Response to “Steroid-Limited Isatuximab-Based Quadruplet Therapy in Elderly, Transplant-Ineligible Multiple Myeloma: A REST Trial Commentary”

We appreciate the thoughtful editorial commentary, “Steroid-Limited Isatuximab-Based Quadruplet Therapy in Elderly, Transplant-Ineligible Multiple Myeloma: A REST Trial Commentary” (1), on our recently published article (2). The authors raise several important and timely questions, which we welcome the opportunity to address. Specifically, they ask whether the addition of bortezomib is justified in frail or very elderly patients; whether similar results can be achieved in more diverse populations or in patients with high risk cytogenetics; the optimal duration of therapy in the absence of dexamethasone; and how the development of subcutaneous (SC) isatuximab (Isa) may influence the regimen’s convenience and scalability.

Elderly patients with multiple myeloma (MM) experience inferior outcomes compared with younger individuals, driven in part by increased treatment-related toxicity, early mortality, and premature discontinuation of therapy (3). Excluding progressive disease, infections remain the leading cause of early mortality in MM (4). Immunosuppression is an inherent feature of the disease and becomes more pronounced with advancing age due to declines in both innate and adaptive immune function. Antimyeloma therapies further compromise immune defenses through multiple mechanisms.

Toxicity is the most common reason for treatment modification during early lines of therapy (5). Several studies have shown that patients are more likely to receive second-line therapy when first-line therapy is discontinued due to disease progression rather than toxicity, emphasizing treatment related adverse events as a major contributor to the high attrition rate observed in elderly patients (6). Optimizing the efficacy-safety balance of initial therapy for transplant-ineligible (TIE) MM patients is important for achieving long-term disease control and improving overall patient outcomes.

Population-level data illustrate the magnitude of this challenge. In Norway, the 5-year relative survival for patients with MM in 2024 was 70.5%. However, among individuals aged >70 years, relative survival was substantially lower at 57.4%, compared with 80.4% in patients aged 18–70 years (7). This difference is partly attributable to increased early mortality and higher rates of treatment-related toxicity leading to therapy discontinuation in older patients.

As noted by the authors, continuous daratumumab-lenalidomide-dexamethasone (Dara-Rd) represents the standard of care for TIE newly diagnosed multiple myeloma (NDMM) patients aged ≥80 years and/or with an International Myeloma Working Group (IMWG) frailty score ≥2, based on the results of the MAIA trial (8).

However, the value of continuous dexamethasone within this regimen has recently been challenged. The IFM 2017-03 trial evaluated a dexamethasone-sparing regimen of daratumumab-lenalidomide (Dara-R), in which dexamethasone (20 mg weekly) was given only during the first two cycles, compared with continuous lenalidomide-dexamethasone (Rd) in frail [simplified frailty index (sFI)] NDMM patients (9). After a median follow-up of 46.3 months, median progression-free survival (PFS) was 53.4 months in the Dara-R group versus 22.5 months in the Rd group, results comparable to those observed in the >75-year subgroup treated with Dara-Rd in the MAIA trial. Importantly, the infection rate was similar between the two arms (19% vs. 21%) and was substantially lower than that observed in the daratumumab (Dara) group in the MAIA trial [32% grade 3/4 infections in the intention-to-treat (ITT), increasing to 42% in the frail subgroup] (10,11). These findings support the concept that reducing steroid exposure can decrease infections without compromising efficacy.

Data from randomized trials evaluating anti-CD38 monoclonal antibodies (mAbs) plus bortezomib-lenalidomide-dexamethasone (VRd) in frail NDMM patients remain limited, and no data exist for patients >80 years. In IMROZ, where 27% of patients were retrospectively classified as frail, Isa-VRd significantly improved outcomes compared with VRd; however, frail patients experienced higher rates of serious adverse events (78% vs. 69%) and pneumonia grade 3 (26% vs. 18%) (12). In REST, patients ≥80 years (31% of the cohort) achieved numerically higher minimal residual disease (MRD)-negative complete remission (CR) rates than younger patients (44% vs. 34%), supporting that adding bortezomib may benefit even very elderly individuals.

Patients with high-risk cytogenetics consistently experience inferior outcomes compared with standard-risk disease. In transplant-eligible NDMM patients with high-risk disease, maintenance therapy with bortezomib has been shown to improve outcomes (13). In the phase 3 BENEFIT study, comparing Isa-VRd with Isa-Rd in TIE NDMM, a subgroup analysis of high-risk patients demonstrated higher rates of sustained MRD-negativity with the quadruplet, supporting the benefit of adding bortezomib also in this subgroup (14). We do not believe that steroid-sparing regimens will improve survival in this subgroup, as early progression remains the predominant driver of poor outcomes. However, prolonged corticosteroid exposure in these patients is also associated with clinically significant adverse effects and can substantially reduce quality of life.

As previously described, continuous treatment with anti-CD38 mAbs is generally well tolerated in frail and elderly patients. A limitation of the REST study was that Isa was administered intravenously and discontinued after 18 cycles, while lenalidomide was continued until disease progression. Lenalidomide is generally considered less well tolerated in elderly patients, as reflected in the median relative dose intensity reported across studies: MAIA 76%, CEPHEUS 81%, IMROZ 78%, REST 83% (2,10,15,16). SC administration of Isa, seeking regulatory approval in 2026, reduces infusion-related reactions, shortens time spent in hospital, and has potential for home-based administration, making continuous treatment more feasible.

We thank the authors for pointing out these considerations and agree that addressing them will be essential for refining treatment strategies in older individuals with NDMM. As the likelihood of surviving to receive second-line therapy declines with increasing age, we argue that the most effective and tolerable therapy should be used in first line in these patients. Considering the discussion above, we therefore suggest that a modified quadruplet regimen, with limited dexamethasone exposure and weekly bortezomib dosing, is the appropriate first-line treatment for older and frail patients. In this context, SC administration of an anti-CD38 mAb should be continued until disease progression or the development of unacceptable toxicity.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0001/coif). F.B.A. reports consulting fees, payment/honoraria, and participation on advisory boards for Sanofi and Johnson & Johnson (J&J). F.S. reports payment or honoraria for serving on the Advisory Board from GSK, BMS, Janssen/J&J, Oncopeptides, Sanofi, Galapagos, Pfizer, Regeneron; and honoraria from Amgen, BMS, Takeda, Abbvie, Janssen/J&J, Oncopeptides, Sanofi, Pfizer, GSK, Menarini, and Astra-Zeneca. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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