Treatment of Multiple Myeloma

Publication Date: April 1, 2019

Treatment

Transplant Eligible

Patients should be referred to a transplant center to determine transplant eligibility. ( EB , H , H , M )
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Chronologic age and renal function should not be the sole criteria used to determine eligibility for stem cell transplantation (SCT). ( EB , H , H , M )
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The optimal regimen and number of cycles remain unproven. However, at least 3-4 cycles of induction therapy including an immunomodulatory drug, proteasome inhibitor and steroids is advised prior to stem cell collection. ( EB , H , H , M )
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Upfront transplant should be offered to all transplant-eligible patients. Delayed initial SCT may be considered in select patients. ( EB , H , B , S )
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Agents associated with stem cell toxicity, such as melphalan and/or prolonged immunomodulatory drugs exposure (more than 4 cycles), should be avoided in patients who are potential candidates for SCT. ( EB , H , H , M )
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Ample stem cell collection (sufficient for more than one SCT) should be considered upfront, due to concern for limited ability for future stem cell collection after prolonged treatment exposure. ( EB , H , H , M )
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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. ( EB , H , H , M )
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High-dose melphalan is the recommended conditioning regimen for Auto SCT. ( EB , H , B , S )
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Tandem autologous SCT should not be routinely recommended. ( EB , L , B , M )
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Salvage or delayed SCT may be used as consolidation at first relapse for those not choosing to proceed to transplant initially. ( EB , H , H , M )
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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. ( EB , H , B , M )
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Consolidation therapy is not routinely recommended but may be considered in the context of a clinical trial. For patient’s ineligible or unwilling to consider maintenance therapy, consolidation therapy for at least 2 cycles may be considered. ( EB , H , H , M )
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Lenalidomide maintenance therapy should be routinely offered to standard risk patients starting at approximately day 90-110 at 10-15 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. ( EB , H , B , S )
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For patients intolerant of or unable to receive lenalidomide, bortezomib maintenance every 2 weeks may be considered. ( IC , H , H , M )
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For high-risk patients, maintenance therapy with a proteasome inhibitor +/- lenalidomide may be considered. ( IC , H , H , M )
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There is insufficient evidence to make modifications to maintenance therapy based on depth of response, including minimal residual disease (MRD) status. ( IC , H , H , W )
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The quality and depth of response should be assessed by IMWG (International Myeloma Working Group) criteria. ( EB , H , B , S )
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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. ( EB , H , H , S )
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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. ( EB , H , B/H , )
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Whole-body low dose 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. FDG-PET/CT and/or MRI 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 non-secretory and oligosecretory myeloma and if CT or skeletal survey is inconclusive). ( EB , H , H , S )
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Transplant Ineligible

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, patient-specific factors including age, comorbidities, functional status, frailty status and patient preferences should also be considered. ( EB , H , B , M )
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Initial treatment for patients with multiple myeloma who are transplant ineligible should include at minimum a novel agent (immunomodulatory drug or proteasome inhibitor) and a steroid if possible. ( EB , H , B , S )
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Triplet therapies for patients with multiple myeloma who are transplant ineligible, including bortezomib-lenalidomide-dexamethasone should be considered. Daratumumab + bortezomib + melphalan + prednisone may also be considered. ( EB , H , B , S )
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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. ( EB , H , H , M )
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Continuous therapy should be offered over fixed duration therapy when initiating an immunomodulatory drug or proteasome inhibitor-based regimen. ( EB , H , B , S )
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The goal of initial therapy for transplant ineligible patients should be achievement of the best quality and depth of remission. ( EB , H , H , M )
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Depth of response for all patients should be assessed by IMWG criteria (Table 5) regardless of transplant eligibility. ( EB , H , H , S )
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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. ( IC , I , H , W )
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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. ( IC , H , H , W )
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It is recommended that patients be monitored closely with consideration of dose modifications based on levels of toxicity, neutropenia, fever/infection, tolerability of side effects, performance status, liver and kidney function and in keeping with the goals of treatment. ( IC , H , H , W )
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Relapsed Disease

Treatment for 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. ( IC , H , H , M )
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All clinically relapsed patients with symptoms due to myeloma should be treated immediately. ( EB , H , B , S )
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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 (proteasome inhibitors, immunomodulatory drugs or monoclonal antibodies). ( EB , H , B , S )
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Treatment of relapsed multiple myeloma may be continued until disease progression. There is not enough data to recommend risk based versus response-based duration of treatment (such as MRD). ( EB , H , H , M )
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Prior therapies should be taken into consideration when selecting the treatment at first relapse. A monoclonal antibody-based regimen in combination with an immunomodulatory drugs and/or proteasome inhibitor should be considered. Triplet regimens are preferred based on tolerability and comorbidities. ( EB , H , H , W )
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Autologous stem cell transplantation, if not received after primary induction therapy, should be offered to transplant eligible patients with relapsed multiple myeloma. Repeat stem cell transplant may be considered in relapsed multiple myeloma if PFS after first transplant is 18 months or greater. ( EB , H , B/H , W )
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The risk status of the patients should be assessed using the Revised ISS staging system for all patients at the time of diagnosis. ( EB , H , B , S )
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Repeat risk assessment at the time of relapse should be performed and should include bone marrow with FISH for myeloma abnormalities seen with progression including, 17p and 1q abnormalities. FISH for primary abnormalities (translocations and trisomies), if seen in the initial diagnostic marrow, does not need to be repeated. ( EB , H , B , S )
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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. ( EB , H , B , S )
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In patients with genetic high-risk disease a triplet combination of proteasome inhibitor, immunomodulatory drug and a steroid should be the initial treatment, followed by one or two autologous SCT, followed by a proteasome inhibitor-based maintenance until progression. ( EB , H , B , S )
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In patients with renal insufficiency, drugs should be modified based on renal clearance. ( EB , H , B , S )
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In patients with plasma cell leukemia or extra medullary disease, cytotoxic chemotherapy may have a role. ( EB , H , H , M )
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The IMWG revised response criteria should be used for response assessment. ( EB , H , B , S )
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All measurable parameters need to be followed including light and heavy chain analysis. ( EB , H , B , S )
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All responses excluding marrow and imaging should be confirmed as per IMWG criteria. ( EB , H , B , S )
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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. ( EB , H , B , S )
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Recommendation Grading

Disclaimer

Overview

Title

Treatment of Multiple Myeloma

Authoring Organizations

Publication Month/Year

April 1, 2019

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Target Patient Population

Patients with multiple myeloma

Target Provider Population

Medical oncologists, radiation oncologists, hematologists, surgeons, nurses, advanced practice providers, oncology pharmacists

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Management, Treatment

Keywords

multiple myeloma, hematologic malignancies

Source Citation

DOI: 10.1200/JCO.18.02096 Journal of Clinical Oncology 37, no. 14 (May 10, 2019) 1228-1263.

Supplemental Methodology Resources

Data Supplement, Methodology Supplement