We provide an overview on soft-tissue extramedullary plasmacytomas (EMPs) in multiple myeloma (MM). We reviewed the incidence of EMPs in MM, myeloma bone marrow homing, possible mechanisms of extramedullary spread, and prognosis and response to therapy. The incidence of EMPs is 7% to 18% at MM diagnosis and up to 20% at relapse. The current notion that EMPs are more frequent after treatment with novel agents remains to be proven, especially considering that different patterns of disease recurrence can emerge as patients live longer in the era of novel drugs. Bone marrow genetic abnormalities are not associated with extramedullary spread per se, which also suggests that microenvironmental interactions are key. Possible mechanisms of extramedullary spread include decreased adhesion molecule expression and downregulation of chemokine receptors. EMPs usually show plasmablastic morphology with negative CD56 expression. High-dose therapy with autologous stem-cell transplantation (ASCT) can overcome the negative prognostic impact of extramedullary disease in younger selected patients. EMPs do not typically respond to thalidomide alone, but in contrast, responses to bortezomib have been reported. The incidence of EMPs in patients with MM is high and is associated with poor outcome in patients treated conventionally. A potential first-line treatment option seems to be a bortezomib-containing regimen followed by ASCT, whenever possible. Experimental studies on the mechanisms of myeloma cell adhesion, myeloma growth at extramedullary sites, and drug sensitivity are priorities for this area of continuing therapeutic challenge.

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes.

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography–computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.

The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group [ECOG] score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m², or melphalan 140 mg/m² plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant [NS]), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS.

Key Points: VRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.

Summary.  Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M‐protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M‐protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non‐evolving SMM (n = 26) with stable M‐protein that abruptly increases when symptomatic MM develops. Thirty‐four patients developed symptomatic MM. The median time to progression in the overall series was 3·2 years and the only feature associated with a shorter time to progression was the evolving versus non‐evolving type (1·3 vs. 3·9 years respectively, P = 0·007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty‐seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8·2 and 3·5 years respectively.