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Patient-Centered Management of Smoldering and Newly Diagnosed Multiple Myeloma

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Released: November 06, 2026

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The care of patients with high-risk smoldering multiple myeloma (MM) or newly diagnosed MM requires an individualized, risk-adapted approach at every stage. This commentary covers evidence for subcutaneous daratumumab monotherapy from the AQUILA trial for high-risk MM, and the utility of quadruplets for patients with newly diagnosed MM based on the results from the PERSEUS, CASSIOPEIA, GMMG-HD7, and CEPHEUS trials, as well as support for intensified maintenance based on the AURIGA trial results.

Carol Ann Huff
Carol Ann Huff, MD
Treatment of HR SMM and NDMM

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In this commentary, Carol Ann Huff, MD, addresses the need for and importance of managing patients with high-risk smoldering multiple myeloma (MM) or newly diagnosed MM with the use of an individualized, risk-adapted approach at every stage of the disease.

Patient-Centric Management of Smoldering MM
Smoldering MM is an asymptomatic precursor to active MM, and patient-centric care should begin with confirmation that the patient truly has smoldering rather than active MM. Over the past few decades, different risk stratification models have been developed for the identification of patients who are at high risk of developing active MM. Risk stratification is crucial because a high proportion of individuals with features that classify them as having smoldering MM will not develop active MM. Of the many available risk stratification models, the Mayo 2018 model is most frequently used. This model considers bone marrow plasma cells >20%, M spike >2 g/dL, and serum free light chain (FLC) ratio >20 as major laboratory and bone marrow measurements at baseline. Individuals who test positive for all 3 factors are considered to be at high risk of developing active MM. More recently in 2020, the International Myeloma Working Group (IMWG) point-based model expanded risk stratification by incorporating cytogenetic and fluorescence in situ hybridization (FISH) findings, including t(4;14), t(14;16), 1q gain, and del13q/monosomy 13. With the inclusion of these factors, patients can be classified more precisely into 1 of 4 risk groups: low, low/intermediate, intermediate, and high.

Once a patient is confirmed as having smoldering MM, risk stratification guides the degree and frequency of monitoring as well as discussions about potential treatment options. Of importance, the IMWG risk stratification model helps to distinguish patients who may remain stable for years without treatment from those with a substantial short-term risk of progression. However, projections based on the risk model should be made with considerations for the patient’s age, preexisting comorbidities, treatment burden, adverse effects, quality of life, and the patient’s treatment goals and preferences.

The randomized phase III AQUILA trial investigated the anti-CD38 monoclonal antibody, daratumumab, when administered subcutaneously for up to 3 years vs active monitoring for patients with high-risk smoldering MM.  Daratumumab significantly reduced progression to active MM and improved overall survival (OS), with 5-year OS rates of 93% vs 86.9% for active monitoring (HR: 0.52; 95% CI: 0.27-0.98). Based on these findings, the FDA approved subcutaneous daratumumab monotherapy for adults with high-risk smoldering MM on November 6, 2025. To date, this is the only approved treatment for patients with high-risk MM. Even though clinical trials of lenalidomide-based therapy have shown improvement in progression-free survival (PFS), the duration of lenalidomide therapy can be substantial, and its use is associated with toxicities such as thrombosis and secondary malignancies.

Observation remains appropriate for many patients with a diagnosis of high-risk smoldering MM; however, when utilized, it should be active rather than passive. Patients need clear education about their diagnosis, symptoms that should prompt urgent review, and the utility of repeated testing. In general, high-risk smoldering MM warrants reassessment every 3 months, whereas those at lower risk of developing active MM should be monitored at 3- to 6-month intervals adjusted to laboratory trends and clinical circumstances. Because risk can change over time, repeat assessment is important even when the initial findings are reassuring. It is important to note that participation in clinical trials should be discussed with patients across all risk groups when a suitable study is available.

Intensive treatment strategies including multiagent induction, transplantation, bispecific antibodies, and CAR T-cell therapy have produced deep responses and encouraging rates of measurable residual disease (MRD) negativity in clinical trials. However, these approaches remain investigational. Noteworthy ongoing phase III trials for patients with high-risk smoldering MM include the DETER-SMM, ITHACA, and LINKER-SMM2. DETER-SMM is investigating lenalidomide and dexamethasone with or without intravenous daratumumab for patients with high-risk smoldering MM (NCT03937635). ITHACA is investigating lenalidomide and dexamethasone with or without the anti-CD38 monoclonal antibody, isatuximab, administered intravenously for patients with high-risk smoldering MM (NCT04270409). Finally, LINKER-SMM2 is investigating linvoseltamab vs daratumumab for patients with high-risk smoldering MM (NCT07393282).

Initial Diagnosis, Patient Evaluation and Consideration of Treatment Goals in Active MM
In the United States, the SLiM-CRAB criteria are used to diagnose a patient with active MM. The CRAB criteria include increased calcium levels >11 mg/dL, renal insufficiency defined as serum creatinine >2 mg/dL or creatinine clearance <40 mL/min, anemia (hemoglobin <10 g/dL or 2 g/dL less than normal), and the presence of bone lesions (≥1 osteolytic lesions seen on skeletal radiography or whole-body FDG PET/CT). The SLiIM  criteria include ≥60% monoclonal plasma cells in the bone marrow, an involved-to-uninvolved serum FLC ratio ≥100 with the involved FLC ≥100 mg/L, and MRI with >1 focal marrow lesion. The presence of a single feature in the CRAB criteria (abnormal calcium level, renal impairment, anemia or bone damage) can indicate the presence of end-organ damage due to myeloma. Once the presence of active MM is confirmed, the disease stage needs to be ascertained and cytogenetic/FISH risk assessments should be performed before treatment ensues. The patient should be assessed for transplant eligibility, level of frailty, and performance status. Also, renal, cardiac and hepatic function, and risk of neuropathy should be assessed. Treatment decisions should be made with consideration for patient preferences, comorbid conditions, and treatment goals.

