Leukemia & Lymphoma, July 2014; 55(7): 1687–1690 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.853296
LETTER TO THE EDITOR
Autologous stem cell transplant can overcome poor prognosis in patients with multiple myeloma with extramedullary plasmacytoma Jian Li1, Kai-Ni Shen1, Wen-Rong Huang2, Li-Hong Li3, Huan Chen4, Wen-Ming Chen3, Kai-Yan Liu4, Li Yu2 & Dao-Bin Zhou1 1Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, People’s Republic of China, 2Department of Hematology, Chinese PLA General Hospital, Beijing, People’s Republic of China, 3Department of Hematology, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China and 4Department of Hematology, Peking University People’s Hospital, Beijing, People’s Republic of China
Multiple myeloma (MM) is a malignant condition of plasma cells, usually confined to the bone marrow. Under certain circumstances, extramedullary plasmacytomas (EMPs) may develop as a result of direct spread from the bone or hematogenous metastasis. About 7–18% of newly diagnosed myelomas are complicated by plasma cell tumors outside the bone marrow, with an additional incidence of EMP of 20% later during the course of the disease [1–4]. In spite of the increasing incidence of extramedullary disease, few studies have investigated the clinical features and prognosis of MM with EMP. Varettoni et al. [1], Wu et al. [2] and Usmani et al. [5] demonstrated that patients with MM without extramedullary involvement had better long-term outcomes than those with EMPs. However, these studies did not restrict the treatment strategy. Since transplant has become first-line therapy for MM in patients younger than 65 years, the use of high-dose therapy (HDT) may be promising for patients with MM with EMP. Therefore we conducted a retrospective analysis of patients with MM with EMP at the time of their initial diagnosis and investigated the effect of autologous stem cell transplant (ASCT) on their prognosis. One hundred and forty-nine patients with MM who underwent ASCT from 1 January 2005 to 31 December 2011 were included. Of these, 28 had confirmed EMP when MM was initially diagnosed, which was defined as a mass of neoplastic monoclonal plasma cells in the soft tissue surrounding the bones or extraosseous organs, while solitary and bony plasmacytomas were excluded. Myeloma response and relapse before or after transplant were assessed based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Differences in continuous and dichotomous variables were tested by Student’s t-test and χ2 test, respectively. Improvements of response status after ASCT were evaluated through the McNemar test. All tests were
two-sided with p-values of less than 0.05 considered to be statistically significant. Survival curves were plotted according to the method of Kaplan and Meier, and between-group comparisons of progression-free survival (PFS) and overall survival (OS) were done with the log-rank test. Prognostic factors for PFS and OS were analyzed by a Cox proportional hazards model. Twenty-eight of 149 patients had extramedullary involvement at the initial diagnosis of MM (median age 53.5 years, male/female 1:1). Table I outlines the clinical and laboratory features of patients with EMP. Soft tissue masses arising from the bone were most common (82.1%), including vertebrae (39.3%), rib (14.3%), clavicle (7.1%), inferior maxilla (7.1%), maxillae (3.6%), pelvis (3.6%), sternum (3.6%) and sternoclavicular joint (3.6%). Other locations with hematogenous spread included the pleura (n ⫽ 1), mediastinum (n ⫽ 1), liver (n ⫽ 2) and stomach (n ⫽ 1). Extramedullary involvement was found to be associated only with lower International Staging System (ISS) stage at the time of diagnosis of MM (p ⫽ 0.003). In the EMP group, most patients (71.4%) received a bortezomib-based regimen as induction chemotherapy. Sixteen (57.1%) patients in the EMP group and 82 (70.7%, response status of five patients unknown) in the non-EMP group achieved at least a very good partial response (VGPR) (p ⫽ 0.168). EMP in 19 (67.9%) patients with MM disappeared after induction; 14 of them received bortezomib-based frontline therapy and the response rate of extramedullary disease to bortezomib-based therapy reached 70%. All patients underwent ASCT after induction chemotherapy with a conditioning regimen of melphalan alone or melphalan plus bortezomib. Ruling out the two patients with unknown response status, the two groups responded comparably well to HDT, with 46.6% complete response (CR), 35.7%
J.L., K.-N.S. and W.-R.H. contributed equally to this study. Correspondence: Dao-Bin Zhou, Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China. Tel: 86-10-69155020. Fax: 86-10-69158291. E-mail: [email protected] Received 13 May 2013; revised 27 August 2013; accepted 3 October 2013
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Table I. Demographic and disease characteristics of patients with multiple myeloma with or without EMP at the time of diagnosis. Characteristic Age, years, median (range) Sex, M/F M-protein type, n (%) IgG IgA Light chain alone IgD Non-secretory Unknown Durie–Salmon stage, n (%) I II III Unknown ISS disease stage, n (%) I II III Unknown FISH analysis for cytogenetic abnormalities, n (%) ⫹ 1q21* del(13qRB1)† del(13qDS)† Translocation at IgH locus‡ del(17p)§ Serum creatinine, μmol/L, median (range) Serum albumin, g/L, median (range) CD34 cells, ⫻ 106/kg, median (range) Neutrophil engraftment time, days, median (range) Platelet engraftment time, days, median (range)
Non-EMP (n ⫽ 121)
EMP (n ⫽ 28) 53.5 (31–66) 14/14
Total (n ⫽ 149)
p-Value
53 (29–65) 69/52
53 (29–66) 83/66
NS NS
8 (28.6) 11 (39.3) 5 (17.9) 3 (10.7) 1 (3.6) 0 (0.0)
56 (46.3) 26 (21.5) 20 (16.5) 13 (10.7) 1 (0.8) 5 (4.1)
64 (43.0) 37 (24.8) 25 (16.8) 16 (10.7) 2 (1.3) 5 (3.4)
NS NS NS NS NS
0 (0.0) 5 (17.9) 23 (82.1) 0 (0.0)
2 (1.7) 16 (13.2) 97 (80.2) 6 (5.0)
2 (1.3) 21 (14.1) 120 (80.5) 6 (4.0)
NS NS NS
12 (42.9) 7 (25.0) 7 (25.0) 2 (7.1)
21 (17.4) 46 (38.0) 46 (38.0) 8 (6.6)
33 (22.1) 53 (35.6) 53 (35.6) 10 (6.7)
0.003 NS NS
2 (7.1) 4 (14.3) 4 (14.3) 6 (21.4) 1 (3.6) 85.0 (42.1–130.0) 36.0 (21.0–47.0) 3.40 (1.04–12.06) 11 (10–13) 11 (8–42)
10 (8.3) 6 (5.0) 5 (4.1) 20 (16.5) 6 (5.0) 79.7 (28.8–813.1) 33.0 (17.8–81.0) 3.185 (0.58–16.27) 11 (8–31) 12 (1–43)
12 (8.1) 10 (6.7) 9 (6.0) 26 (17.4) 7 (4.7) 81.0 (28.8–813.1) 34.0 (17.8–81.0) 3.335 (0.58–16.27) 11 (8–31) 12 (1–43)
NS NS NS NS NS NS NS NS NS NS
EMP, extramedullary plasmacytoma; F, female; FISH, fluorescence in situ hybridization; Ig, immunoglobulin; ISS, International Staging System; M, male; NS, not significant. *12 patients with EMP and 37 without EMP were available for assessment. †12 patients with EMP and 33 without EMP were available for assessment. ‡10 patients with EMP and 43 without EMP were available for assessment. §11 patients with EMP and 43 without EMP were available for assessment.
