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Multiple myeloma presenting as fever of unknown origin
European Journal of Internal Medicine 14 (2003) 94–97 www.elsevier.com / locate / ejim
Original article
Multiple myeloma presenting as fever of unknown origin Olivier Lambotte a , Bruno Royer a , Philippe Genet c , Pauline Brice b , Jean-Claude Brouet a , a, Jean-Paul Fermand * a
ˆ Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France Immuno-Hematology Unit, Department of Clinical Immunology, Hopital b ˆ Saint-Louis, Paris, France Department of Hematology, Hopital c ˆ d’ Argenteuil, Argenteuil, France Department of Hematology, Hopital Received 13 July 2002; received in revised form 18 November 2002; accepted 29 November 2002
Abstract Background: Multiple myeloma (MM) itself is not considered to be responsible for fever and is not usually listed among the causes of fever of unknown origin (FUO). Methods: We report three cases of MM presenting with specific fever that we analyze in combination with the three previously published cases. Results: MM could easily be suspected in most, but not all, cases, emphasizing that bone marrow aspiration should be a part of ‘standard’ FUO investigations. All patients underwent extensive, sometimes potentially harmful, investigations. Conventional treatment of MM produced a sustained improvement in the temperature curve and inflammatory syndrome in all cases within a few months. Fever recurred during nearly all relapses. Six patients died, one after a disease course of more than 8 years. Conclusions: This series shows that MM may present as a FUO and that useless and hazardous investigations may be avoided given the possibility of specific fever in this disease. Chemotherapy must be considered without much delay after a reasonable work-up to eliminate any associated process, especially infections. 2003 Elsevier Science B.V. All rights reserved. Keywords: Myeloma; Specific fever; Fever of unknown origin
1. Introduction During the course of multiple myeloma (MM), fever is a common event and leads to investigation for infections, which are major causes of mortality in patients suffering from it. However, MM itself is rarely considered to be responsible for fever. Kyle attributed fever to myeloma in 1% of 869 patients but did not indicate when it was observed in the course of the disease [1]. Taking into account only fever at disease presentation, we observed three cases of MM with specific fever, presenting as a prolonged condition, which we report in combination with the three cases already published in the literature [2–4]. *Corresponding author. Tel.: 133-1-4249-9548; fax: 133-1-42494040. E-mail address: [email protected] (J.-P. Fermand).
This series shows that MM may present as a fever of unknown origin (FUO) and illustrates the difficulties encountered by clinicians managing a myeloma patient with prolonged fever.
2. Materials and methods Of all the myeloma patients treated in our department during the last 10 years, three fulfilled previously defined criteria for FUO [5]. Fever was considered MM-specific because no other cause was found and because it disappeared after MM treatment. These three cases have been analyzed in combination with three cases previously reported in the English literature [2–4], identified by a Medline search from 1966 to 2000. One case was not included because the highest reported temperature was
0953-6205 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00021-9
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97
37.9 8C [3]. Patients with cytologically atypical disease presenting with fever, a high LDH level, and extramedullary tumors composed of immunoblastic-like plasma cells were not included in this study [6–9].
