Factors Associated with Post-Transplant Complications Among Older Adults with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation

Introduction

Autologous hematopoietic stem cell transplantation (ASCT) is an important part of treatment for patients with multiple myeloma (MM). Older adults undergoing ASCT are at a higher risk of post-transplant complications such as oral mucositis and renal impairment, among other toxicities. Previous studies lacked consensus regarding the ability of traditional risk scores such as Karnofsky Performance Scale (KPS) index and Hematopoietic Cell Transplantation – Comorbidity Index (HCT-CI) to accurately predict post-transplant complications in this population. Novel and accurate predictors for post-ASCT complications are urgently needed.

Methods

We included adults ≥ 60 years (y) (at the time of transplant) with MM who underwent ASCT at a single institution and received either full-dose melphalan (200 mg/m²) or dose-reduced melphalan (140 mg/m²). At baseline, all patients underwent a pre-ASCT comprehensive geriatric assessment including estimation of frailty using deficit accumulation frailty index (FI) (Giri S et al JAGS 2021). Pre-ASCT skeletal muscle mass (SMM) estimation was performed using the D3-Creatine urine dilution method (Shankaran et al JCSM 2018).

Primary outcome was the occurrence of pre-defined composite end-point of death or life-threatening event (DLTE) specified as any 1 of the following: - ICU admission for any indication, acute respiratory failure requiring positive pressure ventilation, acute renal failure requiring hemodialysis, incidence of cardiac arrhythmias lasting >60 days, severe sepsis requiring inotropic/vasopressor support, severe oral mucositis requiring specialized nutritional support for >7 days or occurrence of stroke. Secondary outcomes were occurrence of any severe (grade ≥ 3) non-hematological toxicity (severe toxicity) within 100 days post-ASCT ascertained using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and the number of such severe toxicities per patient.

We developed univariable and multivariable generalized linear models to test the association between age at the time of ASCT, sex, race/ethnicity, melphalan dose, SMM, FI, KPS and HCT-CI, and primary and secondary outcomes. Binomial logistic regression was used to analyze the association between predictors, and occurrence of DLTEs and severe toxicities while Poisson regression was used for counts of serious toxicities. All hypothesis testing was two sided and the level of significance was chosen as 0.05.

Results

A total of 60 patients were included: median age at ASCT was 67 (Interquartile Range (IQR): 64 – 71) y; 65% men, 65% non-Hispanic white, 20% frail (FI > 0.35), 62% received full-dose melphalan, median SMM 25.55 (IQR: 21.35 – 33.41) kg, 27% with KPS ≤ 80, and 40% with HCT-CI ≥3. At 100 days post-ASCT, no deaths were observed but 15% (n=9) of the participants developed ≥1 DLTE and 78% (n=47) developed ≥1 severe toxicity. Among patients developing severe toxicities, the number of discrete toxicities ranged from 1-7 per patient.

In univariable models, only FI was associated with occurrence of DLTE, SMM was associated with occurrence of severe toxicity, and SMM, FI, and HCT-CI were associated with counts of severe toxicities. In multivariable models, FI (aOR, 2.16 per 0.1 increase; 95% CI, 1.24 – 4.47) was independently associated with DLTE while KPS and HCT-CI did not show any statistically significant association with occurrence of DLTE. Reduced SMM (aOR, 0.89 per kg increase; 95% CI, 0.80 – 0.98) was associated with higher odds of severe toxicity. Lastly, both SMM (adjusted Incidence Rate Ratio (aIRR), 0.96; 95% CI, 0.93 – 0.99) and FI (aIRR, 1.22; 95% CI, 1.07 – 1.39) were significantly associated with counts of severe toxicities within 100 days post-ASCT.

Conclusion

Our study reports a low prevalence of death or life-threatening events within 100 days post-ASCT among older adults with multiple myeloma. We found that traditional risk scores like KPS and HCT-CI were not associated with occurrence of DLTEs and severe toxicities whereas SMM and FI emerged as possible novel predictors of post-ASCT toxicity that need to be further explored in future studies.