Defining the biological boundaries of daratumumab monotherapy: long-term insights from the CENTAURUS trial in high-risk smoldering multiple myeloma

The transition from monoclonal gammopathy of undetermined significance (MGUS) to overt symptomatic multiple myeloma (MM) is driven by progressive remodeling of the bone marrow microenvironment, where stromal cells, immune subsets, and extracellular matrix components cooperate to sustain clonal plasma cell survival (1). Strategies that can interrupt these ecological interactions may be essential for identifying therapeutic targets in the early phases of plasma cell dyscrasias and overcoming drug resistance. While smoldering multiple myeloma (SMM) is classically defined by an intermediate clonal burden [e.g., 10–59% bone marrow plasma cells (BMPC)] without end-organ damage, it is a heterogeneous condition rather than merely a biologic stage between MGUS and active MM (2). Thus, the clinical trajectory of SMM varies considerably; whereas some patients maintain an indolent course, a subset of patients rapidly progress to symptomatic MM with end-organ damage (3). This biologic heterogeneity in SMM has led to the need to seek optimal management of this population, other than universally adopting a watchful waiting strategy (4).

Over the past decade, risk stratification to identify patients with SMM has been explored. Among these advancements, the identification of the “20/2/20” model for risk-stratifying SMM proposed by the group from Mayo in 2018 has shifted the focus toward proactive intervention for SMM; BMPC >20%, serum M-protein >2 g/dL, and an involved-to-uninvolved FLC ratio >20 are independently associated with shorter progression to active MM (5). These Mayo 2018 criteria were further refined by the International Myeloma Working Group (IMWG) in 2020, integrating cytogenetic abnormalities [t(4;14), t(14;16), +1q, and/or del13q] detected by interphase fluorescence in situ hybridization (6). However, it is increasingly evident that conventional clinical parameters do not fully capture the molecular complexity of precursor plasma cell disorders. Recent comprehensive genomic landscape analyses have demonstrated that the evolutionary trajectory of MM and its precursor conditions is not merely dictated by isolated somatic events, but rather by profound genomic instability, including accelerated APOBEC-mediated mutagenesis, chromothripsis, and dynamic subclonal diversification. These structural and mutational hallmarks indicate that high-risk SMM is not merely a statistical risk category but rather represents early symptomatic myeloma at the molecular level (7). Indeed, comprehensive genomic profiling redefined malignant transformation in SMM, conferring a highly precise risk stratification that outperforms existing clinical models (8).

The therapeutic landscape has recently reached a major milestone with the publication of the results of the Phase 3 AQUILA trial, which demonstrated that up to 3-year administration of daratumumab, a first-in-class anti-CD38 monoclonal antibody against MM, significantly improves progression-free survival (PFS) and delays time to subsequent therapy compared with active monitoring in patients with high-risk SMM. Of the 390 patients, 194 and 196 were assigned to the daratumumab and active-monitoring groups, respectively. With a median 65.2 months follow-up, the hazard ratio for disease progression or death in the daratumumab group compared with the active monitoring group was 0.49 [95% confidence interval (CI), 0.36–0.67; P<0.001] (9). Since patient enrollment for the trial started prior to the publication of the Mayo 2018 criteria, the study utilized its own “high-risk” eligibility criteria based on the relevant risk factors available at the time of its design. Yet, even as anti-CD38 therapy for high-risk SMM is being incorporated into clinical practice, the findings from the long-term follow-up of the Phase 2 CENTAURUS trial are profound. It offers a unique 85-month window into the durability, biological limits, and patient-centered evolution of this strategy—questions that Phase 3 trials are only beginning to address (10).

