Steroid-limited isatuximab-based quadruplet therapy in elderly, transplant-ineligible multiple myeloma: a REST trial commentary

Introduction

The treatment of newly diagnosed multiple myeloma (NDMM) in transplant-ineligible patients poses unique clinical challenges. This population, typically older and frailer, is particularly vulnerable to the toxicities of standard multidrug regimens, including corticosteroids (1). While corticosteroids are a foundational component of most myeloma therapies due to their synergistic anti-myeloma effects, their prolonged use is associated with well-documented adverse events such as glucose intolerance, mood disturbances, muscle wasting, immunosuppression, and increased infection risk (1,2). These toxicities have been reported in multiple phase 3 trials of transplant-ineligible patients; for example, in MAIA [Dara-Rd (daratumumab plus lenalidomide and dexamethasone)], grade 3–4 hyperglycemia occurred in ~7% and peripheral edema in 38.5% of patients receiving prolonged dexamethasone (3). In elderly patients, these effects are often amplified and can contribute to treatment discontinuation and reduced quality of life. As a result, there is growing interest in designing treatment strategies that reduce or eliminate long-term steroid exposure without compromising efficacy. Previous studies have shown that adjusting the dose and schedule of lenalidomide and dexamethasone can maintain efficacy while reducing toxicity in elderly, intermediate-fit NDMM patients, highlighting the potential benefits of tailored, steroid-sparing approaches (4).

The introduction of daratumumab, an anti-CD38 monoclonal antibody, marked a major therapeutic advancement in this setting. When added to lenalidomide and dexamethasone, daratumumab significantly improved response depth and survival outcomes, establishing the Dara-Rd regimen as a standard of care. This was demonstrated in the phase 3 MAIA trial, which showed a significant progression-free and overall survival benefit for Dara-Rd compared to Rd alone in transplant-ineligible patients (3). Building on this, the CEPHEUS trial evaluated a quadruplet regimen combining Dara-VRd (daratumumab with bortezomib, lenalidomide, and dexamethasone), further supporting the benefit of four-drug combinations in the frontline setting (5). However, CEPHEUS excluded patients over the age of 80 years and retained continuous steroid use, limiting its applicability to the most vulnerable segment of the NDMM population.

Isatuximab, another anti-CD38 monoclonal antibody, was initially approved in the relapsed/refractory setting in combination with agents such as pomalidomide or carfilzomib. More recently, its role has expanded into the frontline setting, following a trajectory similar to daratumumab. Trials such as IMROZ and BENEFIT demonstrated that isatuximab-based quadruplet regimens, particularly when combined with bortezomib, lenalidomide, and dexamethasone, achieve high rates of measurable residual disease (MRD) negative responses and prolong progression-free survival (6,7). However, like CEPHEUS, both IMROZ and BENEFIT excluded patients aged 80 years or older and incorporated continuous corticosteroid use. The REST trial was therefore designed to evaluate a modified isatuximab-based quadruplet regimen that included patients aged 80 years and above and limited corticosteroid exposure to the first two treatment cycles, aiming to assess whether treatment depth and durability could be preserved with improved tolerability in this particularly vulnerable patient population (8).

REST trial overview

The REST trial is a multicenter, open-label, single-arm, phase 2 trial designed to evaluate the safety and efficacy of a modified quadruplet regimen for patients with NDMM who were ineligible for autologous stem cell transplantation. A key innovation in the study was its inclusion of patients over 80 years old, unlike the IMROZ and BENEFIT trials, and its steroid-limited approach. The median age was 77 years, and 31% of participants were older than 79 years. Dexamethasone was administered only during the first two treatment cycles, after which the regimen continued with isatuximab, bortezomib, and lenalidomide alone. This approach was intended to minimize the long-term toxicities associated with corticosteroids while maintaining regimen potency.

Eligible participants were adults (≥65 or <65 years with comorbidities precluding transplant) with newly diagnosed, measurable multiple myeloma. Key exclusion criteria included prior or current systemic therapy for multiple myeloma, except for emergency use of a short course of corticosteroids before treatment. Patients received isatuximab 10 mg/kg intravenously (IV) weekly in cycle 1 and every 2 weeks thereafter until cycle 18, subcutaneous bortezomib 1.3 mg/m² weekly for 3 of 4 weeks per cycle, and oral lenalidomide 25 mg on days 1–21 of each 28-day cycle. Dexamethasone 20 mg was administered once weekly during cycles 1 and 2. The treatment duration was until disease progression or unacceptable toxicity.

