The American Society of Clinical Oncology (ASCO) released an update to their guidelines on Treatment of Multiple Myeloma. This guideline update follows multiple randomized controlled trials that studied new therapies and new combinations of existing therapies which showed improvements in progression-free survival.
Since the 2019 guideline, changes in how smoldering versus active myeloma are defined, along with new clinical trial data, have created a need for updated recommendations. In response the ASCO's Evidence-Based Medicine Committee (EBMC) and Ontario Health (Cancer Care Ontario; OH-CCO) jointly updated the guideline to address emerging evidence and evolving clinical practice.
While the guideline is comprehensive, this article will only focus on a small portion of the available information, we encourage you to view the full guideline on our website or at the link below for more helpful information on this topic.
Major Changes and Key Takeaways from the 2026 Update
Smoldering Multiple Myeloma
- Daratumumab therapy may be offered to patients with high-risk smoldering myeloma.
Transplant-Eligible Multiple Myeloma
- Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as initial therapy for transplant eligible patients. They should also be offered at least lenalidomide maintenance, with or without daratumumab, carfilzomib, and/or dexamethasone.
Transplant-Ineligible Multiple Myeloma
- Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as therapy for suitable transplant-ineligible patients.
Relapsed Multiple Myeloma
- Patients with relapsed or refractory multiple myeloma should be offered triplet therapy or T-cell redirecting therapies according to a set of recommended principles.
Comparison of Recommendations
| Topic | 2025 | 2019 |
|---|---|---|
| Smoldering Multiple Myeloma | Patients with high-risk smoldering multiple myeloma may be offered active monitoring or daratumumab (for up to 36 months). Lenalidomide is not routinely recommended. Therapy for patients with smoldering multiple myeloma who are not at high risk is not recommended. Active multiple myeloma should be excluded using current diagnostic algorithms and procedures for smoldering multiple myeloma. | Not addressed. |
| Transplant Eligible—Evaluation of Eligibility | Unless clearly ineligible, patients should be referred to a transplant center at time of diagnosis to determine transplant eligibility. Eligibility for autologous stem cell transplantation 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. | Patients should be referred to a transplant center to determine transplant eligibility. Chronologic age and renal function should not be the sole criteria used to determine eligibility for SCT. |
| Transplant Eligible—Initial Therapy | Transplant-eligible patients should be offered 4 months of induction therapy with either daratumumab or isatuximab, each in combination with bortezomib, lenalidomide, and dexamethasone. 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. Carfilzomib can be used as a substitute for bortezomib in the recommended induction and consolidation regimens if toxicity is a concern. | The optimal regimen and number of cycles remain unproven. However, at least three to four cycles of induction therapy including an immunomodulatory drug, proteasome inhibitor (PI), and steroids is advised prior to stem-cell collection. Ample stem-cell collection (sufficient for more than one SCT) should be considered up front, due to concern for limited ability for future stem-cell collection after prolonged treatment exposure. The level of minimal response required to proceed to SCT is not established for patients receiving induction therapy—patients should be referred for SCT independent of depth of response. Tandem ASCT should not be routinely recommended. Salvage or delayed SCT may be used as consolidation at first relapse for those not choosing to proceed to transplant initially. Allogeneic transplant for multiple myeloma is not routinely recommended but may be considered in select high-risk patients or in the context of a clinical trial. |
| Transplant Eligible—Conditioning and Transplant | Up-front transplantation should be offered to all transplant-eligible patients. Agents associated with stem-cell toxicity such as melphalan should be avoided in patients who are potential candidates for ASCT. 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. High-dose melphalan is the recommended conditioning regimen for ASCT. | Up-front transplant should be offered to all transplant-eligible patients. Delayed initial SCT may be considered in select patients. Agents associated with stem-cell toxicity, such as melphalan and/or prolonged immunomodulatory drug exposure (more than four cycles), should be avoided in patients who are potential candidates for SCT. High-dose melphalan is the recommended conditioning regimen for ASCT. |
| Transplant Eligible—Maintenance | Lenalidomide should be offered as maintenance therapy. See Clinical Interpretation regarding duration of therapy. Carfilzomib or daratumumab may be added to lenalidomide with or without dexamethasone. See Clinical Interpretation for details on when these additions may be appropriate. | Consolidation therapy is not routinely recommended but may be considered in the context of a clinical trial. For patients ineligible or unwilling to consider maintenance therapy, consolidation therapy for at least two cycles may be considered. Lenalidomide maintenance therapy should be routinely offered to standard-risk patients starting at approximately day 90 to 110 at 10 to 15 mg daily until progression. A minimum of 2 years of maintenance therapy is associated with improved survival, and efforts to maintain therapy for at least this duration are recommended. For patients intolerant of or unable to receive lenalidomide, bortezomib maintenance every 2 weeks may be considered. For high-risk patients, maintenance therapy with a PI with or without lenalidomide may be considered. There is insufficient evidence to make modifications to maintenance therapy based on depth of response, including minimal residual disease (MRD) status. |