In the phase 2 CENTAURUS trial, 123 patients with intermediate- or high-risk SMM were randomized 1:1:1 (41 patients per arm) to receive 8-week cycle daratumumab (16 mg/kg, intravenously) across three distinct schedules. The long-intense arm received weekly administration in cycle 1, every 2 weeks in cycles 2–3, every 4 weeks in cycles 4–7, and every 8 weeks in cycles 8–20; the intermediate arm received weekly administration in cycle 1 followed by every 8 weeks for cycles 2–20; and the short-intense arm received a single 8-week cycle of weekly administration. Furthermore, eligible patients in the two longer-duration arms could enter an extension phase after completing the initially planned 20 cycles. As CENTAURUS started prior to AQUILA, it used even more outdated criteria for moderate to high-risk SMM (11). The key differences in study design between the CENTAURUS and AQUILA trials are summarized in Table 1.

While the co-primary endpoint of a >15% complete response rate was not met, the other co-primary endpoint of <0.346 progressive disease/death rate per patient-year was achieved across all dosing arms. At a median follow-up of 85.2 months, the long-intense dosing schedule demonstrated superior and durable clinical activity, including an overall response rate (ORR) of 58.5% and a median PFS that has not yet been reached. Median PFS, including the extension phase, per investigator assessment, was not reached [90% CI, 63.4 months to not evaluable (NE)] in the long-intense arm, 84.4 months (90% CI, 49.6 to NE) in the intermediate arm, and 74.1 months (90% CI, 40.2–77.2) in the short-intense arm. Long-term results further highlighted an acceptable safety profile of daratumumab monotherapy, with no new safety signals or increased risk of second primary malignancies observed over 7 years (10). Although intermediate- and long-intense schedules prolonged PFS compared with the short-intense group, the lack of a plateau in any cohort suggests that daratumumab merely delays progression rather than providing essential disease modification.

One of the critical findings from the updated long-term CENTAURUS data is the observation of biochemical progression. Despite initial stabilization, approximately half of the patients experienced biochemical relapse within three years; median time to biochemical progression was 38.6 months (90% CI, 35.0–47.0) in the long-intense arm, 31.4 months (90% CI, 25.4–60.8) in the intermediate arm, and 14.8 months (90% CI, 11.1–20.4) in the short-intense arm (10). This “3-year ceiling” provides a biological rationale for the design of the AQUILA trial, which utilized a fixed treatment duration of 3 years (9). It suggests that daratumumab monotherapy for SMM acts as an interim barrier. SMM is characterized by complex clonal architecture, and monotherapy targeting a single antigen may exert selective pressure without fully eradicating the malignant compartment. This allows the intrinsic genomic instability of high-risk subclones to lead to adaptive resistance and clonal escape. From a socioeconomic perspective, this finding is provocative. AQUILA’s fixed-duration model appears more aligned with the biological reality observed in CENTAURUS, offering a more sustainable path for early intervention without exposing healthcare systems to the financial toxicity of indefinite antibody administration. Furthermore, because the fundamental objective of daratumumab intervention in high-risk SMM is to delay progression to symptomatic MM, the complete response rate used as the co-primary endpoint in the CENTAURUS trial per se may not adequately capture meaningful clinical benefit.

A major concern regarding early intervention for SMM is whether it affects subsequent therapy after progression to active MM by selecting refractory clones. Unfortunately, even at the 85-month follow-up, CENTAURUS provides limited insights into this issue because it lacks a control arm. In the study, 50 of 123 patients (10, 17, and 23 patients in the long-intense, intermediate, and short-intense groups, respectively) received various first-line subsequent systemic therapies for MM. As a result, ORRs for the subsequent first-line therapy were 60.0%, 82.4%, and 73.9% in the long-intense, intermediate, and short-intense groups, respectively, and PFS on the first-line therapy (i.e., PFS2) was not reached in any dosing cohort (10). While these data are reassuring, defining the biological boundaries of monotherapy requires examining the immune context. Daratumumab exerts its activity through complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. In the early stages of disease, microenvironmental factors such as natural killer (NK) cell competence, macrophage polarization, and T-cell exhaustion profiles profoundly modulate this efficacy (12). Furthermore, any therapeutic intervention in asymptomatic individuals must be carefully weighed against the risk of overtreatment, including potential immune suppression or increased susceptibility to infections. Further investigations are needed to determine whether daratumumab monotherapy provides a durable window of disease control without impairing the immune microenvironment or the benefit of future intensive combinations for active MM (13).

