ASCO’s Updated Living Guideline for Multiple Myeloma: FAQs and Key Updates

Scope and Methodology  
This week’s blog answers frequently asked questions (FAQs) about the recently published updated living guideline on the treatment of multiple myeloma — a collaboration between the American Society of Clinical Oncology (ASCO) and Ontario Health (Cancer Care Ontario). It is intended for patients, care partners, and oncology professionals. This blog article was medically reviewed by IMF Chief Medical Officer Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, on February 4, 2026. The blog reflects medical guidance available at the time of review and is not routinely updated.  
 
 

What is the updated guideline about? 

Published in the Journal of Clinical Oncology and co-chaired by IMF Chief Medical Officer Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, the updated living guideline on how to treat multiple myeloma  (https://ascopubs.org/doi/10.1200/JCO-25-02587)was recently released by the American Society of Clinical Oncology (ASCO), who worked alongside Ontario Health (Cancer Care Ontario).  

The updated guideline covers: 
    • Smoldering multiple myeloma (including high-risk)
    • Transplant-eligible multiple myeloma 
    • Transplant-ineligible multiple myeloma 
    • Relapsed/refractory multiple myeloma 
 
The recommendations are based on a review of 217 scientific articles, covering 161 clinical trials. 
 

Smoldering Multiple Myeloma (SMM) 
 

What is smoldering multiple myeloma? 

Smoldering multiple myeloma (SMM) is an early, asymptomatic form of myeloma. Patients do not have organ damage or myeloma-related symptoms but are at risk of developing active disease. 
 

Should smoldering multiple myeloma be treated? 

The guideline provides conditional recommendations on managing SMM. 
    • Patients should receive active monitoring (watch and wait) rather than immediate treatment. 
    • However, based on the results of the phase 3 AQUILA trial, the guideline makes the recommendation of offering daratumumab (Darzalex) to high-risk SMM patients (HR-SMM) for up to 36 months. 
    • It should be noted that the guideline strongly recommends AGAINST giving treatment to SMM patients who are NOT at high risk of disease progression. 
    • All patients with SMM should engage in shared decision-making with their providers to determine the best course of treatment based on options available. 
 

Why is daratumumab recommended only for HR-SMM patients? 

The guideline’s conditional recommendation on offering daratumumab to HR-SMM patients is partly based on the results of the phase 3 AQUILA trial, where: 
    • Overall survival (OS) improved (HR 0.52; 95% CI, 0.27–0.98) 
    • Progression-free survival (PFS) improved (HR 0.49; 95% CI, 0.36–0.67) 
    • There was a higher risk of significant side effects during treatment (RR 1.49; 95% CI, 1.04–2.14) 
 
Overall, the benefits were judged to outweigh the risks for many high-risk patients. 
 
 

Are there other ongoing studies for SMM? 

Yes. Ongoing phase 3 trials include: 
    • DETER-SMM / ECOG-EAA173 Trial: daratumumab + lenalidomide 
    • ITHACA Trial: isatuximab-irfc (Sarclisa®) + lenalidomide + dexamethasone 
 
Currently, no other treatments have been recommended by the updated guideline for SMM. 
 
 

Transplant-Eligible Multiple Myeloma (TE-MM) 

Who is considered transplant-eligible? 

Patients who are fit enough for autologous stem cell transplantation (ASCT) based on age, overall health, and organ function. 
 
 

What is the recommended initial treatment before transplant? 

The guideline gives a strong recommendation for 4 months of induction therapy using: 
    • daratumumab or isatuximab 
    • bortezomib (Velcade®) 
    • lenalidomide (Revlimid®) 
    • dexamethasone 
 
This is often called a quadruplet regimen. 
 
If lenalidomide is not available, thalidomide (Thalomid®) may be used as a substitute. Carfilzomib may also be used as a substitute for bortezomib. 
 

Can treatment last longer than 4 months before transplant? 

Yes. At least 4 cycles are recommended, but more cycles may be given if a patient must wait for a transplant. 
 
 

What happens around the time of transplant? 

    • Upfront ASCT is strongly recommended for eligible patients. 
    • High-dose melphalan is recommended as the conditioning chemotherapy. 
    • Drugs that damage stem cells should be avoided before stem cell collection. 
    • Stem cells should be collected after 4–6 months of induction, even if transplant is delayed. 
 

Is consolidation therapy recommended? 

Yes, in some cases. Patients receiving daratumumab-based induction may receive the same regimen after transplant as consolidation. 
 
 

What about maintenance therapy? 

    • Lenalidomide maintenance is strongly recommended. 
    • Adding carfilzomib or daratumumab (with or without dexamethasone) to lenalidomide is a conditional option. 
 
 

Transplant-Ineligible Multiple Myeloma (TI-MM) 
 

What treatments are recommended if a patient cannot undergo ASCT? 

For frail or transplant-ineligible patients, the guideline strongly recommends: 
    • An anti-CD38 antibody plus 
    • bortezomib 
    • lenalidomide 
    • dexamethasone 
 
 

Are there alternative options? 

Yes. Reasonable alternatives include: 
    • daratumumab + lenalidomide + dexamethasone 
    • bortezomib + lenalidomide + dexamethasone 
 

Why might quadruplet therapy still be used in older or frail patients? 

In some patients, faster disease control may: 
    • Reduce pain 
    • Improve quality of life 
    • Improve fitness enough to later allow transplantation 
 
Because frailty can change over time, geriatric assessment is recommended, especially for patients 65 years and older. 
 
 

What is the main goal of treatment in transplant-ineligible myeloma patients? 

The goal is to achieve the best possible depth and quality of response, while preserving quality of life. 
 

Patients should be: 
    • Closely monitored 
    • Adjusted for side effects, infections, blood counts, kidney and liver function 
    • Regularly assessed for quality of life and treatment goals 
 
 

Relapsed/Refractory Multiple Myeloma (RRMM) 
 

When should RRMM be treated? 

The guideline strongly recommends immediate treatment for any patient who has relapsed or is experiencing symptoms related to multiple myeloma. 
 

How should relapsed disease be managed?  

The guideline’s Good Practice Statement states that treatment should depend on: 
    • Previous therapies and responses 
    • Side effects from prior treatments 
    • Disease biology and cytogenetic risk 
    • Frailty, other medical conditions, and patient preferences 
 
 

What treatments are available at relapse? 

Depending on eligibility and prior therapy, options may include: 
    • Triplet drug regimens 
    • CAR T-cell therapy 
    • Bispecific antibodies 
 

Is there a preferred order/sequence for these treatments? 

No clear sequence has been established yet, although it is noted that CAR T cell therapy should be considered at first relapse. 

The guideline also notes that: 
    • Evidence on optimal sequencing is limited. 
    • Treatment decisions must rely on clinical judgment. 
    • This is an evolving area of research. 
 
 

Key Takeaway from the Updated ASCO Guideline 

This updated ASCO guideline emphasizes personalized care, balancing treatment effectiveness, side effects, quality of life, and patient preferences across all stages of multiple myeloma. Ongoing clinical trials continue to refine how and when newer therapies should be used. 
 
(NOTA BENE: The Expert Panel and the ASCO staff dedicated the updated ASCO guideline to the memory of IMF Board Member and Patient Advocate Jack Aiello, who was an Expert Panel member.) 

Reference: 
Lisa K. Hicks et al. Treatment of Multiple Myeloma: ASCO–Ontario Health (Cancer Care Ontario) Living Guideline. J Clin Oncol 0, JCO-25-02587 DOI:10.1200/JCO-25-02587 (https://ascopubs.org/doi/10.1200/JCO-25-02587)