Maintenance Therapy in the Era of Quadruplets for Multiple Myeloma: When, What, and for How Long?

Abstract

Quadruplet therapy—combining a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody—has redefined frontline treatment for newly diagnosed multiple myeloma (NDMM) and is now the standard of care. Given the deep and durable responses seen with these regimens, it is time to reconsider the role of continuous maintenance therapy. In this commentary, we argue that indefinite maintenance lacks solid evidence in the quadruplet era and may pose unnecessary toxicity risks.

The current paradigm of continuous therapy was established with lenalidomide after large phase III trials showed (vs. placebo or observation) improvement in progression-free survival (PFS) [1, 2] and overall survival (OS) [1]. In those trials (Table 1), the vast majority of patients received a doublet induction or even chemotherapy-based therapy with no PI or IMiD. The magnitude of the unmet need is highlighted by the PFS in the control arm, 22% at 4 years in one study [2], and 39% at 3 years in another [1]. With so much territory to conquer, the continuous use of an active drug showed meaningful improvement in outcomes, yet stained by increased risk of second malignancies and frequent treatment discontinuation for toxicity. Even with this meaningful improvement, the optimal duration of maintenance remained unknown, ranging anywhere between 1 year fixed duration [5] to continuous therapy [6] with likely diminishing benefit with increasing time [7]. As upfront therapies have improved with the widespread adoption of triplets and subsequently quadruplets, it becomes crucial to critically revisit the merit of continuous therapy.

The CASSIOPEIA trial evaluated daratumumab added to bortezomib, thalidomide, and dexamethasone (D-VTd), with a second randomization to either daratumumab maintenance or observation [8]. In this trial, 2 years of fixed maintenance therapy with daratumumab was found to be beneficial compared to observation, including among patients who received D-VTd induction (HR 0.76; p = 0·048). Yet, a much larger effect size of daratumumab maintenance was seen among patients who received VTd induction (HR 0.34, p < 0.0001). This is the only trial with direct randomized evidence for any maintenance therapy with quadruplet induction and brings forth a few important considerations. First, there is a strong interaction between induction therapy and maintenance therapy, an element not well studied previously, casting doubt on the extent of benefit of even lenalidomide continuous therapy in the era of quadruplets. Second, as illustrated by the median PFS of 72.1 months for patients treated with Dara-VTd and no maintenance, with more effective upfront therapy, there is far less territory to be conquered by maintenance. Lastly, no OS benefit has been demonstrated with daratumumab maintenance thus far, including in the VTd arm, despite long-term follow-up. Simply put, the effect size of continuous lenalidomide (or any other therapy) just cannot be extrapolated to modern therapy. Although some benefit can be assumed, its existence and size are not known.

The subsequent trial, PERSEUS, evaluated daratumumab in addition to bortezomib, lenalidomide, and dexamethasone (D-RVD) followed by daratumumab and lenalidomide maintenance [9]. After at least 24 months of maintenance, daratumumab was discontinued if patients had sustained MRD negativity at 10⁻⁵ for at least 12 months; lenalidomide maintenance continued until disease progression or toxicity. A total of 207 patients (64.3%) were able to discontinue daratumumab maintenance per protocol. Although there was an increase in the rates of MRD negativity over time (12 month 65.1%, 24 month 72.1%, 36 month 74.6%), this trial makes it impossible to isolate the effect of maintenance as a whole due to the absence of a second pre-maintenance randomization. Additionally, the contribution of each component of maintenance therapy and its respective duration is unknown. Moreover, given the excellent outcomes, with a median PFS expected to be over 15 years, the role of maintenance, particularly beyond 24 months among both MRD negative and MRD positive patients, remains unclear.

In transplant-ineligible patients, the IMROZ and CEPHEUS trials introduced quadruplet therapy followed by continuous maintenance. In IMROZ, isatuximab was added to the RVD backbone (Isa-RVD), with bortezomib stopped after 6 months, whereas isatuximab, lenalidomide, and dexamethasone were continued indefinitely until disease progression or toxicity [10]. Overall, Isa-RVD had an impressive 60-month PFS estimated at 63.2% and MRD negativity rates of 55.5%.