VGPR and 14.3% partial response (PR) in the EMP group, and 57.1% CR, 30.3% VGPR and 10.9% PR in the non-EMP group. In the EMP group, seven patients who were in CR before HDT maintained CR after autograft, whereas one patient progressed. Among the 20 patients who had not achieved CR after chemotherapy, six upgraded to CR after ASCT. Eight patients with less than VGPR improved their response status to better than VGPR. McNemar test confirmed the favorable impact of ASCT on the enhancement rate of VGPR (p ⫽ 0.039). Overall, the possibility of improving from less than CR before ASCT to CR after ASCT was similar between the EMP and non-EMP groups (p ⫽ 0.569). After transplant, the extramedullary lesions of three patients (soft tissue surrounding rib, pelvis and mediastinum) disappeared. One patient whose liver plasmacytoma responded completely to induction therapy relapsed after ASCT, in the same location. After a median follow-up period of 23 (range 3–79) months, 14 (50%) patients in the EMP group and 40 (33.3%) in the non-EMP group progressed. Disease status data was lost for one patient in the latter group, who was excluded from the analysis. Although there was no statistical difference in PFS between groups after transplant (p ⫽ 0.202), the 3-year PFS was higher in the non-EMP group (53.0% and 33.1%, respectively) and the median PFS was longer than in the EMP group (58 months vs. 26 months). Five (17.9%) patients in the EMP group and 20 (16.5%) in the nonEMP group died during the follow-up period. The OS was
comparable between groups (p ⫽ 0.456) with a 3-year OS of 79.3% and 78.5%, respectively. Median OS was not reached in the EMP group and was 67 months among patients without extramedullary disease at the time of diagnosis (Figure 1). ISS stage, Durie–Salmon stage, response status before and after HDT, serum creatinine, cytogenetic abnormalities and maintenance therapy were assessed for their influence on OS and PFS. OS was related to none of the above-mentioned factors. As for PFS, CR status after transplant was confirmed to be the only independent factor predicting a better prognosis (hazard ratio [HR] ⫽ 0.159, 95% confidence interval [CI] 0.043–0.593, p ⫽ 0.006). Survival of patients with EMPs arising from hematogenous metastasis and osseous extension was further analyzed separately. These two groups of patients showed similar demographic and clinical characteristics, without significant difference in PFS and OS (p ⫽ 0.241 and p ⫽ 0.920, respectively). However, the median PFS of the five patients with EMP from hematogenous dissemination was shorter (16 months vs. 33 months). Based on our study results, 28 (18.8%) patients had extramedullary manifestations at the time of MM diagnosis. As indicated in prior articles [1,2], 68–85% EMPs arose as the result of direct spread from adjacent bone lesions (82.1% in our cohort). This special group of patients shared almost the same clinical features compared to those without EMP when first diagnosed with MM, except that the EMP group
Letter to the Editor 1689
Figure 1. (a) Progression-free survival after transplant in patients with multiple myeloma with or without EMP at diagnosis (EMP n ⫽ 28, nonEMP n ⫽ 120). (b) Overall survival after transplant in patients with multiple myeloma with or without EMP at diagnosis (EMP n ⫽ 28, nonEMP n ⫽ 121).
was associated with a more favorable ISS stage at diagnosis (p ⫽ 0.003), in accordance with a study by Wu et al. [2]. The better ISS stage in patients with extramedullary disease might also partly explain their improved survival after ASCT. As discussed, extramedullary lesions are quite sensitive to bortezomib-based treatment. The effectiveness of thalidomide in soft tissue extramedullary disease has been challenged [6,7], since it might alter the expression of adhesion molecules, such as CD56 and Syndecan-1, thus interfering with homing of neoplastic cells to the bone marrow microenvironment [7]. Unlike thalidomide, bortezomib is more likely to exert a favorable anti-EMP effect through extensive tissue penetration [8,9]. The role of lenalidomide
in managing patients with MM with extramedullary disease is also promising. Since most conclusions have been based on the relapse setting, case reports or small sample clinical trials, further investigations of the efficacy of novel agents are required. We found no significant difference in response rate to pre-transplant chemotherapy, whether or not there was extramedullary involvement. Moreover, a substantial improvement in response status was seen after HDT in both groups, which confirms the feasibility and superiority of transplant in patients with MM complicated by EMP at diagnosis. Plasmacytomas of three patients responded to HDT and only one patient underwent relapse of extraosseous plasmacytoma after transplant, which means there was no significant EMP recurrence after transplant. Uncertainty has been raised whether novel treatment approaches such as thalidomide, bortezomib, ASCT and allogeneic stem cell transplant (Allo-SCT) would increase the possibility of EMP relapse [10–13]. Even though Minnema et al. [10] reported that 20.4% of patients had extramedullary disease relapse following Allo-SCT, this might be associated with inherent biological features of the disease rather than the therapeutic method, since they found that EMP recurrence was more common among patients with deletion of chromosome 13 (p ⫽ 0.06). Varettoni et al. [1] demonstrated the only risk factor for EMP relapse during follow-up to be the presence of extramedullary involvement at MM diagnosis, rather than treatment strategy. Besides, it could be that novel agents and transplant might increase survival long enough for patients to experience EMP relapse afterward. There have been no clinical trials focusing on treatment for patients with MM with EMP at initial diagnosis. The absence of a relationship between extramedullary disease and long-term prognosis in patients with MM after ASCT is consistent with prior research [1,2]. This particular variation has always been considered an indicator of more aggressive disease, resistance to conventional therapeutic options and poor prognosis [1,2,5]. ASCT as first-line therapy for patients younger than 65 years old, however, may reverse the negative influence of extramedullary spread on MM prognosis, and CR status posttransplant was a significant prognostic factor for predicting PFS among this group of people. EMPs from hematogenous spread are generally associated with plasmablastic morphology, which might indicate biological aggressiveness and a worse outcome [14,15]. Our study found that ASCT resulted in a comparable outcome of patients with MM with EMP from hematogenous metastasis to those with EMP arising from focal bone, which would be a further demonstration of the superiority of transplant among these patients. Nevertheless, the number of subjects with EMP in our study was relatively small, and thus further studies would be necessary. In conclusion, a bortezomib-containing induction regimen followed by HDT would be the optimal treatment schedule for patients with MM with EMP at the time of initial presentation, without increasing the rate of EMP recurrence. Further studies are necessary to address whether ASCT is equally effective in patients with MM with EMP arising from bone and patients with EMP from hematogenous metastasis.
