BACKGROUND Fit and young (< 65 years) patients (pts) with newly diagnosed Multiple Myeloma (NDMM) are candidates to high dose chemotherapy followed by autologous stem cell transplantation (ASCT), but for people who are too frail or old the path is not so clear. The current approach involves an assessment through the calculation of scores which are not objective and deeply influenced by age. A frailty score capable of directing therapeutical choices is an unmet need and, in this regard, the immunological profile of T cells has been proposed as a variable related to frailty. To evaluate the relationship between the quantity of senescent T cells (STC) in the peripheral blood of NDMM pts and clinical and prognostic aspects of their disease, an observational prospective study called IMMUNO-NDMM was conducted at the Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.

AIMS The primary aim of the study was to determine whether older pts (≥ 65 years) with NDMM had a greater degree of T cell senescence compared to younger pts, as seen in the general population. Secondly, we explored the relationship between a senescent immunophenotype and other variables such as frailty, serological pro-inflammatory factors, disease burden and biometric data. Since only preliminary data are available, we hereby showed only the results obtained analyzing the first samples.

METHODS We collected clinical and laboratory data from pts with NDMM at our institution. Frailty was assessed through the IMWG Frailty Score (IMWG-FS). We took and analyzed one sample of peripheral blood from every patient involved in the study. Mononuclear cells were extracted using Ficoll-Paque®. The obtained cells were labeled with fluorochromes to create two analytical panels for senescence and exhaustion. Senescence was assessed by identifying CD8⁺ CD28⁻ CD57⁺ KLRG1⁺ cells, exhaustion by markers like PD1, TIM3, LAG3, TIGIT, BTLA, together with CD45RO and CD62L for the memory phenotype. These analyses were performed through flow cytometer BD FACS Fortessa® and BD FACS Diva® software.

RESULTS Between July and December 2024, data from 20 pts with NDMM were collected and analyzed. The median age was 72.6 years. A total of 14 pts (70%) were ≥ 65 years, and 5 out of 20 (25%) were older than 80 years and classified as frail. Most pts had low ISS. Fourteen pts (70%) started a first line treatment, of which six (43%) were candidates to ASCT. With a median treatment time of 3.5 months, all pts except one were in VGPR or better. The STC percentages were heterogeneous (from 9% to 74% of total T cells), with 61% of pts exceeding 50%. Median age tended to be higher in pts who had STC > 50% (82 vs 70 years). Median STC percentage was particularly high in pts > 80 years (67%), compared to pts ≤ 65 years and between 66 and 80 years (40% and 43% respectively). An association was found between frailty and senescence (p=0.035): frail pts (high IMWG-FS) had more frequently a higher quantity of STC (57% vs 9%), while no differences in STC count were found between ‘intermediate’ and ‘fit’ pts according to the same score. In this regard, every frail patient who started a treatment needed a dose reduction of one or more drugs and suffered at least one toxicity. Conversely, pts classified as intermediate didn't need any therapy adjustments, while two fit pts did. Variables such as BMI, ISS, inflammation markers and disease burden were not associated with STC values.

CONCLUSIONS The preliminary data presented demonstrate the feasibility and reliability of the analyses planned in the protocol. Although no association between age and percentage of STC was found, valuable information was obtained, suggesting that age could not be the only determinant of frailty in NDMM patients, and that the use of senescence as a variable could be reasonable. The small sample size makes statistical considerations less reliable, and confirmation of the results will be necessary after the planned follow-up.

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2025
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