The primary endpoint was MRD-negative complete response during or after 18 cycles of study treatment, with MRD negativity assessed at a sensitivity of 10⁻⁵. Secondary endpoints were overall response rate (ORR) and best overall response defined according to the International Myeloma Working Group (IMWG) response criteria, progression-free survival, overall survival, safety evaluations during the first 18 cycles, and changes in health-related QoL trajectories and patient-reported steroid toxicity during cycles 1 and 2, and cycles 4 and 5. Fifty-one patients were enrolled between June 2021 and January 2023. The median age was 77 years (range, 70–88 years), and 31% were aged 80 years or older. Frailty scoring based on IMWG criteria showed 41% were intermediate-fit and 45% frail. All patients received at least one dose of study treatment.

At a median follow-up of 27.0 months [interquartile range (IQR), 23.0–33.7 months], MRD-negative complete response was observed in 19 patients [37%, 95% confidence interval (CI): 25.3–51.0%], with a median treatment duration of 22 months (IQR, 15.2–28.8 months; range, 1.4–35.1 months). Disease progression or death occurred in 18 patients (35%), and 8 patients (16%) had died. During the first 18 cycles, the most common grade 3–4 adverse events were neutropenia (55%), infections (41%), and thrombocytopenia (22%). Serious adverse events of grade 3 or higher were reported in 27 patients (53%), with 14 patients (27%) discontinuing treatment before cycle 19, most commonly due to disease progression (16%) or adverse events (8%). The ORR was 100%, with 47% of patients achieving complete response or better and 82% achieving very good partial response or better. Median progression-free survival was not reached. The estimated 12-month progression-free survival was 86% (95% CI: 77–96%), and overall survival was 90% (95% CI: 82–99%). At 18 months, progression-free survival and overall survival were 78% (95% CI: 67–90%) and 88%, respectively.

Discussion

The REST trial supports a tolerability-optimized, steroid-sparing strategy that may reduce treatment-related morbidity in older patients. It also reinforces the growing role of anti-CD38 monoclonal antibodies in frontline therapy. While daratumumab has become standard in this setting, isatuximab continues to expand from relapsed/refractory indications into NDMM based on IMROZ, BENEFIT, and now REST, with REST providing the first prospective evaluation in an elderly and frail population using a limited-steroid design.

When comparing REST with the IMROZ and BENEFIT trials, several key differences in treatment design, patient characteristics, and safety outcomes must be considered. While all three trials evaluated isatuximab-based quadruplet regimens, REST employed a uniquely tolerability-focused approach. It used once-weekly bortezomib for only eight cycles, capped dexamethasone exposure to the first two cycles, and stopped isatuximab after 18 cycles. In contrast, IMROZ and BENEFIT maintained standard or prolonged steroid exposure and continued isatuximab until progression. IMROZ administered twice-weekly bortezomib for 12 cycles, followed by every-other-week dosing, maintained full-dose steroids throughout, and incorporated indefinite isatuximab maintenance. BENEFIT also included extended steroid use, tapering only after cycle 12, though it used weekly bortezomib and also maintained isatuximab until disease progression. This design already represented an early step toward steroid reduction, whereas REST pursued an even more limited approach by restricting dexamethasone to only two cycles. These regimen differences are particularly relevant when contextualized with patient demographics. REST had a median age of 77 years and included 31% of patients aged 80 or older, whereas IMROZ and BENEFIT enrolled younger populations (median ages 72 and 73 years, respectively) and excluded patients over 80 years. Although REST enrolled an older and frailer population than IMROZ and BENEFIT, the number of frail participants was modest. IMROZ showed Isa-VRd (isatuximab, bortezomib, lenalidomide, and dexamethasone) outperformed VRd (bortezomib, lenalidomide, and dexamethasone) in frail patients, highlighting the need to balance rapid disease control with treatment-related frailty (9). Longer follow-up will clarify whether outcomes in REST align with IMROZ and CEPHEUS.

