Chapter 5 – Treatment of relapsed multiple myeloma

Contributor: Michel Delforge

2 – Immediate treatment initiation or watchful waiting

According to the International Myeloma Working Group (IMWG) criteria, progressive disease in MM is defined as an increase in the serum M-spike of at least 25% (with a minimum value of 0.5 g/dL), or ≥200 mg of light chain increase in a 24-h urine collection compared with the lowest (nadir) value. Additional criteria are an increase in the difference of involved and non-involved free-light chains of ≥100 mg/L in patients without a measurable serum or urine M-component. Without clinical signs or symptoms, this is called a biochemical relapse. For patients with non-secretory myeloma, the disease status should be followed by bone marrow aspiration and imaging such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission-tomography (PET)-CT. A clinical relapse includes biochemical progression associated with end organ damage defined by the so-called ‘CRAB’ criteria (symptoms of hypercalcemia, renal insufficiency, anemia, and bone disease), including new or an increase in size of existing bone lesions or soft tissue plasmacytomas [8]. For a biochemical, smoldering, or asymptomatic relapse, a careful watch and wait approach is justified. However, when there is a rapid increase in paraprotein (eg, doubling time of less than 3 months), or when the initial disease presentation was complicated by severe organ damage (eg, renal failure), anti-myeloma treatment should not be delayed in order to avoid irreversible organ damage or serious disease-related complications [9]. One should also keep in mind that, especially at later relapses, the phenotype of the disease can change in an individual patient including decreased paraprotein secretion with increased cell proliferation in the bone marrow or at extramedullary sites that can even include the central nervous system.

Diagnostic work-up at relapse should include a careful clinical examination to detect any co-existing disease, a full blood count, evaluation of kidney and liver function, and dosage of serum and urine paraprotein, eventually supplemented by measurement of serum free light chains. Although not mandatory, a bone marrow aspiration/bone biopsy is recommended when relapse is suspected but cannot be confirmed by paraprotein measurement, in case of non-secretory myeloma, or unexplained cytopenia [10]. Skeletal imaging by conventional X-ray or CT is recommended to detect new bone lesions, and MRI or PET-CT for soft tissue or extramedullary plasmacytomas [11]. Given the complexity of MM and the availability of different new agents for relapsed myeloma, fluorescence in situ hybridization (FISH), and molecular genetics (gene expression profiling) gain increasing importance to guide treatment optimization for individual patients, not only at diagnosis, but also at relapse.

Figure 5.1 Decision algorithm for treatment of relapsed multiple myeloma.

Bort, bortezomib; Cyclo, cyclophosphamide; Dara, daratumumab; DaraRd, daratumumab, lenalidomide, low dose dexamethasone; DaraVD, daratumumab, bortezomib, dexamethasone; Dex, dexamethasone; Elo, elotuzumab; EloRd, elotuzumab, lenalidomide, low dose dexamethasone; EloVD, elotuzumab, bortezomib, dexamethasone; IMiD, immunomodulatory drug; Ixa, izaxomib; IxaRd, izaxomib, lenalidomide, low dose dexamethasone; Kd, carfilzomib, low dose dexamethasone; KRd, carfilzomib, lenalidomide, low dose dexamethasone; PanoVD, panobinostat, bortezomib, dexamethasone; Rd, lenalidomide, low-dose dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone; Vd, bortezomib, low dose dexamethasone.