SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 patients are expected to die of the disease.
Recommendations on the treatment of multiple myeloma, was first published jointly by ASCO and Cancer Care Ontario in 2019. These two organizations jointly updated these recommendations to provide guidance, following the introduction of new therapies and review of 161 relevant randomized trials.
This clinical practice guideline update focused on four topics.
Smoldering Multiple Myeloma:
1.1. Patients with high-risk smoldering multiple myeloma may be offered active monitoring or Daratumumab (for up to 36 months). Lenalidomide is not routinely recommended.
Qualifying Statements for Recommendation 1.1:
In the AQUILA trial, high-risk smoldering multiple myeloma was defined as ≥10% clonal plasma cells in bone marrow and at least one of the following: (1) a serum M-protein level of at least 3 g/dl; (2) IgA smoldering multiple myeloma; (3) immunoparesis with reduced levels of two uninvolved immunoglobulin isotypes; (4) a ratio of involved FLCs to uninvolved FLCs (FLC ratio) in serum of 8 to <100; (5) a percentage of clonal plasma cells in bone marrow of more than 50% to <60%.
It should be noted that this definition differs from other contemporary criteria for high-risk smoldering multiple myeloma and that using the AQUILA definition of high-risk may classify some patients as high-risk who would not meet high-risk criteria in other classification systems. Therefore, careful discussion and consideration of individual patient factors is essential when evaluating management options.
1.2. Therapy is not recommended for patients with smoldering multiple myeloma who are not at high risk
1.3. Active multiple myeloma should be excluded using current diagnostic algorithms and procedures for smoldering multiple myeloma.
Transplant-Eligible MM: Evaluation of Eligibilty
2.1.1. Unless clearly ineligible, patients should be referred to a transplant center at time of diagnosis to determine transplant eligibility.
2.1.2. Eligibility for Autologous Stem Cell Transplantation (ASCT) should not be based solely on a patient’s chronological age or renal function. Instead, a comprehensive assessment of overall health, performance status, frailty, and comorbidities should guide the decision.
Transplant-Eligible MM: Initial Therapy
2.2.1. Transplant-eligible patients should be offered 4 months of induction therapy with either Daratumumab or Isatuximab, each in combination with Bortezomib, Lenalidomide, and Dexamethasone.
Qualifying Statement for Recommendation 2.2.1: In areas where Lenalidomide may be difficult to obtain, Thalidomide is a reasonable substitute in Daratumumab-containing regimens. At least four cycles of therapy should be considered the baseline, but patients can receive more cycles if they must wait for transplant.
2.2.2. For patients who received Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone and planned to receive post-transplant consolidation, two cycles of Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone can be offered following induction therapy and stem cell transplantation.
2.2.3. Carfilzomib can be used as a substitute for Bortezomib in the recommended induction and consolidation regimens, if toxicity is a concern.
Transplant-Eligible MM: Conditioning and Transplant
2.3.1. Up-front transplantation should be offered to all transplant-eligible patients.
2.3.2. Agents associated with stem-cell toxicity such as Melphalan should be avoided in patients who are potential candidates for ASCT.
2.3.3. Regardless of transplant intent, ample stem cells (sufficient for at least two ASCT) should be collected following 4-6 months of induction therapy to allow for potential stem cell transplants later.
2.3.4. High-dose Melphalan is the recommended conditioning regimen for ASCT.
Transplant-Eligible MM: Maintenance
2.4.1. Lenalidomide should be offered as maintenance therapy.
2.4.2. Carfilzomib or Daratumumab may be added to Lenalidomide with or without Dexamethasone.
Transplant-Eligible MM: Measurement of Response
2.5.1. Depth of response should be assessed with each cycle using IMWG criteria as a guideline. Frequency of assessment may be less frequent but at minimum every 3 months, once best response is attained or while receiving maintenance therapy.
MRD status may be valuable in assessing depth of response but should not be relied on as the sole measure.
Whole-body low-dose CT scan, FDG PET/CT and/or diffusion-weighted MRI are the recommended methods for assessing bone lesions at baseline and during surveillance.
Transplant-Ineligible MM: Therapy
3.1.1. A CD38-targeted monoclonal antibody (Daratumumab OR Isatuximab) in combination with Bortezomib, Lenalidomide, and Dexamethasone should be offered to transplant-ineligible patients who are not frail and can tolerate therapy.
3.1.2. Daratumumab, Lenalidomide, and Dexamethasone OR Bortezomib, Lenalidomide, and Dexamethasone are reasonable alternatives in transplant-ineligible patients who are not suitable candidates for quadruplet therapy
Transplant-Ineligible MM: Goals of Therapy and Measurement of Response
3.2.1. The goal of initial therapy for transplant-ineligible patients should be achievement of the best quality and depth of response. Depth of response for all patients should be assessed per Recommendation 2.5.1 regardless of transplant eligibility.
3.2.2. Upon initiation of therapy, one should define patient-specific goals of therapy. Quality of life (including symptom management and tolerability of treatment) should be assessed at each visit to determine if the goals of therapy are being maintained/met, and this should influence the intensity and duration of treatment. The goals should be redefined periodically, based on response, symptoms, and quality of life.
3.2.3. Patients should be monitored closely with consideration of dose modifications based on levels of toxicity, neutropenia, fever/infection, tolerability of adverse effects, performance status, liver and kidney function, and in keeping with the goals of treatment.
Relapsed/Refractory MM: Therapy
4.1. Treatment of biochemically relapsed myeloma should be individualized. Factors to consider include patient’s tolerance of prior treatment, rate of rise of myeloma markers, cytogenetic risk, presence of comorbid conditions (ie, renal insufficiency), frailty, and patient preference.
4.2. All relapsed patients with disease-related symptoms due to myeloma should be treated immediately.
4.3. Triplet therapy or T-cell redirecting therapies should be offered to eligible patients with relapsed/refractory multiple myeloma based on the following principles:
a) Whenever possible, patients should be offered treatment regimens that include agents that are different than those in their prior therapies.
b) Triplets should be offered to eligible patients.
c) CAR T-cell therapy should be offered to eligible patients. A thorough patient-centered discussion regarding the risks, benefits, and timing of CAR T-cell therapy is advised.
d) Patient preferences with respect to toxicity tolerance, dose and schedule convenience, and means of administration should be factored in with shared decision making when deciding between triplet or CAR T-cell therapy.
e) CAR T-cell therapy may not be appropriate for patients with rapidly progressive relapsed myeloma given the time required for CAR T-cell manufacturing. In this setting, an agent that is immediately available may be favored over CAR T-cell therapy.
f) If the patient is unable to receive triplet or CAR T-cell therapy (based on tolerability, frailty, access, etc), doublet therapy is reasonable.
g) Bispecific antibodies should be offered to eligible patients (including older and frail patients).
h) The optimal sequencing of therapy is an evolving consideration. In the context of a limited evidence base, sequencing decisions should be made based on patient factors, disease characteristics, mechanism of action, and prior treatment responses.
i) Patients for whom existing options have been exhausted or for whom the risks are likely to outweigh the benefits should be offered best supportive care and hospice referral.
4.4.1. ASCT, if not previously received, may be offered to transplant-eligible patients with relapsed multiple myeloma.
4.4.2. Repeat ASCT should not be offered in relapsed multiple myeloma unless the patient experienced a long remission (typically considered >4-5 years) from first transplant.
Treatment of Multiple Myeloma: ASCO–Ontario Health (Cancer Care Ontario) Living Guideline. Hicks LK, Messersmith HJ, Hadidi SA, et al. J Clin Oncol. 2026;44:914-941.
