Abstract

Background: There are few data on the incidence and prognosis of extramedullary (EM) multiple myeloma (MM). There are concerns about a possible increase of EM relapses with the expanding use of high-dose therapy (HDT) and biological agents.

Patients and methods: The incidence of EM disease, its relationship with prior exposure to HDT or novel agents, and its prognostic impact were analyzed in 1003 MM patients. Based on the different therapies available, three periods were considered: 1971–1993, conventional-dose chemotherapy; 1994–1999, HDT for younger patients; and 2000–2007, introduction of novel agents.

Results: Overall, 13% of patients had EM disease, 7% at diagnosis and 6% later. In the 2000–2007 period, there was a significant increase of EM involvement, at diagnosis (P = 0.02) and during follow-up (P = 0.03). The risk of EM spread was not significantly increased after HDT [hazard ratio (HR 0.6)], bortezomib (HR 1.62), or thalidomide/lenalidomide (HR 1.07). EM disease was associated with shorter overall (HR 3.26, P < 0.0001) and progression-free (HR 1.46, P = 0.04) survival.

Conclusions: The incidence of EM disease has increased, probably due to the availability of more sensitive imaging techniques and the prolongation of patients’ survival. HDT or novel agents seem not to increase the risk of EM disease. EM involvement confers a poor prognosis.

introduction

Multiple myeloma (MM) is characterized by an uncontrolled proliferation of plasma cells, usually restricted to the bone marrow. Extramedullary (EM) spread of MM may occur either at diagnosis or during the course of the disease. Few studies have systematically evaluated the incidence, the presenting features, and the prognosis of EM MM [1–3].

Although MM remains incurable with current approaches, a significant improvement of survival has been obtained with the introduction of high-dose therapy (HDT) and novel agents such as thalidomide (Thalomid®; Celgene Corp., Summit, NJ), its analogue lenalidomide (Revlimid®; Celgene Corp.), and bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceuticals Research and Development, L.L.C., Raritan, NJ) [4, 5]. In recent years, a high incidence of EM relapses has been reported after autologous and allogeneic stem-cell transplantation (SCT) [6–12] or during treatment with thalidomide [13, 14], raising concerns about the possible increase of EM relapses with the expanding use of transplant and biological agents.

The aims of this study were (i) to evaluate the cumulative incidence of EM MM in a large cohort of patients diagnosed over a 40-year period and to assess variations over time; (ii) to investigate the possible relationship between the use of HDT or novel agents and EM spread of disease; and (iii) to assess the prognostic impact of EM involvement.

patients and methods

One-thousand and three consecutive MM patients diagnosed at our institution from January 1971 to December 2007 were included in the analysis. The study was approved by the institutional review board and conducted in accordance with the Helsinki Declaration of 1964, as revised in 2000. Baseline data were extracted from databases and medical records. Follow-up information was collected at each visit. Cytogenetic data were available only in a minority of patients and were not considered in this analysis. All patients were human immunodeficiency virus negative. The incidence of EM disease was evaluated throughout three periods of time corresponding to the different therapeutic strategies available: 1971–1993, conventional-dose chemotherapy (CDT); 1994–1999, HDT as up-front treatment of patients aged <65 years; and 2000–2007, introduction of novel agents. Durie and Salmon criteria were used for diagnosis and staging [15]. The International Staging System was retrospectively applied to those patients for whom albumin and β2-microglobulin at diagnosis were available [16]. Response to therapy was assessed according to the European Group for Bone Marrow Transplant registry/International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry criteria [17]. Complete response is defined as negative immunofixation on the serum and urine, less than 5% plasma cells in the bone marrow and disappearance of any soft tissue plasmacytomas if present at baseline; partial response is defined as ≥50% reduction of serum M-protein, reduction in urinary M-protein by ≥90% or to <200 mg per 24 hours, and, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas. EM disease in patients with MM was defined as the presence of plasma cell tumor outside the bone marrow, either in the form of soft-tissue mass spreading from bone or arising in extraosseous organs. Patients with solitary plasmacytoma were excluded. The presence of EM disease was diagnosed in most cases by magnetic resonance imaging (MRI) or computed tomography (CT) scan, which were carried out whenever an EM spread of disease was suspected on the basis of clinical or radiographic findings. In a few patients (9%) observed in the first period of the study, EM disease was diagnosed by physical examination and X-rays. Histologic confirmation was obtained whenever possible.