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Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Varettoni M, Corso A , Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol 2010; 21:325–330. [2] Wu P, Davies FE, Boyd K , et al. The impact of extramedullary disease at presentation on the outcome of myeloma. Leuk Lymphoma 2009;50:230–235. [3] Blade J, Kyle RA , Greipp PR. Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol 1996;93:345–351. [4] Blade J, Lust JA , Kyle RA . Immunoglobulin-D multiple-myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol 1994;12:2398–2404. [5] Usmani SZ, Heuck C, Mitchell A , et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica 2012;97:1761–1767. [6] Rosinol L, Cibeira T, Blade J, et al. Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica 2004;89:832–836. [7] Avigdor A , Raanani P, Levi I, et al. Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma. Leuk Lymphoma 2001;42:683–687.
[8] Raanani P, Shpilberg O, Ben-Bassat I. Extramedullary disease and targeted therapies for hematological malignancies—is the association real? Ann Oncol 2007;18:7–12. [9] Rosinol L, Cibeira MT, Martinez J, et al. Thalidomide/dexamethasone (TD) vs. bortezomib (Velcade)â/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Velcadeâ as induction regimens prior autologous stem cell transplantation (ASCT) in multiple myeloma (MM): results of a phase III PETHEMA/GEM trial. Blood 2009;114(Suppl. 1): Abstract 130. [10] Minnema MC, van de Donk NWCJ, Zweegman S, et al. Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome. Bone Marrow Transplant 2008;41:779–784. [11] Ali R, Ozkalemkas F, Ozkan A , et al. Bortezomib and extramedullary disease in multiple myeloma: the shine and dark side of the moon. Leuk Res 2007;31:1153–1155. [12] Alegre A , Granda A , Martinez-Chamorro C, et al. Different patterns of relapse after autologous peripheral blood stem cell transplantation in multiple myeloma: clinical results of 280 cases from the Spanish Registry. Haematologica 2002;87:609–614. [13] Perez-Simon JA , Sureda A , Fernandez-Aviles F, et al. Reducedintensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia 2006;20:542–545. [14] Cerny J, Fadare O, Hutchinson L, et al. Clinicopathological features of extramedullary recurrence/relapse of multiple myeloma. Eur J Haematol 2008;81:65–69. [15] Blade J, de Larrea CF, Rosinol L, et al. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 2011;29:3805–3812.
