Older Age As a Prognostic Factor for Overall Survival for Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation
Authors: Cordas Dos Santos David M. , Saliba Rima M. , Patel Romil , Bashir Qaiser , Hosing Chitra , Kebriaei Partow , Khouri Issa F. , Nieto Yago , Popat Uday , Lee Hans C. , Manasanch Elisabet E. , Patel Krina K. , Thomas Sheeba K. , Weber Donna M. , Orlowski Robert Z. , Champlin Richard E , Qazilbash Muzaffar H. 
Published: October 2019

Abstract
Background
High-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is considered the standard of care for newly diagnosed, transplant-eligible multiple myeloma (MM) patients. Due to improvements in induction, stem cell mobilization, and dose adjustment of the conditioning regimen, auto-HCT is increasingly used in older MM patients, with several retrospective analyses showing similar clinical outcomes compared to younger patients.
Methods
To further confirm these results, we performed a single-center retrospective analysis of MM patients undergoing auto-HCT between January 2006 and December 2016. Patients were divided into two groups: older (> 70 years) and younger (≤ 70 years).
Results
1128 patients (182 older, 946 younger) were included in this analysis. Patient characteristics are summarized in the attached Table. More patients (59% vs. 45%, p = 0.01) in the older cohort had ISS stage II or III disease. Older cohort was more likely to receive reduced-dose melphalan (140 mg/m²) as conditioning regimen (32% vs 3%, p = <0.0001). There was no significant difference in high-risk cytogenetics, induction regimens, and response to induction, or post-transplant maintenance between the older and younger cohorts. The overall median follow-up among survivors was 49 months in the older and 52 months in the younger group. One-hundred-day non-relapse mortality (NRM) was 2/182 (1.1%) and 6/946 (0.6%) (p = 0.5) in the older and younger groups, respectively. However, 1-year NRM was significantly higher in the older vs. younger cohort (7 /182 (4%; unknown 3, pneumonia or respiratory failure 4) vs. 9/946 (1%; unknown 2, pneumonia or respiratory failure 4, cardiac failure 3), HR 4.1, p = 0.005). Post-transplant, 75 (41%) and 431 (45%) achieved complete remission (CR) in the older and younger groups, respectively (p = 0.29). There was no significant difference in the rate of disease progression post-transplant between older (31%) and younger (30%) groups (p = 0.3). The 5-year progression free survival (PFS) was 24% and 37% in the older and younger groups, respectively (HR 1.3, p = 0.02). Similarly, 5-year overall survival (OS) was 56% and 73% in the older and younger groups (HR 1.8, p = <0.001). In univariate analyses, age > 70 years, high-risk cytogenetics, serum creatinine level > 2 mg/dl and ISS stage III were associated with worse PFS and OS. In contrast, melphalan 200 mg/m² for conditioning and achievement of CR after induction therapy were associated with better PFS and OS. These 6 factors were studied in multivariate analyses using a classification and regression tree (CART) method. In CART analysis for PFS, ISS stage II or III, and high-risk cytogenetics were associated with shorter PFS. Similarly, in CART analysis for OS, older age (> 69 years), ISS stage II or III, and high-risk cytogenetics were associated with a shorter OS.
Conclusion
In this large single-center analysis, there was no difference in 100-day NRM, CR rates and the risk of progression after auto-HCT between the older and the younger patients. However, older age was associated with a shorter PFS and OS due to increased NRM. On multivariate CART analysis, ISS stage II or III and high-risk cytogenetics were associated with a worse PFS and OS, while age > 69 years was associated with a worse OS only. The impact of comorbidities on NRM is being evaluated in ongoing analyses.

Disclosures
Lee: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Thomas:Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Array Pharma: Research Funding. Orlowski:BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Millenium Pharmaceuticals: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.