statistical analysis

The prevalence of EM disease at diagnosis was estimated according to the binomial model and differences between consecutive periods of study were evaluated by means of the chi-square test for comparisons of proportions. The person-time incidence rate of EM relapses during follow-up was calculated dividing the number of events by the total person-years observed within each period of study. The Poisson model was used to compare the incidence of EM disease throughout the three periods of study. The occurrence of EM disease during follow-up was analyzed with survival techniques, accounting for dependence of events occurring to the same patient. Potential risk factors for the development of EM disease during follow-up were examined using a Cox proportional hazards model. Progression-free survival (PFS) and overall survival (OS) were evaluated with the Kaplan–Meier product-limit method. PFS was calculated from the date of diagnosis to the date of disease progression, or last follow-up for censored cases. OS was calculated from the date of diagnosis to death or last follow-up for censored cases. The Gehan–Wilcoxon test was used to compare survival curves. The prognostic effect of EM involvement was assessed by means of Cox proportional hazards regression, considering EM disease as a time-dependent covariate. All analyses were carried out using Statistica 7.1 (Statsoft Inc., Tulsa, OK) software, Stata 9 (StataCorp LP, College Station, TX) software, and Microsoft Excel. A P value ≤0.05 was considered statistically significant.

results

The median follow-up of the entire MM population was 30 months (range 1–338), corresponding to 3850 person-years. Overall, 132 of 1003 patients (13%) had EM disease at the time of diagnosis or during follow-up. Histologic examination of EM mass was done in 72 of 132 cases (54%). EM biopsy was obtained more frequently at diagnosis (54 of 76 patients, 71%), than during the course of the disease (18 of 56 patients, 32%). Nine of 132 patients (7%) had concurrent or subsequent plasma cell leukemia. Table 1 shows the main presenting features of MM patients with or without EM involvement. EM MM was associated with younger age and higher prevalence of male gender. A prior history of monoclonal gammopathy of undetermined significance (MGUS) was less frequent in patients with EM MM. Nonsecretory subtype, λ chain expression, advanced stage, and extensive bone disease were significantly more common in EM MM.

Table 1.

Presenting features of MM patients according to the presence of EM disease

Characteristics at diagnosis Patients with EM disease (n = 132) Patients without EM disease (n = 871) P value 
Age (years), median (range) 58 (31–80) 60 (26–87) 0.03 
Sex, male/female ratio 1.9 1.1 0.007 
Prior MGUS, % of patients 18 38 <0.0001 
Type of myeloma, % of patients    
    IgG 60 65 NS 
    IgA 19 21 NS 
    IgM <1 NS 
    IgD <1 NS 
    Light chain 11 12 NS 
    Nonsecretory 0.0001 
Type of light chain, k/λ ratio 1.1 1.8 0.02 
Stage (Durie–Salmon), % of patients    
    I 21 37 <0.0001 
    II 15 
    III 70 48 
International Staging System, % of patients    
    I 40 33 NS 
    II 39 44 
    III 21 23 
Hemoglobin (g/dl), median (range) 12.7 (4–15.8) 10.6 (7–14.8) NS 
Serum M-protein (g/dl), median (range) 3.36 (0.5–11.4) 1.4 (0.1–12.3) NS 
Urine M-protein (g/l), median (range) 0.3 (0–4.3) 0.4 (0–30.8) NS 
Bone marrow plasma cells, % 35 (5–100) 40 (1–100) NS 
No. of lytic bone lesions    
    None 25 52 <0.0001 
    <3 14 14 
    ≥3 61 34 
Characteristics at diagnosis Patients with EM disease (n = 132) Patients without EM disease (n = 871) P value 
Age (years), median (range) 58 (31–80) 60 (26–87) 0.03 
Sex, male/female ratio 1.9 1.1 0.007 
Prior MGUS, % of patients 18 38 <0.0001 
Type of myeloma, % of patients    
    IgG 60 65 NS 
    IgA 19 21 NS 
    IgM <1 NS 
    IgD <1 NS 
    Light chain 11 12 NS 
    Nonsecretory 0.0001 
Type of light chain, k/λ ratio 1.1 1.8 0.02 
Stage (Durie–Salmon), % of patients    
    I 21 37 <0.0001 
    II 15 
    III 70 48 
International Staging System, % of patients    
    I 40 33 NS 
    II 39 44 
    III 21 23 
Hemoglobin (g/dl), median (range) 12.7 (4–15.8) 10.6 (7–14.8) NS 
Serum M-protein (g/dl), median (range) 3.36 (0.5–11.4) 1.4 (0.1–12.3) NS 
Urine M-protein (g/l), median (range) 0.3 (0–4.3) 0.4 (0–30.8) NS 
Bone marrow plasma cells, % 35 (5–100) 40 (1–100) NS 
No. of lytic bone lesions    
    None 25 52 <0.0001 
    <3 14 14 
    ≥3 61 34 

MM, multiple myeloma; EM, extramedullary; MGUS, monoclonal gammopathy of undetermined significance; NS, not significant.

