A PubMed search was done using the terms “myeloma”, “relapsed”, and “trial” to identify clinical trials on relapsed myeloma published in English (exclusively) between Jan 1, 2013, and Sept 30, 2020. Published data were analysed by an interdisciplinary panel of experts representing all cooperative groups worldwide on behalf of the International Myeloma Working Group. Levels of evidence and grades of recommendations were assigned using established criteria in line with the Grading of
Policy ReviewTreatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group
Introduction
The treatment of multiple myeloma has changed drastically in the past decade with the incorporation of novel agents into therapeutic strategies. These new drugs, in various combinations, have been added to national and international clinical guidelines and have transformed the approach to the treatment of patients with multiple myeloma, resulting in substantial improvements in overall survival.1, 2
With the availability of at least seven different classes of approved agents, including alkylators, steroids, proteasome inhibitors, immunomodulatory agents, histone deacetylase inhibitors, monoclonal antibodies, and selective inhibitors of nuclear export, which can be combined in doublet, triplet, or even quadruplet regimens and used with or without high-dose therapy and autologous stem-cell transplantation (ASCT), or in some cases as continuous treatment, the choice of the optimal strategy at diagnosis and at relapse represents a challenge for physicians. Moreover, next-generation immunotherapies or targeted agents will soon improve the therapeutic armamentarium. Also somewhat problematic is the scarcity of trials addressing important questions, such as the integration of the first salvage regimen into the assessment of front-line therapies to define optimal treatment sequencing strategies in homogeneous or at least similar patient populations. Furthermore, few data are available on the efficacy of the different approved regimens in specific patient populations, such as those with refractory disease versus those being treated for relapse after a treatment-free interval, those with biochemical versus symptomatic relapse, those with relapse after one previous line of therapy versus those with more advanced disease, those with high-risk versus standard-risk cytogenetic profiles, and those with extramedullary disease, among others.3
Several phase 3 trials have shown improved survival outcomes (progression-free survival, overall survival, or both) with the use of triplet combinations, suggesting that at least two active drugs should be combined with steroids, if patients can safely tolerate this therapeutic regimen. However, combinations of the aforementioned agents are unfortunately associated with a high cost, which raises two important issues: drug access in both low-income and middle-income countries and in high-income countries, and the definition of value versus patient benefit.
At the time of relapse, the treatment choice is affected by many patient-related and disease-related factors, such as patient preference, age, cytogenetic profile, pre-existing toxicities, comorbidities, and aggressiveness of the relapse, but mostly by the type of, and the response to, previous therapies.4 The aim of this Policy Review is to discuss the currently available data for the treatment of relapsed and refractory multiple myeloma and to propose clear recommendations and guidelines for routine practice, recognising the challenges of clinical trial complications and translating phase 2 and 3 study results to real-world practice.5
Section snippets
Treatment of relapsed and refractory disease in patients who have received one previous line of therapy
The most important question for most cases of myeloma relapse, or disease that is resistant to therapy, is whether a patient has lenalidomide-refractory disease or not (figure 1). A second consideration that will be increasingly important is whether the disease is progressing on front-line therapies that include daratumumab.
On the basis of the overall survival benefits seen in randomised trials and meta-analyses, lenalidomide is used as part of the front-line therapy for newly diagnosed
First relapse in patients with lenalidomide-refractory disease
Patients with lenalidomide-refractory disease were rightly excluded from randomised phase 3 trials testing lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone plus a third agent (either a proteasome inhibitor [carfilzomib11 or ixazomib12] or a monoclonal antibody [elotuzumab13 or daratumumab14]). The precise effect of lenalidomide-based triplet combinations in patients with lenalidomide-refractory disease is unknown, but it would most likely lead to suboptimal results, and
First relapse in patients with disease not refractory to lenalidomide
In patients who have received bortezomib-based front-line therapy (ie, bortezomib plus cyclophosphamide plus dexamethasone, bortezomib plus thalidomide plus dexamethasone, or bortezomib plus melphalan plus prednisone) without lenalidomide maintenance, or patients treated with a fixed duration of lenalidomide with progression occurring more than 6 months after cessation of therapy, second-line therapy should be based on lenalidomide and dexamethasone regimens, such as carfilzomib plus
First relapse in patients progressing on front-line daratumumab-based combinations
The approval of daratumumab-based regimens (daratumumab plus bortezomib plus melphalan plus prednisone [ALCYONE trial]41, 42 and daratumumab plus lenalidomide plus dexamethasone [MAIA trial]43) as the front-line therapy for myeloma is making treatment decisions challenging. So far, no data exist to support daratumumab retreatment at second line, and salvage therapy with isatuximab in patients progressing on daratumumab is unlikely to be a suitable option because both antibodies target the same
Salvage ASCT
Front-line ASCT is the standard of care for fit patients younger than 70 years of age in many countries.1, 2 Nevertheless, given the absence of an overall survival benefit of front-line ASCT in patients with standard-risk disease, compared with bortezomib plus lenalidomide plus dexamethasone followed by lenalidomide maintenance, for example,44 some investigators and patients prefer to delay ASCT to the time of the first relapse, after harvesting and storing stem cells during induction. In this
Treatment of relapsed and refractory disease after two or more previous lines of therapy
The treatment of patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy is becoming particularly challenging. Lenalidomide and bortezomib are often used as part of front-line therapy or at first relapse. Monoclonal antibodies (eg, daratumumab and elotuzumab) and carfilzomib are also being increasingly used during the first two lines of treatment. Therefore, at the time of the second relapse, all agents considered but not used for first
Search strategy and selection criteria
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