Cytognos: Other: laboratory services agreement ; Euroflow: Patents & Royalties; Agilent: Other: laboratory services agreement ; BD biosciences: Other: laboratory services agreement . Valent:SkylineDx: Current Employment, Current equity holder in publicly-traded company. D'Agostino:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Gay:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees. Broijl:Amgen: Other: Advisory boards/honoraria; Sanofi: Other: Advisory boards/honoraria; Janssen: Other: Advisory boards/honoraria; Bristol Myers Squibb: Other: Advisory boards/honoraria. Munshi:GSK: Consultancy; Amgen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Novartis: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Takeda Oncology: Consultancy; Bristol-Myers Squibb: Consultancy; Adaptive Biotechnology: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Legend: Consultancy. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. Zweegman:Janssen: 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; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. van de Donk:Takeda: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Pfizer: 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, Research Funding; Karyopharm: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.