EM disease at diagnosis

Overall, 76 of 1003 MM patients (7%) had EM disease at the time of diagnosis of MM. The prevalence of EM involvement at diagnosis was substantially stable in the first and second period of the study (1971–1993: 4%, 1994–1999: 6%, P = 0.28), while it increased significantly thereafter (2000–2007: 12%, P = 0.02). The majority of patients (64 of 76, 84%) had a single plasmacytoma. Sites involved were soft tissues surrounding the axial skeleton in 85% of cases. Plasmacytomas of lymph nodes, liver, kidney, airways, skin, and breast, accounted for 15% of cases. Induction therapy consisted of CDT in 56 patients (74%) and novel agents in 20 (26%). After induction, 57 patients (35%) received HDT. Radiotherapy (RT) on plasmacytoma was delivered in 38 patients (50%). Of 72 assessable patients, 54 (72%) achieved at least a partial response, including 11 (15%) complete responses all achieved after HDT. Patients presenting with EM disease at diagnosis were at higher risk of subsequent EM relapses [hazard ratio (HR) 13].

EM disease during follow-up

Overall, 56 of 1003 MM patients (6%) showed EM spread during follow-up, after a median time of 19 months from diagnosis (range 2–143). In addition, 34 of the 76 patients with EM disease at diagnosis had further EM relapses. The total number of events observed during the course of the disease was 128. The incidence of EM localizations during follow-up increased from 6.5 × 1000 person-years in the period 1971–1993 to 15.4 × 1000 person-years in the period 1994–1999 (P = 0.055), up to 48.4 × 1000 person-years in the period 2000–2007 (P = 0.03). The mean time from diagnosis to the onset of EM spread was significantly longer in the period 2000–2007 as compared with previous periods (34.6 versus 18.9 months, P = 0.03). Plasmacytomas were localized in soft tissues surrounding the skeleton in 72% of cases, and in the remaining 28% involved other sites (airways, skin, central nervous system, liver, lymph nodes, breast, testis, and gastrointestinal tract). In 21 of 128 cases (16%), EM spread involved multiple sites and in 50 (39%) was not associated with marrow progression. Patients developing EM disease during follow-up showed significantly lower levels of serum M-protein and hemoglobin and higher levels of lactate dehydrogenase (LDH) compared with patients with EM at diagnosis (Table 2). In multivariate analysis, the risk of EM spread was not increased by prior HDT (HR 0.6) or treatment with bortezomib (HR 1.62) or thalidomide/lenalidomide (HR 1.07). Systemic treatment of EM disease consisted of CDT (69% of cases), novel agents (14%), or both (17%). RT was delivered in 57 of 128 EM relapses (44%). An objective response was achieved in 34% of cases.

Table 2.

Disease characteristics according to the time of EM disease

Characteristics EM at diagnosis (n = 76) EM during follow-up (n = 56) P value 
Hemoglobin (g/dl), median (range) 12.7 (3–15.8) 11.5 (7–14.8) 0.02 
Serum albumin (g/dl), median (range) 4 (2.9–4.9) 3.7 (2–5.2) NS 
Serum M-protein (g/dl), median (range) 3.3 (0.5–11.4) 1.6 (0.2–12.3) 0.02 
Urine M-protein (g/l), median (range) 0.3 (0–4.3) 0.3 (0–2.6) NS 
Bone marrow plasma cells (%) 35 (5–100) 40 (3–100) NS 
No. of lytic bone lesions (% of patients)    
    0 23 14 NS 
    1–3 16 14 
    >3 61 73 
β2-microglobulin (μg/l) 2780 (1439–11 700) 3560 (445–23 600) NS 
LDH (U/l) 314 (113–1188) 505 (127–7960) 0.009 
Characteristics EM at diagnosis (n = 76) EM during follow-up (n = 56) P value 
Hemoglobin (g/dl), median (range) 12.7 (3–15.8) 11.5 (7–14.8) 0.02 
Serum albumin (g/dl), median (range) 4 (2.9–4.9) 3.7 (2–5.2) NS 
Serum M-protein (g/dl), median (range) 3.3 (0.5–11.4) 1.6 (0.2–12.3) 0.02 
Urine M-protein (g/l), median (range) 0.3 (0–4.3) 0.3 (0–2.6) NS 
Bone marrow plasma cells (%) 35 (5–100) 40 (3–100) NS 
No. of lytic bone lesions (% of patients)    
    0 23 14 NS 
    1–3 16 14 
    >3 61 73 
β2-microglobulin (μg/l) 2780 (1439–11 700) 3560 (445–23 600) NS 
LDH (U/l) 314 (113–1188) 505 (127–7960) 0.009 

