Multiple Myeloma (MM) is often diagnosed in patients (pts) aged > 75 years. These very elderly subjects are under-represented in clinical controlled trials, with a diagnostic work-up reduced in comparison to younger pts, especially from a biologic point of view. In addition, a wide range of less intensive therapies is employed according to responsible physician decision. In the present real-life multicentric study, clinic and biologic features, treatment choice and treatment results in all consecutive pts aged > 75 years newly diagnosed with symptomatic MM according to SLIM-CRAB criteria at 10 Italian Centres in a 7-year period were collected and analysed. From 1/2018 to 12/2024, 321 pts [M/F 155/166 (48.3%/51.7%), median age 79.5 years, interquartile range (IQR) 76.5 – 82.9]with newly diagnosed symptomatic MM aged > 75 years were observed. At diagnosis, 108 pts (33.6%) had Hb < 10 g/dl, 50 pts (15.6%) creatinine > 2 mg/dl, 56 pts (17.4%) LDH level above normal value: β2-microglobulin (β2-MG) was > 5.5 mg/l in 107 pts (35.9%). According to ISS classification, 83 pts (27.9%) were stage 1, 108 (36.2%) stage 2 and 107 (35.9%) stage 3: the remaining 28 pts were not evaluable for ISS due to lack of β2-MG values at diagnosis. Karyotype with FISH analysis was available in 179 pts (55.7%): 49 pts (27.4%) had a normal karyotype, while 130 pts (72.6%) had at least one alteration: the most common alterations were gain/ampl(1q) in 39 pts (21.8%), t(11;14) in 21 pts (11.7%) and del(13q)/monosomy 13 in 20 pts (11.2%). High risk alterations were reported in 29/179 pts (16.2%): among them, t(4;14) and del(17p) were present in 15 pts each (both in 1 pt). First-line treatment consisted of VMP scheme in 91 pts (28.3%), Rd scheme in 81 pts (25.2%), Dara-based schemes in 102 pts (31.7%) (Dara-VMP in 80 cases and Dara-Rd in 22 cases, respectively), VD/VP scheme in 14 pts (4.3%) and MP scheme in 12 pts (3.7%): the remaining 21 pts were treated frontline with other different schemes, each employed in < 5 subjects. Among the 307 pts fully evaluable for response to 1st line treatment, 17 (5.5%) achieved a stringent complete remission (sCR), 59 (19.2%) a CR, 98 (31.9%) a very good partial remission (VGPR) and 75 (24.4%) a partial remission (PR), with an overall response rate (ORR) of 81.0%: twenty-eight pts (9.2%) had a stable disease (SD) and 30 pts (9.8%) a disease progression (DP). Among 249 pts who achieved any type of response, 4 (1.6%) discontinued 1st line treatment due to toxicity and 106 (42.6%) relapsed after a median time from 1st line start of 18.4 months (IQR 11.9 – 32.1). A 2nd line treatment was feasible in 88 out of 106 relapsed pts (83.0%), after a median time from 1st line of 19.8 months (IQR 12.3 – 33.6): Dara-Rd was the most commonly employed 2nd line treatment (37 out of 88 pts, 42.0%). At the last follow-up, 188 pts (58.5%) are still alive, 18 (5.6%) were lost to follow-up and 115 (35.9%) died (34 from disease progression, 11 from infective complications, 8 from cardiac diseases, 4 from neoplasia, 3 from senectus and the remaining 55 from unreported causes). Median overall survival (OS) of the entire cohort was 58.7 months (95%CI 46.5 – 70.9). Several clinic and biologic features at diagnosis were tested for their prognostic role on OS: at univariate analysis, age ≥ 80 years (p<0.001), Hb < 10g/dl (p=0.002), creatinine level > 2 mg/ml (p=0.027), β2-MG > 5.5 mg/l (p<0.001), elevated LDH levels (p<0.001), ISS classification (p<0.001) had a statistically significant poor prognostic role, while gender (p=0.130), previous monoclonal gammopathy (p=0.554), R-ISS classification (p=0.118) and high-risk karyotype (p=0.143) did not. At multivariate Cox analysis, only elevated LDH [Odds Ratio (OR) 2.31, 95%CI 1.48-3.62, p<0.001], ISS intermediate-risk (OR 1.99, 95%CI 1.08-3.67, p=0.027), ISS high-risk (OR 2.83, 95%CI 1.56-5.11, p<0.001) and age ≥ 80 years (OR 1.59, 95%CI 1.06-2.39, p=0.025) retained an independent prognostic value. Our real-life data suggest that very elderly pts with newly diagnosed MM can have a very good ORR to current treatments with a relatively long survival, and should be considered for the best available approaches irrespective from the age. In this setting, the prognostic role of clinic features seems to be more important compared to karyotype: as a consequence, ISS classification should be regarded as the best tool in the prognostication of very elderly MM pts at diagnosis

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2025
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