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LETTER TO THE EDITOR
Autologous stem cell transplant can overcome poor prognosis in patients with multiple myeloma with extramedullary plasmacytoma Jian Li1, Kai-Ni Shen1, Wen-Rong Huang2, Li-Hong Li3, Huan Chen4, Wen-Ming Chen3, Kai-Yan Liu4, Li Yu2 & Dao-Bin Zhou1 1Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, People’s Republic of China, 2Department of Hematology, Chinese PLA General Hospital, Beijing, People’s Republic of China, 3Department of Hematology, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China and 4Department of Hematology, Peking University People’s Hospital, Beijing, People’s Republic of China
Multiple myeloma (MM) is a malignant condition of plasma cells, usually confined to the bone marrow. Under certain circumstances, extramedullary plasmacytomas (EMPs) may develop as a result of direct spread from the bone or hematogenous metastasis. About 7–18% of newly diagnosed myelomas are complicated by plasma cell tumors outside the bone marrow, with an additional incidence of EMP of 20% later during the course of the disease [1–4]. In spite of the increasing incidence of extramedullary disease, few studies have investigated the clinical features and prognosis of MM with EMP. Varettoni et al. [1], Wu et al. [2] and Usmani et al. [5] demonstrated that patients with MM without extramedullary involvement had better long-term outcomes than those with EMPs. However, these studies did not restrict the treatment strategy. Since transplant has become first-line therapy for MM in patients younger than 65 years, the use of high-dose therapy (HDT) may be promising for patients with MM with EMP. Therefore we conducted a retrospective analysis of patients with MM with EMP at the time of their initial diagnosis and investigated the effect of autologous stem cell transplant (ASCT) on their prognosis. One hundred and forty-nine patients with MM who underwent ASCT from 1 January 2005 to 31 December 2011 were included. Of these, 28 had confirmed EMP when MM was initially diagnosed, which was defined as a mass of neoplastic monoclonal plasma cells in the soft tissue surrounding the bones or extraosseous organs, while solitary and bony plasmacytomas were excluded. Myeloma response and relapse before or after transplant were assessed based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Differences in continuous and dichotomous variables were tested by Student’s t-test and χ2 test, respectively. Improvements of response status after ASCT were evaluated through the McNemar test. All tests were
two-sided with p-values of less than 0.05 considered to be statistically significant. Survival curves were plotted according to the method of Kaplan and Meier, and between-group comparisons of progression-free survival (PFS) and overall survival (OS) were done with the log-rank test. Prognostic factors for PFS and OS were analyzed by a Cox proportional hazards model. Twenty-eight of 149 patients had extramedullary involvement at the initial diagnosis of MM (median age 53.5 years, male/female 1:1). Table I outlines the clinical and laboratory features of patients with EMP. Soft tissue masses arising from the bone were most common (82.1%), including vertebrae (39.3%), rib (14.3%), clavicle (7.1%), inferior maxilla (7.1%), maxillae (3.6%), pelvis (3.6%), sternum (3.6%) and sternoclavicular joint (3.6%). Other locations with hematogenous spread included the pleura (n ⫽ 1), mediastinum (n ⫽ 1), liver (n ⫽ 2) and stomach (n ⫽ 1). Extramedullary involvement was found to be associated only with lower International Staging System (ISS) stage at the time of diagnosis of MM (p ⫽ 0.003). In the EMP group, most patients (71.4%) received a bortezomib-based regimen as induction chemotherapy. Sixteen (57.1%) patients in the EMP group and 82 (70.7%, response status of five patients unknown) in the non-EMP group achieved at least a very good partial response (VGPR) (p ⫽ 0.168). EMP in 19 (67.9%) patients with MM disappeared after induction; 14 of them received bortezomib-based frontline therapy and the response rate of extramedullary disease to bortezomib-based therapy reached 70%. All patients underwent ASCT after induction chemotherapy with a conditioning regimen of melphalan alone or melphalan plus bortezomib. Ruling out the two patients with unknown response status, the two groups responded comparably well to HDT, with 46.6% complete response (CR), 35.7%
J.L., K.-N.S. and W.-R.H. contributed equally to this study. Correspondence: Dao-Bin Zhou, Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China. Tel: 86-10-69155020. Fax: 86-10-69158291. E-mail: [email protected] Received 13 May 2013; revised 27 August 2013; accepted 3 October 2013
