New ASCO Guideline Offers Recommendations for Smoldering Multiple Myeloma

The American Society of Clinical Oncology (ASCO), in collaboration with Ontario Health (Cancer Care Ontario), has issued an updated living guideline offering recommended treatment strategies for patients with smoldering multiple myeloma and other populations, according to a publication in the Journal of Clinical Oncology.¹

Authors reviewed 217 articles detailing 161 clinical trials in multiple myeloma to form their recommendations across various patient populations. The updated guideline sought to answer key questions related to smoldering myeloma, transplant-eligible multiple myeloma, transplant-ineligible multiple myeloma, and relapsed multiple myeloma.

Smoldering Myeloma

Regarding patients with smoldering multiple myeloma, the guideline authors addressed whether asymptomatic myeloma should be managed and with what regimens. Based on moderate-quality evidence, the authors issued a conditional recommendation for the use of active monitoring or daratumumab (Darzalex) for up to 36 months among patients with smoldering disease; there was no routine recommendation for lenalidomide (Revlimid). Additionally, the guideline offered a strong recommendation based on low-quality evidence to not administer therapy for patients with smoldering disease who are not at a high risk. A Good Practice Statement noted that active multiple myeloma should be excluded using current diagnostic algorithms and procedures for smoldering disease.

Of note, the conditional recommendation for the use of daratumumab in this population was partly based on findings from the phase 3 AQUILA trial (NCT03301220), in which investigators assessed the agent vs active monitoring among those with smoldering multiple myeloma.² Treatment with daratumumab in the AQUILA trial correlated with improvements in overall survival (OS; HR, 0.52; 95% CI, 0.27-0.98) and progression-free survival (PFS; HR, 0.49; 95% CI, 0.36-0.67) compared with active monitoring, although the investigational agent increased the risk of important adverse effects (AEs) during treatment (RR, 1.49; 95% CI, 1.04-2.14).

The overall survival (OS) and progression-free survival (PFS) benefits of daratumumab, the authors wrote, outweigh a probable increase in AEs for most patients, thereby supporting the conditional recommendation for the agent as an alternative to active monitoring. Ongoing investigations in smoldering multiple myeloma include the phase 3 DETER-SMM/ECOG-EAA173 trial (NCT03937635) of daratumumab plus lenalidomide as well as the phase 3 ITHACA trial (NCT04270409) evaluating isatuximab-irfc (Sarclisa) plus lenalidomide and dexamethasone.

Transplant-Eligible Multiple Myeloma

The guideline authors aimed to answer the following clinical questions associated with the management of transplant-eligible disease:

1. Who should be offered autologous stem cell transplantation (ASCT), and based on what criteria?
2. What is the optimal initial therapy before ASCT?
3. What types of consolidation and/or maintenance therapy after ASCT are recommended, and for how long?

Regarding initial therapy before transplantation, the guideline authors issued a strong recommendation based on moderate-quality evidence for the use of induction therapy consisting of 4 months of daratumumab or isatuximab in combination with bortezomib (Velcade), lenalidomide and dexamethasone.

“In areas where lenalidomide may be difficult to obtain, thalidomide [Thalomid] is a reasonable substitute in daratumumab-containing regimens,” the guideline authors wrote as a qualifying statement for their recommendation.¹ “At least 4 cycles of therapy should be considered the baseline, but patients can receive more cycles if they must wait for transplant.”

Based on moderate-quality evidence, the authors provided a conditional recommendation that, among patients treated with daratumumab plus bortezomib, lenalidomide and dexamethasone who plan to receive post-transplant consolidation, clinicians may administer the same regimen following induction therapy and stem cell transplantation. Additionally, the guideline includes a conditional recommendation based on low-quality evidence for carfilzomib (Kyprolis) as a substitute for bortezomib in the recommended induction and consolidation regimens if toxicity represents a concern.

In terms of conditioning and transplantation, the guideline authors issued strong recommendations for offering upfront transplantation to all patients who are eligible for transplant, avoiding agents associated with stem-cell toxicity such as melphalan (Alkeran) among candidates for ASCT, and administering high-dose melphalan as a conditioning regimen for ASCT. These recommendations were accompanied by a Good Practice Statement noting that regardless of transplant intent, clinicians should collect ample stem cells following 4 to 6 months of induction therapy to permit potential future stem cell transplants.