3. Results There were four men and two women with a mean age of 58 years (range 39–75 years). The patients had fever for a mean of 5.8 months (range 2–18 months, median 3.5 months) before MM was diagnosed. The temperature curve showed a continuous fever in two cases and a hectic fever in three. Fever was associated with night sweats, weight loss, and poor condition in four cases. Two patients complained of bone pain. Physical examination was unremarkable, showing only symptomatic anemia in two cases and mild jaundice in one. Four patients had lytic bone lesions on X-rays. Laboratory investigations are reported in Table 1. Routine serum electrophoresis disclosed an abnormal monoclonal band in three of six patients, hypogammaglobulinemia in two, and polyclonal hypergammaglobulinemia in one. These last three patients had Bence Jones proteinuria; the others had IgG MM. Serum and urine immunoelectrophoresis detected monoclonal components in all cases except one case of Bence Jones kappa MM. Interestingly, in one case, a first set of immunological investigations had been negative. In all cases, bone marrow aspiration ascertained the diagnosis of MM, showing more than 10% of dystrophic plasma cells. To rule out associated causes of fever, numerous
95
investigations, particularly microbiological, were performed in all cases (Table 1). In the three reported cases, before and after admission to our unit, fever investigations included: repeated blood and urine cultures, search for tuberculosis, serologies for Brucellosis, Rickettsiae, and Bartonellae species; serologies for HIV, cytomegalovirus, Epstein–Barr Virus, hepatitis B and C; search for antinuclear antibodies, polynuclear anticytoplasmic antibodies, and cryoglobulin. Leishmaniae were sought by bone marrow smear examination, culture, and serology. Abdominothoracic CT scan, echocardiography, GI and bronchial endoscopies were also performed in the three patients. Intravenous urography was performed in one. At least one bone marrow biopsy was done in all patients. Liver and temporal artery biopsies were performed in cases 1 and 2, and in cases 2 and 3, respectively. Most patients received repeated courses of antibiotic agents, including antituberculous agents in two, with no result. In some cases, conventional or high doses of steroids produced transient and partial improvement in fever and general status. Similarly, nonsteroid anti-inflammatory drugs were sometimes administered with partial benefit. However, sustained normalization of the temperature curve was obtained only after initiation of the chemotherapy regimen, combining alkylating agents with corticosteroids in all cases. Of note, resolution of fever usually needed two to three monthly courses of chemotherapy. Patients were followed for a median of 19.5 months (range 3–100 months). A total of six relapses occurred with specific fever recurrence in five. All patients died except one.
Table 1 Main laboratory results in MM patients admitted to our department (cases 1–3) and in those reported in the literature [2–4] Case 1
Case 2
Case 3
Ref. [2]
Ref. [3]
Ref. [4]
62
110
61
ESR (mm / h) N: ,20 C-reactive protein (mg / l) N: ,5 mg / l Fibrinogen (g / l) N: 2–4 g / l White-cell count (per mm 3 ) N: 4000–10 000 Platelet count (per mm 3 ) N: 150 000–300 000 Hemoglobin (g / dl) N: 12–17 Creatinine (mmol / l) N: ,110 Calcium (mmol / l) N: 52.25–2.6 Protein (g / l) N: 560–75 Albumin (g / l) N: 5 35–50 ALAT (U / l) /ASAT (UI) N: ,40 UI Gamma glutamyl transferase (U / l) N: ,50 /Alkaline phosphatase (U / l) N: ,280 Lactic dehydrogenase (U / l) N: ,280 Gammaglobulins (g / l) N: 57.5–16 24-h proteinuria (g / day) N: ,0.1 Urine immunoelectrophoresis Serum immunoelectrophoresis b 2 -Microglobulin (mg / l) N: 51.3–2.4 Myelogram (plasmocytes)
67 34 6.3 4790 189 000 8.7 123 2.29 75 45.2 N/N N/N
155 257 6.79 8700 588 000 9.4 82 3.08 84 17.9 53 / 31 105 / 728
140 187 9 7900 262 000 5.9 68 2.20 71 31 N/N N/N
N: 6.6 17 90% BJk N 5 38% dystrophic
N: 33.5 0.28 BJk1IgGk IgGk 5 74% dystrophic
N 6.2 1.36 80% BJl BJl 3.7 10% dystrophic
Radiographic lesions
Iliopubic, ribs
Skull, pelvis, femur
No
ESR, erythrocyte sedimentation rate; Ht, hematocrit; N, normal; $, polyclonal hypergammaglobulinemia.
