Daratumumab: a game changer in early myeloma

In this issue of Blood, Landgren et al¹ report on the efficacy and safety of daratumumab in smoldering multiple myeloma (SMM). Daratumumab was the first anti-CD38 monoclonal antibody to demonstrate efficacy as a single agent in treating patients with relapsed or refractory multiple myeloma,² leading to its approval by the health authorities. Since its approval, daratumumab has been combined with other antimyeloma agents and compared against different standards of care in phase 3 trials. Because of significant benefit demonstrated in these trials, daratumumab is now widely used as part of the first-line therapy for patients with newly diagnosed multiple myeloma.

Landgren et al report on even earlier use of daratumumab, exploring its use in asymptomatic plasma cell precursor disease. The authors evaluated 3 different arms in intermediate and high-risk SMM, all involving single-agent daratumumab, but with varying levels of intensity. The optimal approach appears to be the “long intense” arm, which aligns with the approved schedule used in multiple myeloma treatment. In this report, the final analysis of this phase 2 study, with a median follow-up of approximately 7 years, continues to demonstrate the clinical activity of daratumumab in patients with SMM with an acceptable safety profile. Favorable outcomes were observed, but the phase 2 trial limits the ability to definitively recommend daratumumab as a single-agent therapy for SMM based solely on this study.

In this context, it would be logical to conclude this article by stating the need for a phase 3 trial to validate these findings. Fortunately, at the time of writing, we already have positive data from the phase 3 AQUILA study.³ Daratumumab as a single agent demonstrated a significant reduction in the probability of progression or death compared with observation (hazard ratio: 0.49, P < .001). This raises a key question: is observation the appropriate comparison? Two phase 3 clinical studies had already demonstrated superiority of early treatment with lenalidomide (R) or R plus dexamethasone (Rd) for 2 years vs observation in terms of progression-free survival (PFS) and overall survival in one of them.^4,5 Of note, these 2 phase 3 trials were conducted by cooperative groups and were not registrational studies. Based on these positive results, there are 2 phase 3 trials ongoing using Rd as control arm and anti-CD38 monoclonal antibodies plus Rd as the experimental arm.

However, the topic of SMM is complex, and important questions deserve further consideration. Is the population included in the CENTAURUS trial the appropriate group to base justification of early treatment? The trial enrolled patients with intermediate- and high-risk SMM, resulting in a heterogeneous cohort. The coprimary end point, which evaluates the rate of progression to active disease or death per year, is challenging to contextualize. An exploratory analysis focusing solely on patients with high-risk SMM, as defined by the Mayo 2018/International Myeloma Working Group 2/20/20 criteria, reported a median PFS of 71 months in the long intense arm. However, this result is difficult to interpret due to the lack of a comparison arm and because it applies to only 36% of the trial population. Is daratumumab as a single agent sufficient for treating asymptomatic patients with myeloma? It is difficult to justify its use as a monotherapy in a disease that, biologically, appears closer to active myeloma.⁶ Although this remains a matter of debate, there are other strategies being explored for the treatment of this asymptomatic disease. These include quadruplet combinations, high-dose melphalan followed by autologous stem cell transplantation, and even BCMA-targeted therapies such as bispecific monoclonal antibodies and BCMA chimeric antigen receptor T cells. What are the main differences between these approaches? Although daratumumab as a single agent has the potential to delay progression to active disease and indeed this has been demonstrated in the phase 3 AQUILA study, the more intensive approaches aim to cure at this early stage of myeloma. This is supported by their ability to induce undetectable measurable residual disease that has been sustained over time and is the best surrogate marker for outcomes. Although the debate between cure and control is important, patient-specific factors such as chronological age, frailty, and comorbidities will play a crucial role in determining the most appropriate option for each patient.

Another topic to address in this study is the definition of one of the coprimary end points, that is, the rate of progressive disease or death per year. In trials conducted in patients with SMM, including the CENTAURUS trial, the definition of progressive disease requires the development of CRAB criteria (hypercalcemia, renal impairment, anemia, or bone disease) or SLiM-CRAB criteria (more than 1 focal lesion on magnetic resonance imaging, a free light chain ratio exceeding 100, or bone marrow plasma cell infiltration of 60% or more). However, in trials conducted in patients with multiple myeloma, biochemical progression is acceptable for defining PFS events. This includes a 25% increase from the lowest confirmed response value without the requirement for CRAB or SLiM-CRAB symptomatology to define an event. This creates a paradoxical situation. In SMM, we aim for early intervention to delay or prevent symptomatology; however, we must wait for SLiM-CRAB criteria to be developed before initiating treatment again. Conversely, in multiple myeloma, we start treatment once SLiM-CRAB criteria are present, but subsequent lines of therapy are initiated as soon as biochemical progression is detected, even in the absence of symptomatology.

In conclusion, (1) we need to refine the assessment of progression risk to myeloma by incorporating genomic studies alongside conventional clinical markers. This will allow for more precise identification of patients eligible for early treatment, thereby minimizing overtreatment and reducing unnecessary toxicity. (2) If we focus on high-risk patients with SMM, who are genomically closer to active myeloma, our approach should prioritize using the most efficacious therapies with the aim of achieving a potential cure. (3) We must not forget that we practice patient-centered care, and the opinions and preferences of patients regarding early treatment before symptomatology arises may be even more relevant in this group of patients than those of patients diagnosed with myeloma.

Conflict-of-interest disclosure: The authors declare no competing financial interests.