Similarly, CEPHEUS evaluated Dara-RVD, also discontinuing bortezomib after 6 months and continuing daratumumab, lenalidomide, and dexamethasone until progression or toxicity [11]. With a median follow-up of 58.7 months, the 54-month PFS rate was 68.1% with MRD negativity rates of 60.9%. Notably, most patients who achieved MRD negativity did so within the first 24 months, with minimal improvement thereafter (56.9% at month 24 vs. 60.9% at month 48), despite ongoing therapy. Although both trials demonstrated impressive outcomes for transplant-ineligible patients treated with quadruplet induction, neither isolates the contribution of indefinite triple-drug maintenance. With median PFS approaching 8 years, the benefit of prolonged therapy—especially in older adults—remains uncertain.

Maintenance therapy is not without significant toxicity. Prolonged lenalidomide use leads to cumulative side effects, including cytopenias, fatigue, gastrointestinal disturbances, and a heightened risk of secondary primary malignancies. In the PERSEUS trial, secondary malignancies occurred in 10.5% of patients on Dara-RVD, with long-term risks still unclear [9]. Continuous anti-CD38 antibody use adds further burden, including hypogammaglobulinemia and a potential risk of recurrent infections. Chronic immunosuppression also compromises the ability to safely receive and mount appropriate vaccine responses, leading to increased vulnerability to opportunistic infections, a growing concern amid resurgent public outbreaks of infections such as measles. Lastly, the financial cost of indefinite dual-agent maintenance—potentially spanning 8–15 years in the quadruplet era—is significant and unsustainable for many.

Given the limited evidence supporting continuous maintenance in the era of quadruplet therapy, a key question emerges: Can we safely stop maintenance? Some evidence comes from the MASTER trial, where patients received quadruplet induction, autologous transplant, MRD-guided quadruplet consolidation, and single-agent lenalidomide maintenance [12]. Therapy was discontinued after achieving two consecutive MRD negative assessments. In this trial, 71% of patients were able to stop therapy (nearly all within 1 year of treatment initiation) with low levels of resurgence among those with 0–1 high-risk cytogenetic abnormalities. Data merged for the MASTER trial and an institutional database demonstrate that on average patients attain sustained MRD negativity 10⁻⁵ at 19.3 months, with the rates of progression being extremely low, particularly for those with 0 (4-year PFS 95%) or 1 high-risk cytogenetic abnormality (4-year PFS 80%) [13]. Similarly, another recent study for Greece demonstrated an impressive 7-year PFS of 90.2% among 52 patients who had discontinued lenalidomide at month 36 following a negative sustained 3-year MRD and imaging [14]. Greater depth of response with MRD threshold of < 10⁻⁶, may be associated with even lower rates of MRD resurgence following cessation of maintenance therapy, as highlighted in the MRD2STOP trial [15]. In transplant-ineligible older adults, the role of prolonged maintenance warrants even closer scrutiny. Both IMROZ and CEPHEUS continued dual maintenance with lenalidomide and anti-CD38 antibodies until progression or toxicity, but the necessity of this strategy remains uncertain. Ongoing trials are actively evaluating whether treatment duration can be safely shortened without compromising outcomes.

Continuous maintenance has become an entrenched practice in myeloma treatment, but this paradigm is no longer supported by robust evidence in the context of modern quadruplet induction. Most trials that established maintenance benefit used less effective regimens and did not address optimal duration. In contrast, contemporary studies show high MRD negativity and durable PFS without a clear additive benefit from indefinite therapy. As we move forward, a more individualized, response-adapted approach to maintenance—especially with clear stopping rules—may better serve patients and reduce long-term toxicity.

The authors have nothing to report.

H.M.: Consultancy/Honoraria fees from BMS, Takeda, Johnson & Johnson, Amgen, Sanofi, Forus, GSK, Pfizer, Research funding Pfizer. L.J.C.: Consultancy/Honoraria fees from BMS, Johnson & Johnson, Amgen, Sanofi, Pfizer, Genetech, Caribou, Adaptive Biotechnologies, AstraZeneca, AbbVie. Research funding from BMS, Johnson & Johnson, Amgen, Caribou, AstraZeneca, Pfizer, AbbVie.