| Transplant Eligible—Measurement of Response | Depth of response should be assessed with each cycle using IMWG criteria as a guideline. Frequency of assessment once best response is attained or while receiving maintenance therapy may be less frequent but at minimum every three months. 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, fluorodeoxyglucose PET/CT and/or diffusion-weighted MRI are the recommended methods for assessing bone lesions at baseline and during surveillance. | The quality and depth of response should be assessed by International Myeloma Working Group (IMWG) criteria. The goal of initial therapy for transplant-eligible patients should be achievement of the best depth of remission. MRD-negative status has been associated with improved outcomes, but it should not be used to guide treatment goals outside the context of a clinical trial. It is recommended that depth of response be assessed with each cycle. Frequency of assessment once best response is attained or on maintenance therapy may be assessed less frequently but at minimum every three months. Whole-body low-dose computed tomography (CT) scan has been shown to be superior to skeletal survey done with plain x-rays and is the preferred method for baseline and routine bone surveillance. Fluorodeoxyglucose positron emission tomography/CT and/or magnetic resonance imaging may be used as alternatives at baseline. They may also be used in select situations (e.g., risk-stratifying smoldering myeloma, for monitoring response of nonsecretory and oligosecretory myeloma, and if CT or skeletal survey is inconclusive). |
| Transplant Ineligible—Therapy | 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. Daratumumab, lenalidomide, and dexamethasone OR bortezomib, lenalidomide, and dexamethasone are reasonable alternatives in transplant-ineligible patients who are not suitable candidates for quadruplet therapy. | Initial treatment recommendations for patients with multiple myeloma who are transplant ineligible should be individualized based on shared decision making between physicians and patients. Multiple factors should be considered; disease-specific factors such as stage and cytogenetic abnormalities, and patient-specific factors including age, comorbidities, functional status, frailty status, and patient preferences should also be considered Initial treatment of patients with multiple myeloma who are transplant ineligible should include at minimum a novel agent (immunomodulatory drug or PI) and a steroid if possible Triplet therapies for patients with multiple myeloma who are transplant ineligible, including bortezomib, lenalidomide, dexamethasone, should be considered. Daratumumab plus bortezomib plus melphalan plus prednisone may also be considered. Physicians/patients should balance the potential improvement in response and disease control with a possible increase in toxicity. Initial dosing should be individualized based on patient age, renal function, comorbidities, functional status, and frailty status. Subsequent dosing may be tailored based on initial response and tolerability. Continuous therapy should be offered over fixed-duration therapy when initiating an immunomodulatory drug or PI-based regimen. |
| Transplant Ineligible—Goals of Therapy and Measurement of Response | 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. 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. 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. | The goal of initial therapy for transplant-ineligible patients should be achievement of the best quality and depth of remission. Depth of response for all patients should be assessed by IMWG criteria (Table 6) regardless of transplant eligibility. There is insufficient evidence to support change in type and length of therapy based on depth of response as measured by conventional IMWG approaches or MRD. Upon initiation of therapy, one should define patient-specific goals of therapy. Quality-of-life assessment (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. Redefining the goals prospectively, based on response, symptoms, and quality of life, is recommended. It is recommended that patients 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—Therapy | 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 (i.e., renal insufficiency), frailty, and patient preference. All relapsed patients with disease-related symptoms due to myeloma should be treated immediately. Triplet therapy or T-cell redirecting therapies should be offered to eligible patients with relapsed/refractory multiple myeloma based on the following principles: Whenever possible, patients should be offered treatment regimens that include agents that are different than those in their prior therapies. Triplets should be offered to eligible patients. See text for details on evidence-based triplet regimens. 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. 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. 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. If the patient is unable to receive triplet or CAR T-cell therapy (based on tolerability, frailty, access, etc.), doublet therapy is reasonable. Bispecific antibodies should be offered to eligible patients (including older and frail patients). 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. 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. ASCT, if not previously received, may be offered to transplant-eligible patients with relapsed multiple myeloma. 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 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 comorbidities (i.e., renal insufficiency), frailty, and patient preference. High-risk patients as defined by high-risk cytogenetics and early relapse post-transplant/initial therapy should be treated immediately. Close observation is appropriate for patients with slowly progressive and asymptomatic relapse. All clinically relapsed patients with symptoms due to myeloma should be treated immediately. Triplet therapy should be administered on first relapse, though the patient’s tolerance for increased toxicity should be considered. A triplet is defined as a regimen with two novel agents (PIs, immunomodulatory drugs, or monoclonal antibodies). Treatment of relapsed multiple myeloma may be continued until disease progression. There are not enough data to recommend risk-based versus response-based duration of treatment (such as MRD). Prior therapies should be taken into consideration when selecting the treatment at first relapse. A monoclonal antibody–based regimen in combination with an immunomodulatory drug and/or PI should be considered. Triplet regimens are preferred based on tolerability and comorbidities. ASCT, if not received after primary induction therapy, should be offered to transplant-eligible patients with relapsed multiple myeloma. Repeat SCT may be considered in relapsed multiple myeloma if progression-free survival after first transplant is 18 months or greater. |
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