Treatment Strategies for Older Myeloma Patients: Comparison
Please note this is a comparison between Version 1 by Alessandra Larocca and Version 2 by Sirius Huang.

While novel therapies have improved outcomes in multiple myeloma (MM), physicians are calling for greater caution when managing this hematologic malignancy in older patients due to their fragility, which increases their vulnerability to toxic events. Additionally, this patient population may be excluded from clinical trials due to comorbidities, whereby available data are not always applicable in real-word clinical practice.

  • multiple myeloma
  • elderly patients
  • frailty

1. Introduction

Multiple myeloma (MM) is a hematologic malignancy that typically occurs in older patients. The median age at the time of diagnosis is 69 years, and more than 30% of patients are older than 75 years [1].
Although new therapies have improved median survival, reaching approximately 6 years [2], the available data suggest that age is a major parameter affecting outcome, which worsens decade by decade, reaching about 28.9 months of median overall survival (OS) in patients aged 80 years and older [3]. The impact of age on survival is also highlighted in many major clinical trials, although the selection of patients enrolled in these studies does not totally reflect the characteristics of the real-world population [3][4][5][3,4,5].
In addition to chronological age, other factors such as the incidence and severity of comorbidities, functional impairments, and independence status are strong predictors of life expectancy [6], which is extremely variable in the same age group, thus suggesting that not only chronological age is important, but also health status.
Although the trend in MM research has always been to increase the efficacy of the therapy by combining different drugs (doublets, triplets, and quadruplets), this does not always translate into a benefit, particularly in more frail patients, who are more sensitive to possible adverse toxicities [7].
Furthermore, the efficacy of therapies tends to decrease during the course of the disease, while the proportion of patients receiving therapies at each subsequent line also constantly decreases. In a study published by Yong and colleagues, including 22% of patients over 75 years old, 62% of patients received second-line treatment, and <25% actually received three lines of therapy [8]. This concept was also highlighted by Fonseca e al. in their study, which showed that transplant-ineligible (NTE) patients who received just one line of therapy were significantly older and exhibited a higher incidence of comorbidities [9].
This premise underlines the necessity of choosing the optimal treatment for each older patient according to their characteristics.

2. First-Line Treatment for Transplant-Ineligible Patients with Multiple Myeloma

When selecting the best first-line treatment for older NDMM patients, several factors need to be considered: patient-related factors (e.g., age, frailty status, organ function, comorbidities, patient preference, and social status), disease-related factors (e.g., renal failure, presence of extramedullary disease [EMD], and presence of high-risk cytogenetics), and treatment-related factors (e.g., efficacy, treatment goals, potential AEs, and impact on quality of life; see Figure 12).
Figure 12.
Clinical considerations for treatment decision in transplant-ineligible patients. Abbreviations: MM, multiple myeloma.
Defining treatment goals for each older patient is crucial. For fit patients, the aim is to achieve good and long-lasting responses, such as complete response (CR) or minimal residual disease (MRD) negativity, using combinations such as triplets or quadruplets. Unlike older fit patients, the main goal in the treatment of intermediate-fit patients is to achieve a balance between efficacy and toxicity, whereas reducing therapy-related toxicities and preserving the best levels of quality of life and independence as long as possible are the key aims for the treatment of frail patients [10][11][32,33]. The VISTA trial showed that the bortezomib–melphalan–prednisone (VMP) triplet was superior to the MP doublet in terms of median (m)PFS (24 months vs. 16 months, hazard ratio [HR] 0.48) and median (m)OS (56 months vs. 43 months, HR 0.69), even in patients older than 75 years [12][34]. Peripheral neuropathy is the major limiting toxicity related to bortezomib, which is mostly administered once a week in clinical practice [13][35]. The FIRST study compared continuous Rd vs. limited-duration Rd (Rd18; 18 months) vs. melphalan–prednisone–thalidomide (MPT), demonstrating a significant advantage of continuous Rd in terms of mPFS (26 months in the Rd vs. 21 in the Rd18 and MPT arms) [14][36]. An improvement of 10 months in OS in the continuous Rd arm vs. MPT was also reported, without significant differences vs. Rd18 [15][22]. Over the last few years, the introduction of the anti-CD38 monoclonal antibody (mAb) daratumumab has substantially changed the treatment landscape for NTE NDMM patients. According to the updated ESMO guidelines, the current standards of care are daratumumab–lenalidomide–dexamethasone (D–Rd), daratumumab–VMP (D–VMP), and bortezomib–lenalidomide–dexamethasone (VRd). If these options are not available, VMP or Rd combinations are recommended [16][17][37,38]. Both the MAIA (D–Rd vs. Rd) and the ALCYONE (D–VMP vs. VMP) studies led to the approval of daratumumab as the backbone of first-line therapy. D–Rd and D–VMP were approved by the European Medicines Agency (EMA) in October 2019 on the basis of the results of these studies. D-Rd was associated with a high overall response rate (ORR) of 93% with a 32% of MRD negativity rate [18][19][39,40]. In the subanalysis of the MAIA study, D–Rd, as compared with Rd, was shown to increase PFS, OS, and MRD negativity rates in several subgroups, including patients aged ≥75 years, those with renal failure, and those with ISS stage III [20][41]. In patients aged ≥75 years, the occurrence of grade 3–4 AEs was similar between the D–Rd and Rd arms (95.5% vs. 95%). The most common AEs were neutropenia (D–Rd 62.4% vs. Rd 41.5%), lymphopenia (D–Rd 21.0% vs. Rd 12.6%), and pneumonia (D–Rd 20.4% vs. Rd 14.5%). Despite this, the discontinuation rate due to treatment-emergent (TE)AEs was lower in the D–Rd than in the Rd arm (7.1% vs. 15.9%). Quality of life (QoL) data also showed a benefit from D–Rd over Rd, particularly in terms of physical functioning, fatigue, and median time of pain relief [21][42]. The ALCYONE study also yielded higher response and MRD negativity rates in the experimental arm vs. the control arm (ORR 91% vs. 74%; MRD negativity 28% vs. 7%). The most common grade ≥ 3 AEs with D–VMP vs. VMP were neutropenia (40% vs. 39%), thrombocytopenia (34% vs. 38%), and infections (23% vs. 15%; with an incidence of pneumonia of 11% vs. 4%) [22][43]. In a retrospective analysis of the MAIA study on frailty, patients were divided into three categories (fit, intermediate, and frail) using a frailty score [23][44] that incorporated age, CCI, and ECOG PS evaluation. Fit and intermediate patients had a longer PFS than frail patients, but the PFS benefit from D–Rd vs. Rd was maintained across all the frailty subgroups. The clinical benefit from D–Rd and D–VMP in NTE NDMM patients was not associated with safety issues. Data are shown in Table 1.
Table 1.
Frailty subgroups and related outcomes in the ALCYONE and MAIA studies.
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