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    Treatment of Multiple Myeloma (beta)

    Based on guidelines from the American Society of Clinical Oncology and Cancer Care Ontario.

    Strength
    Strong recommendation
    Moderate recommendation
    Weak recommendation
    Evidence
    High quality evidence
    Intermediate quality evidence
    Low-intermediate quality evidence
    Low quality evidence
    Insufficient evidence

    Transplant-eligible

    Eligibility
    1. Patients should be referred to a transplant center to determine transplant eligibility.
    2. Chronologic age and renal function should not be the sole criteria used to determine eligibility for SCT.
    Induction Therapy
    1. 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.
    Up-front Transplant
    1. Up-front transplant should be offered to all transplant-eligible patients. Delayed initial SCT may be considered in select patients.
    Agents to Avoid
    1. 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.
    Stem-cell Collection
    1. 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.
    SCT referral
    1. 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.
    High-dose Melphalan
    1. High-dose melphalan is the recommended conditioning regimen for ASCT.
    Tandem ASCT Not Routinely Recommended
    1. Tandem ASCT should not be routinely recommended.
    Salvage or Delayed SCT
    1. Salvage or delayed SCT may be used as consolidation at first relapse for those not choosing to proceed to transplant initially.
    Allogeneic Transplant
    1. 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.
    Consolidation Therapy
    1. 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
    1. 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.
    Bortezomib Maintenance Therapy
    1. For patients intolerant of or unable to receive lenalidomide, bortezomib maintenance every 2 weeks may be considered.
    Maintenance Therapy with Proteasome Inhibitors
    1. For high-risk patients, maintenance therapy with a PI with or without lenalidomide may be considered.
    Maintenance Therapy
    1. There is insufficient evidence to make modifications to maintenance therapy based on depth of response, including minimal residual disease (MRD) status.
    Response Goals
    1. The quality and depth of response should be assessed by International Myeloma Working Group (IMWG) criteria.
    2. 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.
    3. 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 3 months.
    4. 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

    Initial Treatment
    1. 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.
    2. 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
    1. 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.
    Dosing
    1. 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
    1. Continuous therapy should be offered over fixed-duration therapy when initiating an immunomodulatory drug or PI-based regimen.
    Response Goals
    1. The goal of initial therapy for transplant-ineligible patients should be achievement of the best quality and depth of remission.
    2. Depth of response for all patients should be assessed by IMWG criteria regardless of transplant eligibility.
    3. 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.
    4. 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.
    5. 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 Disease

    First Relapse Therapy
    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 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.
    2. All clinically relapsed patients with symptoms due to myeloma should be treated immediately.
    3. 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).
    4. 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.
    5. 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.
    6. 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.
    Risk Assessment
    1. The risk status of the patients should be assessed using the Revised International Staging System for all patients at the time of diagnosis.
    2. Repeat risk assessment at the time of relapse should be performed and should include bone marrow with fluorescence in situ hybridization for myeloma abnormalities seen with progression, including 17p and 1q abnormalities. Fluorescence in situ hybridization for primary abnormalities (translocations and trisomies), if seen in the initial diagnostic marrow, does not need to be repeated.
    3. Assessment of other risk factors such as renal insufficiency, age, presence of plasma cell leukemia/circulating plasma cells, extramedullary disease, and frailty, should also be considered/performed.
    Patients with Genetic High-risk Disease
    1. In patients with genetic high-risk disease, a triplet combination of PI, immunomodulatory drug, and a steroid should be the initial treatment, followed by one or two ASCTs, followed by a PI-based maintenance until progression.
    Patients with Renal Insufficiency
    1. In patients with renal insufficiency, drugs should be modified based on renal clearance.
    Patients with Plasma Cell Leukemia or Extramedullary Disease
    1. In patients with plasma cell leukemia or extramedullary disease, cytotoxic chemotherapy may have a role.
    Response Assessment
    1. The IMWG revised response criteria should be used for response assessment.
    2. All measurable parameters need to be followed, including light and heavy chain analysis.
    3. All responses excluding marrow and imaging should be confirmed as per IMWG criteria.
    4. Response assessment should be performed after one cycle of therapy, and once a response trend is observed, it may be done every other cycle and less frequently once patient is in a plateau.
    What do the icons mean?  
    Research PaperMikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37(14):1228-1263.