EM, extramedullary; LDH, lactate dehydrogenase; NS, not significant.

outcome of patients with and without EM disease

At the time of the analysis, 340 of 1003 patients (34%) were alive, with a median follow-up of 36 months. The median OS of the MM population included in the study was 32 months for patients diagnosed in the period 1971–1993, 45 months in the period 1994–1999, and 54 months in the period 2000–2007 (P = 0.001). Patients presenting EM involvement at diagnosis had significantly shorter PFS as compared with the rest of MM population (18 versus 30 months, P = 0.003) (Figure 1), while the median OS was not statistically different between the two groups (36 and 43 months, respectively, P = 0.36) (Figure 2). By time-dependent analysis, the presence of EM disease at any time in the course of the disease was associated with significantly shorter OS (HR 3.26, P < 0.0001) and PFS (HR 1.46, P = 0.04). In multivariate analysis, the presence of EM disease retained the negative prognostic impact on OS and PFS even after adjusting for age, sex and stage (HR 3.6 and 1.5, respectively). We evaluated the outcome of patients with EM disease at diagnosis according to treatment received. In the 208 MM patients treated with HDT, the presence of EM involvement did not significantly affect PFS (P = 0.08) and OS (P = 0.17). Among patients who did not receive HDT, those with EM disease had a significantly worse PFS (P = 0.001). OS was comparable (P = 0.16).

Figure 1.

Progression-free survival according to the presence of extramedullary (EM) involvement at diagnosis.

Figure 1.

Progression-free survival according to the presence of extramedullary (EM) involvement at diagnosis.

Figure 2.

Overall survival according to the presence of extramedullary (EM) involvement at diagnosis.

Figure 2.

Overall survival according to the presence of extramedullary (EM) involvement at diagnosis.

discussion

This study describes the incidence, the presenting features, and the outcome of EM myeloma in a large cohort of MM patients diagnosed and followed in a single institution. Overall, 13% of patients had EM involvement (7% at diagnosis and 6% during follow-up). Few studies have systematically evaluated the incidence of EM disease in MM [1–3]. In two studies by Bladé et al., EM involvement was reported in 15%–20% of patients at diagnosis and in an additional 15% during follow-up. Of note, the first of these studies [1] focuses on 53 patients with IgD MM, a subtype known to be associated with a higher frequency of EM disease [18, 19]. The second study [2] describes a series of 72 MM patients aged <40 years, another subset with high incidence of EM involvement. In fact, in a recent survey on 3600 MM patients of the Taiwan National Cancer Registry [20], the prevalence of EM MM was significantly higher in patients aged ≤55 years. Also in our series, the median age of patients with EM MM was significantly lower as compared with the rest of MM population.

This study shows a statistically significant increase of EM involvement, both at diagnosis and during follow-up, in more recent years. The widespread use of more sensitive imaging techniques such as CT scan and MRI may partially explain this finding. Other factors, however, may contribute to the increase of EM involvement during follow-up. In fact, the use of HDT [21, 22] and the introduction of novel agents such as thalidomide, bortezomib and lenalidomide, along with better supportive care, led to significant improvement of survival in the last years. In a study conducted at the Mayo Clinic, median OS of patients diagnosed after 1996 was 44.8 months as compared with 29.9 months for patients diagnosed before (P < 0.001) [5]. A Swedish study showed a progressive increase of OS from 1973 to 2003, with a maximum improvement after 1993 [4]. Similarly, in our series, OS was significantly longer in patients diagnosed after 1994 as compared with those diagnosed before. Then, it is conceivable that the significant increase of EM relapses during follow-up observed in recent years reflects prolongation of patients’ survival. The longer interval from diagnosis to EM spread seen in the last period is consistent with this hypothesis.