9600 N 28.3% Ht 230 2.5 71 30 N/N N/N
$ 7.7 BJl BJl Abnormal plasma cells Vertebrae
3700 48 000 8.6
7.6 105 79.6
22 / 304
56
20.6
Dystrophic
BJk IgGk 2.9 20%
L3
No
IgGl
96
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97
4. Discussion Over a 10-year period we observed three myeloma patients presenting with a FUO, which we report together with the previously published cases [2–4]. In accordance with the recent study of Mueller et al. [10], this series shows that MM may present as a FUO and that useless and hazardous investigations may be avoided if the possibility of specific fever in this disease is kept in mind. We chose to exclude patients with myeloma disease characterized by very immature plasma cells. These patients often present with a lymphoma-like disease characterized by fever, systemic symptoms, elevated serum LDH, and abnormal plasma cells infiltrating bone marrow and extramedullary sites [6–9]. Tumor cells are often indistinguishable from immunoblastic cells and have an immature phenotype so that the disease is sometimes diagnosed as anaplastic myeloma [7–8]. Such presentation can be observed either as a terminal phase of MM [7] or, more rarely, de novo, before any treatment [8–9]. In all patients in the present series, the diagnosis of MM was made by immunochemical analysis of serum and urine proteins and by analysis of bone marrow aspiration, which are not performed in initial laboratory investigations of a FUO [11] but should be considered in all patients presenting with FUO. Most patients were extensively investigated for other causes of prolonged fever, in particular infection [11–13] which is also common during MM, due to depressed humoral immunity [14]. Bacterial agents are by far the most implicated pathogens, usually leading to infections of the respiratory and urinary tract [14,15]. In contrast, the chance of infections with intracellular pathogens, such as tuberculosis, is low during the initial phase of the disease, when cellular immunity is not yet impaired by treatment [16]. Most of our patients also underwent extensive investigations for cancer or vasculitis. Of note, potentially dangerous examinations were performed before MM was diagnosed, particularly imaging using iodine contrast products carrying an increased risk of acute renal failure in MM patients [17]. In our patients and in those reported in the literature, the evolution of the temperature curve during chemotherapy was the key to attributing fever to MM. The beginning of cytotoxic treatment was followed by sustained regression of fever and the inflammatory syndrome within a mean of 2 months. Thus, chemotherapy must be started without much delay after the diagnosis of MM, possibly in combination with empirical anti-infectious drugs, such as antituberculous therapy, according to the clinical context. The prognosis of febrile MM could not be assessed on the basis of the present small series. It is worth noting that in one patient, who was treated with high-dose chemoradiotherapy and autologous stem cell support (case 1), the duration of the disease reached 8 years. In this case, as in most of the other patients, relapses were associated with recurrence of fever. Thus, at least in some patients,
fever may be a marker of myeloma disease and may not always indicate poor prognosis. Why specific fever is rare in MM remains unclear since IL-6 is one of the cytokines involved in triggering fever [18], since it is central to the pathogenesis of MM [19,20], and since high serum IL-6 levels [21,22], although highly variable [23], have been described in patients with MM. A possible explanation is that IL-6 is not a potent endogenous pyrogen [18] and may produce fever only when a large medullar production is not used by MM cells, for instance, when they become independent of exogenous IL-6 [20,24]. Alternatively, other pyrogenic cytokines may be implicated, especially IL-1 and tumor necrosis factor-a [25]. In summary, to avoid useless and hazardous investigations, clinicians must know that MM can occasionally present as a FUO. In this setting, chemotherapy must be considered without much delay after a reasonable work-up to eliminate any associated process, especially infections.
References [1] Kyle RA. Multiple myeloma. Review of 869 cases. Mayo Clin Proc 1975;50:29–40. [2] Duffy TP. The many pitfalls in the diagnosis of myeloma. New Engl J Med 1992;326:394–6. [3] Gross DJ, Shalit M, Levo Y. Fever in multiple myeloma. Isr J Med Sci 1982;18:870–2. [4] Pitz CCM, Lokhorst HM, Hoekstra JBL. Fever as presenting symptom of multiple myeloma. Neth J Med 1998;53:256–9. [5] Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine 1961;40:1–30. [6] Daeninck PJ, Williams GJ, Rubinger M, Johnston JB. Multiple myeloma presenting clinically as lymphoma. Leuk Lymph 1997;28:195–201. [7] Di Stasi M, Cavanna L, Paties C et al. Anaplastic myeloma as extramedullary relapse of multiple myeloma in remission. Acta Haematol 1986;76:202–7. [8] Foucar K, Raber M, Foucar E et al. Anaplastic myeloma with massive extramedullary involvement. Cancer 1983;51:166–74. [9] Barlogie B, Smallwood L, Smith T, Alexanian R. High serum levels of lactic deshydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 1989;110:521–5. [10] Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin caused by multiple myeloma. Arch Intern Med 2002;162:1305–9. [11] Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997;350:575–80. [12] Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997;24:291–302. [13] Larson EB, Featherstone HJ, Petersdorf RG. Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970–1980. Medicine 1982;61:269–92. [14] Jacobson DR, Zolla-Pazner S. Immunosuppression and infection in multiple myeloma. Semin Oncol 1986;13:282–90. [15] Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med 1982;96:47–50. [16] Burton CH, Fairham SA, Millet B et al. Unusual aetiology of persistent back pain in a patient with multiple myeloma: infectious discitis. J Clin Pathol 1998;51:633–4. [17] Brown M, Battle Jr. JD. The effect of urography on renal function in patients with multiple myeloma. Can Med Assoc J 1964;91:786–90. [18] Dinarello CA, Bunn PA. Fever. Semin Oncol 1997;24:288–98.
