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Treating relapsed and refractory disease

Although most myeloma patients achieve disease control with current therapies, almost all will subsequently relapse or progress, necessitating additional interventions and adoption of a systematic approach to treatment

María Cejalvo Hematology Service, University Hospital Dr Peset, Valencia, Spain Javier de la Rubia MD Hematology Service, University Hospital Dr Peset; Universidad Católica de Valencia “San Vicente Mártir” Valencia, Spain

Recently, significant evolution in therapeutic management has been observed in patients with multiple myeloma (MM). The introduction of novel agents has changed the clinical outcome and overall survival at all phases of the disease. Despite these advances, relapses are inevitable and many patients become refractory to their current treatment. Current guidelines do not recognise a uniform standard-of-care treatment for patients with relapsed and/or refractory MM. Multiple treatment options exist for these difficult-to-treat patients, including immunomodulatory agents (IMiDs) and bortezomib (as a single agent or in combination therapy). The choice for the most appropriate therapy in relapsed and refractory MM (RRMM) must balance efficacy, toxicity and patients’ comorbidities. Knowledge of relapse patterns and management of relapsed disease is a critical aspect of MM treatment and an important area of ongoing research. Moreover, the optimal sequence or combination of post-relapse therapeutic strategies remains unclear, and information is needed on the efficacy of each treatment. This article presents a practical guidance in selecting relapsed treatment strategies and highlights the need for an

individualised approach. Definition of relapse

It is well recognised that relapse can take different forms, and several groups have described these relapse patterns. For example, Alegre et al1


analysed 280 patients and categorised them into four patterns: clinically symptomatic disease; asymptomatic disease with isolated increase in monoclonal protein; extramedullary disease; and plasma cell leukaemia. Lenhoff and colleagues2

prospectively followed 397

patients and documented four relapse patterns: classical (increase in monoclonal protein with clinical symptoms); insidious (asymptomatic increase in monoclonal protein); plasmacytoma form; or transformed disease (plasma cell leukaemia; immunoblastic lymphoma). However, the majority of these reports focused on patients relapsing after conventional chemotherapy or autologous stem cell transplantation (ASCT) and data about relapse patterns in elderly patients and in the era of lenalidomide or bortezomib are limited.3


The International Myeloma Working Group clarified the terms ‘relapsed’ and ‘refractory’ to uniform reporting and identified three different categories. Relapsed myeloma refers to disease recurrence in the absence of current therapy after the patient has had an established response. Refractory/relapsed myeloma refers to relapse when a patient is currently on therapy or within 60 days of previous response. Primary refractory myeloma is defined as nonresponsive

disease. Finally, the definition of relapsed disease requires doubling of M component or an increase in the absolute levels of the M protein by ≥1g/dl, involved free light chain ≥20mg/dl, or urine M protein ≥500mg/24 hours in two consecutive measurements in ≤ two months.4

Treatment selection for RRMM patients

There is no accepted standard of care for patients with RRMM and the goal of salvage therapy is to achieve disease control with acceptable toxicity. These two factors are of utmost importance when deciding which strategy to choose, considering that the ideal therapy should take into account both patient- and disease-related factors.5 Therefore, patients’ comorbidities at time of relapse (hepatic and/or renal impairment, residual neuropathy from previous lines, diabetes, particularly in ageing population) are extremely important factors when considering the best treatment option. When the goal of therapy is not a subsequent transplant, the choice of salvage regimen becomes more dependent on long-term tolerability and efficacy. Substantial clinical data support the practice of re-treating patients with agents to which they have been previously exposed.6,7

Re-treatment would be

particularly useful when previous treatment produced a clinically meaningful response of adequate duration such as a treatment- free interval of one year or more without severe toxicity. For patients with a shorter duration of response or unacceptable side effects with previous therapy, switching to a different class of drugs is the most logical approach. Figure 1 shows a treatment


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