In the maintenance setting, lenalidomide may be provided based on a strong recommendation from the guideline authors backed by high-quality evidence. The authors also issued a conditional recommendation supported by moderate-quality evidence for adding carfilzomib or daratumumab to maintenance lenalidomide with or without dexamethasone.

Transplant-Ineligible Multiple Myeloma

In the management of transplant-ineligible multiple myeloma, the guideline authors aimed to answer questions regarding the recommended initial therapy regimens as well as outcome goals after initial treatment for patients.

For patients who are frail and cannot tolerate transplantation, the guideline included a strong recommendation backed by high-quality evidence for the use of an anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, and dexamethasone. A conditional recommendation based on high-quality evidence noted that clinicians may use daratumumab, lenalidomide, and dexamethasone or bortezomib, lenalidomide, and dexamethasone as reasonable alternatives in patients who are not eligible for quadruplet therapy.

“For some patients with symptomatic myeloma, more rapid disease debulking with a quadruplet regimen may mean improved pain control and thus better quality of life. Indeed, given the possibility of dynamic frailty whereby patients’ fitness may improve with effective therapies, starting with a quadruplet may allow some patients with disease-related frailty who were previously considered transplant ineligible to become transplant-eligible with the initiation of treatment,” the guideline authors wrote.^1,3 “Older patients may sometimes benefit from quadruplet therapy in some cases. Geriatric assessment may be valuable in making these decisions and ASCO guidelines recommend all patients with cancer [who are] 65 years and older receiving systemic therapy, including chemotherapy, targeted therapy, and/or immunotherapy with geriatric assessment-identified impairments should have geriatric assessment-guided management included in their care plan.”

The authors also provided a strong recommendation with moderate-quality evidence that the goal of initial therapy for transplant-ineligible populations should entail achieving the best quality and depth of response. According to an accompanying Good Practice Statement, one should define patient-specific goals of therapy after initiating treatment, with an assessment of quality of life at each visit to evaluate whether said goals are being fulfilled. Another Good Practice Statement recommended monitoring patients closely while considering dose modifications based on levels of toxicity, neutropenia, fever or infection, tolerability of toxicity, performance status, liver and kidney function, and goals of treatment.

Relapsed Multiple Myeloma

The guideline authors explored the following clinical questions associated with the management of relapsed disease:

• What are the recommended therapies at the time of first relapse?
• What are recommended treatments following subsequent relapses?
• How might prior treatment influence subsequent therapeutic decisions, and what factors may determine the selection of relapse therapy?

The guideline included a Good Practice Statement noting that management of biochemically relapsed disease should be personalized, as clinicians must consider the patient’s tolerance of prior treatment, the rate of myeloma markers, cytogenetic risk, the presence of comorbid conditions, frailty, and patient preference. Moreover, the authors strongly recommended immediate treatment of all patients with a relapse and disease-related symptoms due to multiple myeloma.

Given an uncertainty as to how to best rank several potential triplet or T-cell–redirecting therapeutic choices evaluated across various clinical trials, the guideline authors issued general recommendations for offering these therapies based on a list of principles clinicians can use to guide their treatment decision-making as patients experience relapses over time. According to the guideline, triplets, CAR T-cell therapy, and bispecific antibodies may be provided to certain eligible patients, although optimally sequencing these different agents represents an evolving paradigm.

“Currently, there is limited evidence regarding optimal sequencing; in this context, sequencing decisions should be based on patient factors, disease characteristics, mechanism of action, and prior treatment responses. There is little evidence upon which a specific sequence of therapy can be justified,” the authors wrote.¹ “Unfortunately, the panel can provide little guidance on this matter until further data are available, and clinicians will need to exercise their best judgment among this uncertainty.”

References

1. Hicks LK, Messersmith HJ, Al Hadidi S, et al. Treatment of multiple myeloma: ASCO-Ontario Health (Cancer Care Ontario) living guideline. J Clin Oncol. Published online January 6, 2026. doi:10.1200/JCO-25-02587
2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi:10.1056/NEJMoa2409029
3. Mian H, Wildes TM, Vij R, Pianko MJ, Major A, Fiala MA. Dynamic frailty risk assessment among older adults with multiple myeloma: a population-based cohort study. Blood Cancer J. 2023;13(1):76. doi:10.1038/s41408-023-00843-5