Some authors reported high incidence of EM relapses after autologous or allogeneic SCT [6–12]. In a study of the Spanish Registry, 14% of patients relapsing after autologous SCT had EM manifestations, with minimal or absent monoclonal protein, indicating the existence of sanctuary sites not reached by intensive chemoradiotherapy [8]. In a study on 70 MM patients receiving reduced-intensity allogeneic SCT, one-third had EM relapse in absence of marrow progression. Since the incidence of isolated EM relapse was higher among patients with chronic graft-versus-host disease, the authors hypothesized that the graft-versus-myeloma effect may control bone marrow disease, while plasma cells outside the bone marrow may escape immune control [12]. There are no studies, however, comparing the risk of EM relapse after HDT and CDT. In our analysis, the incidence of EM relapses was not increased in patients receiving HDT as compared with other treatments.

The introduction of thalidomide, bortezomib, and lenalidomide has expanded the therapeutic armamentarium for MM [23–27]. Some reports indicate low efficacy of thalidomide on EM disease, even in patients with good serological and marrow response, indicating that this agent needs the bone marrow microenvironment to exert its anti-MM effect [28, 29]. In addition, some patients had EM spread while on treatment with thalidomide [13, 14]. These observations have raised concerns about a possible increase of EM relapses with the expanding use of novel agents [30]. Although it is not possible to draw definitive conclusions due to the small number and the relatively short follow-up of patients treated with thalidomide, lenalidomide or bortezomib, in this study the risk of EM relapse seems not increased by prior exposure to these drugs. The presence of EM disease at diagnosis was the only significant risk factor for subsequent EM recurrence, indicating that inherent biological characteristics of the disease rather than treatment are responsible for EM spread.

The analysis of the presenting features of EM MM shows significant differences from the rest of the MM population as regards age, sex, MM subtype, disease stage, and prior history of MGUS. In addition, patients who developed EM spread during follow-up showed significantly lower hemoglobin and M-protein and higher LDH levels compared with those with EM disease at diagnosis. Prior studies showed that high LDH levels are associated with extraosseous disease, unusual aggressive course and short survival [31, 32] in MM patients. Interestingly, Dawson et al. [33] recently reported three MM patients with EM relapse associated with a shift from secretion of intact immunoglobulins to free light chains only. This syndrome, called ‘light chain escape from plateau phase’ (LEPP), was characterized by multiple EM sites of relapse, plasmablastic features, renal failure, high LDH and β2-microglobulin levels, and aggressive clinical course. The authors hypothesized that LEPP results from clonal selection and expansion of precursors that have lost the ability to secrete intact immunoglobulins while acquiring stromal independence and ability to spread outside the bone marrow. Since LEPP occurred after treatment with thalidomide or lenalidomide, the authors indicated that this pattern of relapse may derive from the effect of novel agents on bone marrow microenvironment. Although our patients with EM occurring during follow-up share some of these features, including the aggressive clinical course, we did not find a relationship between EM spread of disease and prior exposure to novel agents.

Data on the prognostic impact of EM involvement in MM are limited and controversial. In a report on 19 patients with EM and extraosseous MM, the disease had an aggressive course, with a median OS of 15 months [3]. Terpos et al. [11] observed that isolated EM relapses after HDT were almost invariably followed by systemic progression with short OS. On the contrary, in a study on 78 patients relapsing after autologous or allogeneic SCT, the outcome of patients with EM or medullary relapse was not significantly different, both in the autologous and in the allogeneic setting [10]. In a time-dependent analysis, this study shows that the presence of EM involvement at any time during the course of disease is associated with shorter PFS and OS, even after adjusting for age, sex, and stage.

At the best of our knowledge, there are no studies focusing on treatment of MM patients with EM disease. Some clinical reports indicate a low efficacy of thalidomide on EM disease [28, 29], while bortezomib seems more promising in this setting [34, 35]. The role of RT, which is the standard treatment of solitary plasmacytoma, is much less defined in MM with EM disease, where RT is usually associated with systemic treatment with chemotherapy or novel agents. Studies aimed at defining the best therapeutic strategy for EM MM are needed.

In conclusion, the higher incidence of EM disease observed in recent years is probably due to the increasing use of more sensitive imaging techniques. However, the prolongation of patients’ survival with new treatment strategies and better supportive care could contribute to the increase of EM involvement observed during follow-up. The risk of EM spread of disease seems not to be influenced by prior exposure to HDT or novel agents. The presence of EM involvement negatively affects survival.

disclosures

The authors of this article do not have any conflict of interest to declare.

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