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97 [19] Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Curr Opin Hematol 1998;5:42–8. [20] Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998;91:3–21. [21] Bataille R, Jourdan M, Zhang XG, Klein B. Serum levels of Interleukin 6, a potent myeloma cell growth factor, as a reflection of disease severity in plasma cell dyscrasias. J Clin Invest 1989;84:2008–11. [22] Wierzbowska A, Urbanska-Rys H, Robak T. Circulating IL-6-type
97
cytokines and sIL-6R in patients with multiple myeloma. Br J Haematol 1999;105:412–9. [23] Emile C, Fermand JP, Danon F. Interleukin-6 serum levels in patients with multiple myeloma. Br J Haematol 1994;86:439–40. [24] Asaoku H, Kawano M, Iwato K et al. Decrease in BSF-2 / IL-6 response in advanced cases of multiple myeloma. Blood 1988;72:429–32. [25] Carter A, Merchav S, Silvian-Draxler I, Tatarsky I. The role of interleukin-1 and tumour necrosis factor-alpha in human multiple myeloma. Br J Haematol 1990;74:424–31.
Original article
Multiple myeloma presenting as fever of unknown origin Olivier Lambotte a , Bruno Royer a , Philippe Genet c , Pauline Brice b , Jean-Claude Brouet a , a, Jean-Paul Fermand * a
ˆ Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France Immuno-Hematology Unit, Department of Clinical Immunology, Hopital b ˆ Saint-Louis, Paris, France Department of Hematology, Hopital c ˆ d’ Argenteuil, Argenteuil, France Department of Hematology, Hopital Received 13 July 2002; received in revised form 18 November 2002; accepted 29 November 2002
Abstract Background: Multiple myeloma (MM) itself is not considered to be responsible for fever and is not usually listed among the causes of fever of unknown origin (FUO). Methods: We report three cases of MM presenting with specific fever that we analyze in combination with the three previously published cases. Results: MM could easily be suspected in most, but not all, cases, emphasizing that bone marrow aspiration should be a part of ‘standard’ FUO investigations. All patients underwent extensive, sometimes potentially harmful, investigations. Conventional treatment of MM produced a sustained improvement in the temperature curve and inflammatory syndrome in all cases within a few months. Fever recurred during nearly all relapses. Six patients died, one after a disease course of more than 8 years. Conclusions: This series shows that MM may present as a FUO and that useless and hazardous investigations may be avoided given the possibility of specific fever in this disease. Chemotherapy must be considered without much delay after a reasonable work-up to eliminate any associated process, especially infections. 2003 Elsevier Science B.V. All rights reserved. Keywords: Myeloma; Specific fever; Fever of unknown origin
1. Introduction During the course of multiple myeloma (MM), fever is a common event and leads to investigation for infections, which are major causes of mortality in patients suffering from it. However, MM itself is rarely considered to be responsible for fever. Kyle attributed fever to myeloma in 1% of 869 patients but did not indicate when it was observed in the course of the disease [1]. Taking into account only fever at disease presentation, we observed three cases of MM with specific fever, presenting as a prolonged condition, which we report in combination with the three cases already published in the literature [2–4]. *Corresponding author. Tel.: 133-1-4249-9548; fax: 133-1-42494040. E-mail address: [email protected] (J.-P. Fermand).
This series shows that MM may present as a fever of unknown origin (FUO) and illustrates the difficulties encountered by clinicians managing a myeloma patient with prolonged fever.
2. Materials and methods Of all the myeloma patients treated in our department during the last 10 years, three fulfilled previously defined criteria for FUO [5]. Fever was considered MM-specific because no other cause was found and because it disappeared after MM treatment. These three cases have been analyzed in combination with three cases previously reported in the English literature [2–4], identified by a Medline search from 1966 to 2000. One case was not included because the highest reported temperature was
0953-6205 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00021-9
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97
37.9 8C [3]. Patients with cytologically atypical disease presenting with fever, a high LDH level, and extramedullary tumors composed of immunoblastic-like plasma cells were not included in this study [6–9].