At a median follow-up of 27.0 months in REST, 18.0 months in BENEFIT, and 60.0 months in IMROZ, the MRD-negative complete response rates were 37%, 37%, and 56%, respectively. While encouraging, these comparisons should be interpreted with caution due to differing trial designs, patient selection criteria, definitions of MRD timing, and treatment durations. IMROZ, for instance, utilized more intensive steroid schedules, more frequent bortezomib dosing, and indefinite isatuximab maintenance, which are factors that may contribute to deeper responses but also increase cumulative toxicity. Nonetheless, the similar MRD response in REST despite a frailer cohort and a more time-limited regimen suggests that carefully optimized treatment intensity may preserve efficacy while improving tolerability in older patients.

A comparison of safety profiles across the three trials further illustrates REST’s unique positioning in balancing efficacy with tolerability. While all three studies reported neutropenia as the most common grade ≥3 adverse event, occurring in 55% of patients in REST, 54% in IMROZ, and approximately 50% in BENEFIT—the incidence of grade ≥3 infections was consistent at around 41% in REST and BENEFIT and slightly higher at 45% in IMROZ. Notably, REST reported a lower rate of grade ≥2 peripheral neuropathy (16%) compared to IMROZ (27%), which may be attributed to REST’s use of once-weekly bortezomib and shorter bortezomib duration. Thrombocytopenia (22%) and serious adverse events (53%) in REST were comparable to rates reported in BENEFIT, and no excessive early mortality was observed despite the advanced age of participants. While the absence of a comparison arm and other regimen differences, such as bortezomib frequency and isatuximab duration, make it difficult to isolate the effect of steroid reduction, the fact that adverse events were similar or slightly improved despite a significantly older cohort and less steroid use suggests a real tolerability advantage. These findings support the regimen’s design as a more appropriate therapeutic approach for frail and elderly patients. In addition, the MAIA trial (Dara-Rd) is an important benchmark, particularly for elderly and frail patients. MAIA included over 20% of participants aged 80 years or older and established Dara-Rd as a standard in this group. The key clinical question is whether adding bortezomib is justified for frail or very elderly patients, given the associated neuropathy risk. REST’s lower rate of grade ≥2 neuropathy (16%) compared with IMROZ (27%) suggests that once-weekly and time-limited bortezomib may mitigate this concern, although Dara-Rd remains a relevant comparator.

Looking forward, the REST model may offer particular advantages for patients with comorbidities such as diabetes, cardiovascular disease, or mood disorders, conditions that are frequently exacerbated by corticosteroids. Quality-of-life assessments in REST showed stable global scores during the initial five cycles, with trends toward improvement once steroids were withdrawn. More detailed domain-specific analyses will be forthcoming, but these early findings reinforce the importance of integrating patient-reported outcomes when assessing steroid-sparing regimens. The trial also invites a reexamination of what constitutes “adequate” induction in NDMM. While recent years have emphasized intensification with four-drug combinations, REST highlights that response depth and durability may still be achievable through careful de-escalation of agents like steroids and bortezomib. The principle of therapeutic parsimony, which emphasizes maximizing clinical benefit while minimizing treatment burden, is becoming increasingly relevant as multiple myeloma is now often managed as a chronic condition (10).

Future studies will need to address unanswered questions: “Can similar results be replicated in more diverse populations or in patients with high-risk cytogenetics?”, “What is the optimal duration of therapy in the absence of dexamethasone?”, “How might subcutaneous isatuximab impact the regimen’s convenience and scalability?”, etc. Moreover, incorporating patient-reported outcomes into future steroid-sparing studies will be essential to fully assess the clinical value of these regimens. In an increasingly complex treatment landscape, the REST trial underscores the importance of regimen personalization for older, transplant-ineligible patients with multiple myeloma. By prioritizing tolerability without compromising efficacy, it provides a practical framework for treating a population often underrepresented in clinical trials. As the number of patients aged 80 years and above continues to rise, REST highlights the potential for tailored strategies to maintain meaningful clinical outcomes while minimizing treatment burden. Its findings support ongoing efforts to refine induction regimens that align not only with disease characteristics, but also with patient-specific needs, comorbidities, and functional goals.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-81/prf

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-25-81/coif). F.E.D. reporting participation on Data Safety Monitoring Boards for BMS, GSK, Janssen, Regeneron, and Takeda. The other author has no 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.

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