Octogenarian newly diagnosed multiple myeloma patients without geriatric impairments: the role of age >80 in the IMWG frailty score

In transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), impaired organ function and reduced physiological reserves may lead to a frail phe-notype limiting the safe use of drugs and worsening patient outcome 1,2 . . (range 80 ≥ = = 0 5


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In transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), impaired organ function and reduced physiological reserves may lead to a frail phenotype limiting the safe use of drugs and worsening patient outcome 1,2 .
Since age in itself does not necessarily define biological frailty, the aim of our analysis was to describe the outcome of NDMM patients aged >80 years without geriatric impairments.
Frail patients were divided into two groups: patients who were determined to be frail by age only (Frail_by_age, i.e., patients aged >80 years with CCI ≤ 1 and ADL > 4 and IADL > 5) vs. patients who were determined to be frail for any other reason (Frail_by_other).
The median follow-up was 65 months. Fit and intermediate-fit patients were used as reference population (No_frail, n = 609, 70%).
In a multivariate Cox model adjusted for ISS, cytogenetics, and treatment protocol, a worse overall survival (OS) was observed in both Frail_by_age (HR 1.51, p = 0.021) and Frail_by_other patients (HR 1.71, p < 0.001), as compared to No_frail patients (Fig. 1A). The median OS was 42.9 months in the Frail_by_age group, 41.6 months in the Frail_by_other group, and 76.5 months in the No_frail group.
Of note, no differences in terms of OS were found between Frail_by_age and Frail_by_other patients (HR 0.89, p = 0.539). Progression-free survival (PFS) and PFS2 data showed no significant differences between the two frail groups as well (Fig. S1A, B).
In the No_frail group, patients remained on study for a median time of 18.9 months, longer than patients in both the Frail_by_age (12.3 months) and Frail_by_other groups (12.4 months; Fig. S2).
Reasons for treatment discontinuation are reported in Table S2. The main reasons for discontinuation were adverse event (60%) in the Frail_by_age group, adverse event (46%) and disease progression (48%) in the Frail_-by_other group, and disease progression (51%) in the No_frail group. A significantly higher risk of drug discontinuation for any cause, excluding progression and death, was reported in the Frail_by_age group (HR 2.34, p < 0.001) and Frail_by_other group (HR 1.49, p = 0.003), as compared to the No_frail group (Fig. 1B). Frail_by_age patients had a higher risk of drug discontinuation compared to Frail_by_other patients as well (HR 1.57, p = 0.018). Nevertheless, the cumulative incidence of grade ≥3 non-hematologic and hematologic toxicities was not significantly different between Frail_by_age and Frail_by_other patients (Fig. S3A, B). At the current follow-up, a second therapy was started in 61% vs. 66% vs. 72% of patients in Frail_by_age vs. Frail_by_other vs. No_frail groups, respectively. Among second therapies, low-dose conventional chemotherapy without novel agents was used in 37% vs. 24% vs. 7% of Frail_by_age vs. Frail_by_other vs. No_frail patients (p < 0.001), suggesting that patients aged >80 years were more likely to receive a suboptimal therapy after the first line. We next analyzed OS by dividing the time from diagnosis into three time frames to account for early deaths (0-2 months) 7 , deaths within 2 years from diagnosis (2-24 months), and late deaths (>24 months; Fig. 1C, D). No significant differences in terms of early deaths were found between the Frail_by_age (HR 1.13, p = 0.909) and the No_frail groups, whereas a higher risk of early death was observed in the Frail_by_other group (HR 5.32, p < 0.001). Within the first 2 months, 21/869 patients died overall (2%), while this percentage was significantly higher in the Frail_by_other group (13/190, 7%). The main cause of death in this time frame was death due to toxicity (62%). Between 2 and 24 months from diagnosis, both Frail_-by_age (HR 1.89, p = 0.012) and Frail_by_other (HR 1.99, p < 0.001) patients showed a significantly higher risk of death, as compared to No_frail patients. In this time frame, the main cause of death was progressive disease (65%), followed by toxicity (24%).
No differences in terms of late deaths were observed among the three groups. The main cause of late death was progressive disease (59%), followed by toxicity (22%).
To exclude an OS bias due to the older age of Frail_by_age patients, we explored the impact of geriatric impairments on patients aged ≤80 years and >80 years (Fig. S4A, B). The presence of geriatric impairments significantly predicted a lower OS in the population aged ≤80 years (HR 1.46, p < 0.001), but not in the population aged >80 years (HR 1.09, p = 0.739), thus supporting the hypothesis that octogenarian NDMM patients are frail independently from the presence of geriatric impairments.
To summarize our findings, octogenarian patients without geriatric impairments usually present with a low disease burden and a good performance status. However, the high rate of drug discontinuations and the difficulty to deliver effective treatments after the first line of treatment may lead to the observed poor survival. To date, this patient population is rare, accounting for <10% of NDMM patients in clinical trials. Nevertheless, the life expectancy and health conditions of the general population are improving 8 . Thus, in the near future, physicians are expected to face a growing percentage of octogenarian NDMM patients without geriatric impairments 9 .
New treatments (e.g., naked monoclonal antibodies) that can be safely delivered continuously for a long period of time may be better tolerated and have a lower discontinuation risk, potentially improving the outcome of this patient population. Indeed, dedicated trials selectively enrolling intermediate-fit and/or frail patients are beginning to emerge 10,11 . In a randomized phase III trial in intermediate-fit patients, 9 cycles of lenalidomidedexamethasone induction followed by low-dose lenalidomide maintenance without steroids produced similar outcomes compared to continuous lenalidomidedexamethasone (median PFS 20.2 vs. 18.3 months), thus showing that, in this patient subgroup, therapy could be de-intensified after induction without affecting patient outcome. Another trial enrolling both intermediate-fit and frail patients explored daratumumab-ixazomibdexamethasone induction followed by daratumumabixazomib maintenance. A total of 70% of intermediate-fit and 61% of frail patients completed induction treatment (9 months) and PFS rates were 78% and 61%, respectively. The early death rate (≤3 months after study entry) was higher in frail patients than in intermediate-fit patients (12% vs. 0%).
Interestingly, in our work, we observed an excess of early toxic deaths (<2 months from diagnosis) in patients who were frail due to geriatric impairments. This observation may support the exploration of dose-escalation strategies in the first months after diagnosis in frail NDMM patients presenting with geriatric impairments.
In conclusion, in this work, we showed that NDMM patients who were frail by age >80 years but who did not present with any geriatric impairments had a similar OS compared to patients who were determined to be frail for any other reason. These data further support that NDMM patients aged >80 years should be classified as frail regardless of the presence/absence of any comorbidities and ADL/IADL limitations. and Karyopharm. M.B. has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GSK; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma. S.B. has received honoraria from Celgene, Amgen, Janssen, and Bristol-Myers Squibb; has served on the advisory boards for Celgene, Amgen, Janssen, and Karyopharm; has received consultancy fees from Janssen and Takeda. The remaining authors declare no competing interests.
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