3. Results There were four men and two women with a mean age of 58 years (range 39–75 years). The patients had fever for a mean of 5.8 months (range 2–18 months, median 3.5 months) before MM was diagnosed. The temperature curve showed a continuous fever in two cases and a hectic fever in three. Fever was associated with night sweats, weight loss, and poor condition in four cases. Two patients complained of bone pain. Physical examination was unremarkable, showing only symptomatic anemia in two cases and mild jaundice in one. Four patients had lytic bone lesions on X-rays. Laboratory investigations are reported in Table 1. Routine serum electrophoresis disclosed an abnormal monoclonal band in three of six patients, hypogammaglobulinemia in two, and polyclonal hypergammaglobulinemia in one. These last three patients had Bence Jones proteinuria; the others had IgG MM. Serum and urine immunoelectrophoresis detected monoclonal components in all cases except one case of Bence Jones kappa MM. Interestingly, in one case, a first set of immunological investigations had been negative. In all cases, bone marrow aspiration ascertained the diagnosis of MM, showing more than 10% of dystrophic plasma cells. To rule out associated causes of fever, numerous
95
investigations, particularly microbiological, were performed in all cases (Table 1). In the three reported cases, before and after admission to our unit, fever investigations included: repeated blood and urine cultures, search for tuberculosis, serologies for Brucellosis, Rickettsiae, and Bartonellae species; serologies for HIV, cytomegalovirus, Epstein–Barr Virus, hepatitis B and C; search for antinuclear antibodies, polynuclear anticytoplasmic antibodies, and cryoglobulin. Leishmaniae were sought by bone marrow smear examination, culture, and serology. Abdominothoracic CT scan, echocardiography, GI and bronchial endoscopies were also performed in the three patients. Intravenous urography was performed in one. At least one bone marrow biopsy was done in all patients. Liver and temporal artery biopsies were performed in cases 1 and 2, and in cases 2 and 3, respectively. Most patients received repeated courses of antibiotic agents, including antituberculous agents in two, with no result. In some cases, conventional or high doses of steroids produced transient and partial improvement in fever and general status. Similarly, nonsteroid anti-inflammatory drugs were sometimes administered with partial benefit. However, sustained normalization of the temperature curve was obtained only after initiation of the chemotherapy regimen, combining alkylating agents with corticosteroids in all cases. Of note, resolution of fever usually needed two to three monthly courses of chemotherapy. Patients were followed for a median of 19.5 months (range 3–100 months). A total of six relapses occurred with specific fever recurrence in five. All patients died except one.
Table 1 Main laboratory results in MM patients admitted to our department (cases 1–3) and in those reported in the literature [2–4] Case 1
Case 2
Case 3
Ref. [2]
Ref. [3]
Ref. [4]
62
110
61
ESR (mm / h) N: ,20 C-reactive protein (mg / l) N: ,5 mg / l Fibrinogen (g / l) N: 2–4 g / l White-cell count (per mm 3 ) N: 4000–10 000 Platelet count (per mm 3 ) N: 150 000–300 000 Hemoglobin (g / dl) N: 12–17 Creatinine (mmol / l) N: ,110 Calcium (mmol / l) N: 52.25–2.6 Protein (g / l) N: 560–75 Albumin (g / l) N: 5 35–50 ALAT (U / l) /ASAT (UI) N: ,40 UI Gamma glutamyl transferase (U / l) N: ,50 /Alkaline phosphatase (U / l) N: ,280 Lactic dehydrogenase (U / l) N: ,280 Gammaglobulins (g / l) N: 57.5–16 24-h proteinuria (g / day) N: ,0.1 Urine immunoelectrophoresis Serum immunoelectrophoresis b 2 -Microglobulin (mg / l) N: 51.3–2.4 Myelogram (plasmocytes)
67 34 6.3 4790 189 000 8.7 123 2.29 75 45.2 N/N N/N
155 257 6.79 8700 588 000 9.4 82 3.08 84 17.9 53 / 31 105 / 728
140 187 9 7900 262 000 5.9 68 2.20 71 31 N/N N/N
N: 6.6 17 90% BJk N 5 38% dystrophic
N: 33.5 0.28 BJk1IgGk IgGk 5 74% dystrophic
N 6.2 1.36 80% BJl BJl 3.7 10% dystrophic
Radiographic lesions
Iliopubic, ribs
Skull, pelvis, femur
No
ESR, erythrocyte sedimentation rate; Ht, hematocrit; N, normal; $, polyclonal hypergammaglobulinemia.