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Table I. Demographic and disease characteristics of patients with multiple myeloma with or without EMP at the time of diagnosis. Characteristic Age, years, median (range) Sex, M/F M-protein type, n (%) IgG IgA Light chain alone IgD Non-secretory Unknown Durie–Salmon stage, n (%) I II III Unknown ISS disease stage, n (%) I II III Unknown FISH analysis for cytogenetic abnormalities, n (%) ⫹ 1q21* del(13qRB1)† del(13qDS)† Translocation at IgH locus‡ del(17p)§ Serum creatinine, μmol/L, median (range) Serum albumin, g/L, median (range) CD34 cells, ⫻ 106/kg, median (range) Neutrophil engraftment time, days, median (range) Platelet engraftment time, days, median (range)
Non-EMP (n ⫽ 121)
EMP (n ⫽ 28) 53.5 (31–66) 14/14
Total (n ⫽ 149)
p-Value
53 (29–65) 69/52
53 (29–66) 83/66
NS NS
8 (28.6) 11 (39.3) 5 (17.9) 3 (10.7) 1 (3.6) 0 (0.0)
56 (46.3) 26 (21.5) 20 (16.5) 13 (10.7) 1 (0.8) 5 (4.1)
64 (43.0) 37 (24.8) 25 (16.8) 16 (10.7) 2 (1.3) 5 (3.4)
NS NS NS NS NS
0 (0.0) 5 (17.9) 23 (82.1) 0 (0.0)
2 (1.7) 16 (13.2) 97 (80.2) 6 (5.0)
2 (1.3) 21 (14.1) 120 (80.5) 6 (4.0)
NS NS NS
12 (42.9) 7 (25.0) 7 (25.0) 2 (7.1)
21 (17.4) 46 (38.0) 46 (38.0) 8 (6.6)
33 (22.1) 53 (35.6) 53 (35.6) 10 (6.7)
0.003 NS NS
2 (7.1) 4 (14.3) 4 (14.3) 6 (21.4) 1 (3.6) 85.0 (42.1–130.0) 36.0 (21.0–47.0) 3.40 (1.04–12.06) 11 (10–13) 11 (8–42)
10 (8.3) 6 (5.0) 5 (4.1) 20 (16.5) 6 (5.0) 79.7 (28.8–813.1) 33.0 (17.8–81.0) 3.185 (0.58–16.27) 11 (8–31) 12 (1–43)
12 (8.1) 10 (6.7) 9 (6.0) 26 (17.4) 7 (4.7) 81.0 (28.8–813.1) 34.0 (17.8–81.0) 3.335 (0.58–16.27) 11 (8–31) 12 (1–43)
NS NS NS NS NS NS NS NS NS NS
EMP, extramedullary plasmacytoma; F, female; FISH, fluorescence in situ hybridization; Ig, immunoglobulin; ISS, International Staging System; M, male; NS, not significant. *12 patients with EMP and 37 without EMP were available for assessment. †12 patients with EMP and 33 without EMP were available for assessment. ‡10 patients with EMP and 43 without EMP were available for assessment. §11 patients with EMP and 43 without EMP were available for assessment.
VGPR and 14.3% partial response (PR) in the EMP group, and 57.1% CR, 30.3% VGPR and 10.9% PR in the non-EMP group. In the EMP group, seven patients who were in CR before HDT maintained CR after autograft, whereas one patient progressed. Among the 20 patients who had not achieved CR after chemotherapy, six upgraded to CR after ASCT. Eight patients with less than VGPR improved their response status to better than VGPR. McNemar test confirmed the favorable impact of ASCT on the enhancement rate of VGPR (p ⫽ 0.039). Overall, the possibility of improving from less than CR before ASCT to CR after ASCT was similar between the EMP and non-EMP groups (p ⫽ 0.569). After transplant, the extramedullary lesions of three patients (soft tissue surrounding rib, pelvis and mediastinum) disappeared. One patient whose liver plasmacytoma responded completely to induction therapy relapsed after ASCT, in the same location. After a median follow-up period of 23 (range 3–79) months, 14 (50%) patients in the EMP group and 40 (33.3%) in the non-EMP group progressed. Disease status data was lost for one patient in the latter group, who was excluded from the analysis. Although there was no statistical difference in PFS between groups after transplant (p ⫽ 0.202), the 3-year PFS was higher in the non-EMP group (53.0% and 33.1%, respectively) and the median PFS was longer than in the EMP group (58 months vs. 26 months). Five (17.9%) patients in the EMP group and 20 (16.5%) in the nonEMP group died during the follow-up period. The OS was
comparable between groups (p ⫽ 0.456) with a 3-year OS of 79.3% and 78.5%, respectively. Median OS was not reached in the EMP group and was 67 months among patients without extramedullary disease at the time of diagnosis (Figure 1). ISS stage, Durie–Salmon stage, response status before and after HDT, serum creatinine, cytogenetic abnormalities and maintenance therapy were assessed for their influence on OS and PFS. OS was related to none of the above-mentioned factors. As for PFS, CR status after transplant was confirmed to be the only independent factor predicting a better prognosis (hazard ratio [HR] ⫽ 0.159, 95% confidence interval [CI] 0.043–0.593, p ⫽ 0.006). Survival of patients with EMPs arising from hematogenous metastasis and osseous extension was further analyzed separately. These two groups of patients showed similar demographic and clinical characteristics, without significant difference in PFS and OS (p ⫽ 0.241 and p ⫽ 0.920, respectively). However, the median PFS of the five patients with EMP from hematogenous dissemination was shorter (16 months vs. 33 months). Based on our study results, 28 (18.8%) patients had extramedullary manifestations at the time of MM diagnosis. As indicated in prior articles [1,2], 68–85% EMPs arose as the result of direct spread from adjacent bone lesions (82.1% in our cohort). This special group of patients shared almost the same clinical features compared to those without EMP when first diagnosed with MM, except that the EMP group
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Figure 1. (a) Progression-free survival after transplant in patients with multiple myeloma with or without EMP at diagnosis (EMP n ⫽ 28, nonEMP n ⫽ 120). (b) Overall survival after transplant in patients with multiple myeloma with or without EMP at diagnosis (EMP n ⫽ 28, nonEMP n ⫽ 121).
