Dynamics of Geriatric Impairments Are Associated with Risk of Treatment Discontinuation in Elderly Patients with Multiple Myeloma
Authors: Smits Febe , Nasserinejad Kazem , Levin Mark-David , Timmers Gert Jan , De Waal Esther G.M. , Regelink Josien C , Velders Gerjo A. , Westerman Matthijs , Durdu-Rayman Nazik , Last-Koopmans Suzanne , van Kampen Roel JW , Stege Claudia A M , Groen Kaz , Seefat Maarten R. , Minnema Monique C. , Sonneveld Pieter , Ypma Paula F , van de Donk Niels W.C.J. , Zweegman Sonja 
Published: December 2024

Introduction
In non-transplant eligible patients with newly-diagnosed multiple myeloma (NTE-NDMM), those classified as intermediate-fit and frail by the International Myeloma Working Group Frailty Index (IMWG-FI) exhibit higher rates of treatment discontinuation (TD) compared to fit patients. There is limited data on the level of geriatric impairments in intermediate-fit and frail patients with MM and whether the extent of geriatric impairments affects treatment discontinuation. In addition, geriatric impairments may change over time. To investigate this, we prospectively investigated the dynamics of geriatric impairments and the association with treatment discontinuation in patients with NTE-NDMM in the HOVON 123 study.
Methods
The HOVON 123 study is a prospective phase II trial for NTE-NDMM patients ≥75 years. Patients were treated with 9 cycles of dose-adjusted melphalan-prednisone-bortezomib. The IMWG-FI and geriatric assessments (GA) were performed at diagnosis, after 3 and 9 cycles of therapy. The GAs consisted of the Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), the Mini Nutritional Assessment (MNA), and physical functioning subscale of the EORTC QLQ-C30. Additionally, 2 functional tests were performed: 4-meter gait speed and hand grip strength. A joint model was employed to assess associations between the longitudinal data of geriatric assessments and time to treatment discontinuation (R statistical program, package JM).
Results
In total 214 patients were included, of whom 143 patients were classified as frail and 71 as intermediate-fit. At diagnosis, frail patients had higher rates of low physical functioning (QLQ-C30 &lt;47 45% vs 15%), malnourishment (MNA &lt;8 20% vs 7%), cognitive dysfunction (MMSE &lt;24 27% vs 15%), depression (GDS &gt;6 35% vs 13%), low gait speed (&lt;0.8m/s in 55% vs 29%) and low grip strength (&lt;27 kg for male and &lt;16 kg for female, 47% vs 27%), as compared to intermediate-fit patients. After 9 cycles, 72 (50%) frail patients and 47 (66%) intermediate-fit patients were still on protocol.
The incidence of improvement was determined only in the patients who could actually improve, by excluding the patients without impairments. Physical functioning was found to be improved after 9 cycles in 24/50 (48%) frail patients and 13/17 (76%) intermediate-fit patients. Nutritional status improved in 14/51 (27%) of frail and in 8/19 (42%) of intermediate-fit patients, cognitive functioning in 11/22 (50%) of frail patients and 0/8 of intermediate-fit patients and depression in 8/25 (32%) of frail patients and in 3/5 (60%) of intermediate-fit patients. For gait speed and grip strength these numbers were 14/42 (33%) of frail and 9/16 (56%) of intermediate-fit patients and 5/23 (22%) of frail and 0/9 of intermediate-fit patients, respectively.
The incidence of deterioration was determined only in the patients who could actually deteriorate, by excluding the patients who were already impaired at diagnosis. Deterioration of physical functioning occurred in 9/44 (20%) frail patients and 4/39 (10%) intermediate-fit patients. Nutritional status deteriorated in 9/58 (16%) of frail and in 7/44 (16%) of intermediate-fit patients, cognitive functioning in 2/54 (4%) of frail and in 1/42 (2%) of intermediate-fit patients and depression in 12/49 (24%) of frail and in 5/43 (12%) of intermediate-fit patients. For gait speed and grip strength these numbers were 9/37 (24%) for frail and 4/36 (11%) for intermediate-fit and 9/38 (24%) of frail and 2/40 (5%) of intermediate-fit patients, respectively.
Impaired physical functioning at diagnosis was associated with a higher risk of treatment discontinuation within 3 cycles (OR 1.95, 95%CI 1.22-3.25, p=0.007). Moreover, by including the GA as a time varying covariate in the time-to-event analysis by a joint model, we found that several domains of the GA were associated with time to TD. Irrespective of frailty level, nutritional status (HR 0.24, 95%CI 0.08 - 0.76, p=0.02), and depression (HR 8.34, 95%CI 1.84 - 37.8, p=0.006) were associated with time to TD.
Conclusion
Geriatric impairments in intermediate-fit and frail patients were highly dynamic during treatment. Improvement was often observed, although occurring more often in intermediate-fit as compared to frail patients. Importantly, geriatric impairments at diagnosis and changes over time were associated with time to TD, irrespective of frailty level.