European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Abstract

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

Figure 1.

Initiation and progression of MM. MGUS is an indolent, asymptomatic condition and pre-malignant precursor form of MM, that may progress into SMM and symptomatic myeloma, and eventually (with a more aggressive disease courses - into extramedullary disease), such as plasma cell leukemia (PCL). During this disease progression, genetic events may accumulate with tumor diversity and genetic lesions increasing, these events evolving through clonal selection. Adapted with kind permission of G. Morgan.

Figure 2.

The initiation of most suitable and well-tolerable treatment in symptomatic, newly diagnosed MM patients involves the consideration of various factors, including whether this patient is a candidate for ASCT and presents with comorbidities, disability and frailty. In relation to these issues, either a 3-drug induction regimen, stem cell collection and ASCT may be considered, or with frailty, initial treatment according to ‘full-go’, ‘moderate-go’ or ‘slow-go’ protocols. 'Full go' patients are defined as those without risk factors of advanced age >75 years, moderate or severe frailty (patients needing help for household tasks and personal care) and comorbidities (FCI = 0), 'moderate-go' with at least one of these risks and 'slow-go' with at least two or more of these risk factors. Intermediate assessment of response (if in e.g. non-transplant eligible patients 6–9 cycles of CTD or VCD are performed) is important.