was associated with a more favorable ISS stage at diagnosis (p ⫽ 0.003), in accordance with a study by Wu et al. [2]. The better ISS stage in patients with extramedullary disease might also partly explain their improved survival after ASCT. As discussed, extramedullary lesions are quite sensitive to bortezomib-based treatment. The effectiveness of thalidomide in soft tissue extramedullary disease has been challenged [6,7], since it might alter the expression of adhesion molecules, such as CD56 and Syndecan-1, thus interfering with homing of neoplastic cells to the bone marrow microenvironment [7]. Unlike thalidomide, bortezomib is more likely to exert a favorable anti-EMP effect through extensive tissue penetration [8,9]. The role of lenalidomide
in managing patients with MM with extramedullary disease is also promising. Since most conclusions have been based on the relapse setting, case reports or small sample clinical trials, further investigations of the efficacy of novel agents are required. We found no significant difference in response rate to pre-transplant chemotherapy, whether or not there was extramedullary involvement. Moreover, a substantial improvement in response status was seen after HDT in both groups, which confirms the feasibility and superiority of transplant in patients with MM complicated by EMP at diagnosis. Plasmacytomas of three patients responded to HDT and only one patient underwent relapse of extraosseous plasmacytoma after transplant, which means there was no significant EMP recurrence after transplant. Uncertainty has been raised whether novel treatment approaches such as thalidomide, bortezomib, ASCT and allogeneic stem cell transplant (Allo-SCT) would increase the possibility of EMP relapse [10–13]. Even though Minnema et al. [10] reported that 20.4% of patients had extramedullary disease relapse following Allo-SCT, this might be associated with inherent biological features of the disease rather than the therapeutic method, since they found that EMP recurrence was more common among patients with deletion of chromosome 13 (p ⫽ 0.06). Varettoni et al. [1] demonstrated the only risk factor for EMP relapse during follow-up to be the presence of extramedullary involvement at MM diagnosis, rather than treatment strategy. Besides, it could be that novel agents and transplant might increase survival long enough for patients to experience EMP relapse afterward. There have been no clinical trials focusing on treatment for patients with MM with EMP at initial diagnosis. The absence of a relationship between extramedullary disease and long-term prognosis in patients with MM after ASCT is consistent with prior research [1,2]. This particular variation has always been considered an indicator of more aggressive disease, resistance to conventional therapeutic options and poor prognosis [1,2,5]. ASCT as first-line therapy for patients younger than 65 years old, however, may reverse the negative influence of extramedullary spread on MM prognosis, and CR status posttransplant was a significant prognostic factor for predicting PFS among this group of people. EMPs from hematogenous spread are generally associated with plasmablastic morphology, which might indicate biological aggressiveness and a worse outcome [14,15]. Our study found that ASCT resulted in a comparable outcome of patients with MM with EMP from hematogenous metastasis to those with EMP arising from focal bone, which would be a further demonstration of the superiority of transplant among these patients. Nevertheless, the number of subjects with EMP in our study was relatively small, and thus further studies would be necessary. In conclusion, a bortezomib-containing induction regimen followed by HDT would be the optimal treatment schedule for patients with MM with EMP at the time of initial presentation, without increasing the rate of EMP recurrence. Further studies are necessary to address whether ASCT is equally effective in patients with MM with EMP arising from bone and patients with EMP from hematogenous metastasis.
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Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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