The history of CENTAURUS is marked by frequent major protocol amendments, including the addition of extension phases, allowing the option to substitute subcutaneous daratumumab in the extension phase, and extending the study period up to 7 years after the last patient’s first dose. Although such study design revisions are commonly viewed as methodological skepticism, they are a direct manifestation of a vital clinical reality, that is, many patients and investigators wished to continue the treatment beyond the original schedule. For patients facing the inevitable progression of their disease, the psychological reassurance of receiving a highly tolerable therapy is profound. This patient-driven demand for treatment continuation also reflects the high acceptability of daratumumab in the asymptomatic setting. In clinical practice, however, this human dimension must be balanced against the rational use of healthcare resources. The desire to continue therapy indefinitely in the absence of CRAB (hypercalcemia, renal insufficiency, anemia, bone lesions) features can lead to overtreatment, where high-cost antibodies are administered out of clinical inertia long after their primary biological benefit has been maximized.

The final analysis of the CENTAURUS trial provides important translational insights into the immunomodulatory effects of sustained daratumumab exposure in SMM. The study demonstrated that daratumumab treatment consistently decreased the absolute numbers of NK cells while simultaneously increasing the absolute numbers of T cells across all dosing arms. Notably, these daratumumab-mediated immune alterations persisted throughout the planned treatment period (10). However, the eventual biochemical progression noted at approximately three years highlights a critical limitation. It implies that although daratumumab induces sustained T-cell expansion, this single-agent immune modulation is ultimately insufficient to permanently counteract the intrinsic biology and immune evasion mechanisms of high-risk disease. This observation reinforces the rationale for ongoing investigations into more potent combination immunotherapies to achieve deeper responses and more durable disease control (14).

As daratumumab monotherapy for high-risk SMM increasingly becomes part of the standard of care following the AQUILA results, the final analysis of the CENTAURUS trial provides both validation and a warning. On the one hand, it robustly validates the strategy of disease control, delaying the onset of symptomatic myeloma and preserving patients’ quality of life. On the other hand, it clearly defines the biological limits of a single-agent approach. Furthermore, it is crucial to recognize that the “high-risk” designation in the CENTAURUS trial relied on arbitrary clinical thresholds rather than contemporary molecular stratifications, suggesting the study cohort may not uniformly represent intrinsically high-risk disease. Moving forward, the paradigm shift toward intervention in SMM must be governed by precision medicine. Integrating translational biomarkers, such as circulating tumor DNA and minimal residual disease assessments, will be crucial to identify patients who truly benefit from early intervention (15-17). In this context, the future role of daratumumab monotherapy for SMM warrants continuous discussion. While lenalidomide-based treatments have historically demonstrated efficacy in improving PFS, recently, more intensive combination regimens are being explored (18,19). If these strategies succeed in eliminating the malignant clone before extensive genomic diversification occurs, the field may approach the theoretical possibility of a functional cure.

In conclusion, while a definitive cure may not yet be achieved, a safe and effective means of altering the disease trajectory of high-risk SMM is now available, provided its biological boundaries are carefully respected. Given the current difficulty in identifying truly optimal candidates using routine clinical parameters, shared decision-making is essential when determining its indication.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0413/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0413/coif). K.M. has received honoraria from Janssen, AstraZeneca, Chugai, Kyowa Kirin, Takeda, Bristol-Myers Squibb, Nippon Shinyaku, AbbVie, Daiichi-Sankyo, and Ono Pharmaceutical. The author has no other conflicts of interest to declare.

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