Treatment of 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. See the Clinical Interpretation in the Living Guideline for details on shared decision-making between these options.

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. See text for further considerations.

Unless clearly ineligible, patients should be referred to a transplant center at time of diagnosis to determine transplant eligibility.

Autologous stem cell transplant (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 patients should be offered four 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 posttransplant consolidation, two cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone can be offered following induction therapy and stem cell transplantation. See Clinical Interpretation in the Living Guideline for details on decision-making.

Carfilzomib can be used as a substitute for bortezomib in the recommended induction and consolidation regimens if toxicity is a concern. See Clinical Interpretation in the Living Guideline for details on decision making.

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 four to six months of induction therapy to allow for potential stem cell transplants later.

High-dose melphalan is the recommended conditioning regimen for ASCT.

Lenalidomide should be offered as maintenance therapy. See Clinical Interpretation in the Living Guideline regarding duration of therapy.

Carfilzomib or daratumumab may be added to lenalidomide with or without dexamethasone. See Clinical Interpretation in the Living Guideline for details on when these additions may be appropriate.

Depth of response should be assessed with each cycle using International
Myeloma Working Group (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 3 months. Measurable residual disease (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.

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. See Clinical Interpretation in the Living Guideline for details on shared decision-making between clinicians and patients on choosing between these options and on geriatric assessment.

Daratumumab, lenalidomide, and dexamethasone OR bortezomib, lenalidomide, and dexamethasone are reasonable alternatives in transplant-ineligible patients who are not suitable candidates for quadruplet therapy. See Clinical Interpretation in the Living Guideline for details on shared decision-making between clinicians and patients regarding who may not be able to receive quadruplet therapy.

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 prior recommendation 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.

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.

T-cell redirecting therapies or triplet therapy 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. 
• Ciltacabtagene autoleucel and teclistamab-based therapy are preferred options at first or early relapse for eligible patients who have not previously received BCMA-directed therapy. For teclistamab-based therapy, teclistamab plus daratumumab is an appropriate option for patients whose disease is not refractory to anti-CD38 therapy while teclistamab monotherapy is reasonable for patients whose disease is refractory to anti-CD38 therapy. 
• Talquetamab plus daratumumab may be offered for initial relapse after one to three prior lines of therapy, particularly after prior BCMA-targeted therapy, as a bridge to BCMA CAR T-cell therapy, or when use of a non-BCMA target is desirable. 
• Other options for initial relapse after one to three prior lines of therapy include idecabtagene vicleucel and triplet regimens, including belantamab mafodotin-based triplets and the combination of mezigdomide, carfilzomib, and dexamethasone. 
• Toxicity associated with these various regimens can be substantial, and different regimens pose different risks. Information on key toxicities by regimen and shared decision making around balancing these risks and benefits can be found in the Clinical Interpretation. 
• 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 CAR T-cell therapy, bispecific antibody-based therapy, and triplet 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. Alternatively, it may be necessary to bridge to CAR T-cell therapy with a non-BCMA-targeted treatment. In this setting, agents that cause prolonged T-cell depletion (such as bendamustine) should also be avoided. 
• If a patient is unable to receive CAR T-cell therapy, bispecific antibody-based therapy, or triplet therapy (based on tolerability, frailty, access, etc.), then doublet therapy is reasonable. 
• Bispecific antibody monotherapy may 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. 
See Clinical Interpretation in the Living Guideline for discussion on shared decision-making among these options and the factors on which the decision should be based. Some agents (e.g., talquetamab, mezigdomide) may not have regulatory approval in all jurisdictions and therefore may not be available for use outside of clinical trials.

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.