The level of fitness is dynamic as pain, hypercalcemia, renal dysfunction, and performance status may improve with treatment over time. Therefore, tests to determine the patient’s fitness level need to be regularly repeated. The presence of high-risk cytogenetics necessitates the use of intensive therapy with careful considerations for clinical trial participation.

Treatment of Newly Diagnosed MM
For fit patients, anti-CD38–based quadruplet therapy is preferred, either daratumumab-based or isatuximab-based. This quadruplet treatment approach includes a proteasome inhibitor, an immunomodulatory drug, and dexamethasone. Although the preferred backbone is bortezomib, lenalidomide, and dexamethasone, carfilzomib may be substituted for bortezomib. Subcutaneously administered anti-CD38 therapy reduces treatment time and the risk of infusion-related reactions. Frail patients or those with major comorbidities may require attenuated triplets or doublets such as daratumumab plus lenalidomide, with dose and schedule adapted to the patient’s level of tolerability.

For transplant-eligible patients who are newly diagnosed with MM, treatment with an anti-CD38 antibody–based quadruplet, autologous stem-cell transplantation (ASCT), consolidation, and maintenance remains a central strategy. In the PERSEUS trial, daratumumab plus bortezomib/lenalidomide/dexamethasone followed by intensification and daratumumab/lenalidomide maintenance significantly improved the 48-month PFS (84.3% vs 67.7%; HR 0.42; P <.0001). In addition, the rate of MRD negativity with the quadruplet vs the triplet was significantly higher (P <.0001). Similarly, the CASSIOPEIA trial showed improved PFS and deeper responses with daratumumab-containing induction/consolidation therapy, with the greatest benefit seen when daratumumab therapy continued into the maintenance phase. The GMMG-HD7 trial supports the use of isatuximab-based quadruplet induction vs the triplet regimen without isatuximab, with a rate of MRD negativity of 66% vs 48% and improved PFS with the quadruplet regimen.

Another important trial is MASTER, which investigated induction therapy with daratumumab plus carfilzomib, lenalidomide, and dexamethasone followed by ASCT, consolidation therapy, and lenalidomide maintenance guided by MRD status. Among patients harboring 2 or more high-risk cytogenetic abnormalities, the 3-year PFS rate was significantly lower than those with standard-risk MM, even with sustained MRD negativity. Patients with 2 or more high-risk features remain a population with high unmet needs.

Post ASCT, lenalidomide maintenance remains the hallmark treatment approach. The use of anti-CD38 antibody-based treatment intensification is supported by clinical data, particularly for those who remain MRD positive. The phase III AURIGA trial investigated daratumumab plus lenalidomide vs lenalidomide alone as maintenance therapy for patients with newly diagnosed MM who were anti-CD38 antibody–naive and still MRD positive after undergoing ASCT post induction therapy. At 12 months, the rate of MRD-negativity was significantly higher with the addition of daratumumab to lenalidomide as maintenance compared with lenalidomide alone (50.5% vs 18.8%; P <.0001). In addition, 30-month PFS rates were 82.7% with the addition of daratumumab vs 66.4% with lenalidomide alone (P = .0361). These results suggest that the addition of an anti-CD38 monoclonal antibody to lenalidomide during maintenance is more effective and worth considering for patients with MRD-positive disease post ASCT and anti-CD38 antibody naive.

Regarding fit, nonfrail patients newly diagnosed with MM for whom ASCT is not planned, the CEPHEUS trial showed that the addition of subcutaneous daratumumab to bortezomib, lenalidomide and dexamethasone resulted in a 54-month PFS rate of 68.1% vs 48.5% with bortezomib, lenalidomide and dexamethasone alone (P = .0005). The MRD negativity rate was higher with the addition of daratumumab vs the triplet therapy alone (60.9% vs 39.4%; P <.0001). These results led to the FDA approval of subcutaneous daratumumab plus bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed MM who are ineligible for ASCT. Another study worth mentioning is BENEFIT for fit, nonfrail, transplant-ineligible patients 65-79 years of age who are newly diagnosed with MM. BENEFIT demonstrated that adding weekly subcutaneous bortezomib to intravenously administered isatuximab plus lenalidomide and dexamethasone substantially increased the rate of MRD negativity. Longer follow-up is needed to determine whether there will be a difference in PFS between arms. At this time, however, the use of an anti-CD38 monoclonal antibody in combination with lenalidomide and dexamethasone remains an evidence-based option when there are tolerability concerns about the use of a 4-drug regimen.

Whether a patient is transplant eligible or not, careful consideration should be given to enrollment in a clinical trial. Ongoing phase III trials of anti-CD38 antibody–based quadruplet therapy for transplant-eligible patients with newly diagnosed MM include DETERMINATION 2 (NCT07624513), AugMMent (NCT07671287), and ELIAS (NCT05665140). For transplant-ineligible patients, ongoing phase III trials of novel agents and approaches include EMN39 (NCT06932562), DURGA-5 (NCT07764978) and M25-586 (NCT07095452).

Overall Conclusions
Treatment of patients should maximize depth and durability of response while preserving functionality and quality of life through individualized dosing approaches, continuous frailty assessment, and MRD-informed risk evaluation. Careful consideration should be given to clinical trial enrollment whenever appropriate.

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