9600 N 28.3% Ht 230 2.5 71 30 N/N N/N
$ 7.7 BJl BJl Abnormal plasma cells Vertebrae
3700 48 000 8.6
7.6 105 79.6
22 / 304
56
20.6
Dystrophic
BJk IgGk 2.9 20%
L3
No
IgGl
96
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97
4. Discussion Over a 10-year period we observed three myeloma patients presenting with a FUO, which we report together with the previously published cases [2–4]. In accordance with the recent study of Mueller et al. [10], this series shows that MM may present as a FUO and that useless and hazardous investigations may be avoided if the possibility of specific fever in this disease is kept in mind. We chose to exclude patients with myeloma disease characterized by very immature plasma cells. These patients often present with a lymphoma-like disease characterized by fever, systemic symptoms, elevated serum LDH, and abnormal plasma cells infiltrating bone marrow and extramedullary sites [6–9]. Tumor cells are often indistinguishable from immunoblastic cells and have an immature phenotype so that the disease is sometimes diagnosed as anaplastic myeloma [7–8]. Such presentation can be observed either as a terminal phase of MM [7] or, more rarely, de novo, before any treatment [8–9]. In all patients in the present series, the diagnosis of MM was made by immunochemical analysis of serum and urine proteins and by analysis of bone marrow aspiration, which are not performed in initial laboratory investigations of a FUO [11] but should be considered in all patients presenting with FUO. Most patients were extensively investigated for other causes of prolonged fever, in particular infection [11–13] which is also common during MM, due to depressed humoral immunity [14]. Bacterial agents are by far the most implicated pathogens, usually leading to infections of the respiratory and urinary tract [14,15]. In contrast, the chance of infections with intracellular pathogens, such as tuberculosis, is low during the initial phase of the disease, when cellular immunity is not yet impaired by treatment [16]. Most of our patients also underwent extensive investigations for cancer or vasculitis. Of note, potentially dangerous examinations were performed before MM was diagnosed, particularly imaging using iodine contrast products carrying an increased risk of acute renal failure in MM patients [17]. In our patients and in those reported in the literature, the evolution of the temperature curve during chemotherapy was the key to attributing fever to MM. The beginning of cytotoxic treatment was followed by sustained regression of fever and the inflammatory syndrome within a mean of 2 months. Thus, chemotherapy must be started without much delay after the diagnosis of MM, possibly in combination with empirical anti-infectious drugs, such as antituberculous therapy, according to the clinical context. The prognosis of febrile MM could not be assessed on the basis of the present small series. It is worth noting that in one patient, who was treated with high-dose chemoradiotherapy and autologous stem cell support (case 1), the duration of the disease reached 8 years. In this case, as in most of the other patients, relapses were associated with recurrence of fever. Thus, at least in some patients,
fever may be a marker of myeloma disease and may not always indicate poor prognosis. Why specific fever is rare in MM remains unclear since IL-6 is one of the cytokines involved in triggering fever [18], since it is central to the pathogenesis of MM [19,20], and since high serum IL-6 levels [21,22], although highly variable [23], have been described in patients with MM. A possible explanation is that IL-6 is not a potent endogenous pyrogen [18] and may produce fever only when a large medullar production is not used by MM cells, for instance, when they become independent of exogenous IL-6 [20,24]. Alternatively, other pyrogenic cytokines may be implicated, especially IL-1 and tumor necrosis factor-a [25]. In summary, to avoid useless and hazardous investigations, clinicians must know that MM can occasionally present as a FUO. In this setting, chemotherapy must be considered without much delay after a reasonable work-up to eliminate any associated process, especially infections.
References [1] Kyle RA. Multiple myeloma. Review of 869 cases. Mayo Clin Proc 1975;50:29–40. [2] Duffy TP. The many pitfalls in the diagnosis of myeloma. New Engl J Med 1992;326:394–6. [3] Gross DJ, Shalit M, Levo Y. Fever in multiple myeloma. Isr J Med Sci 1982;18:870–2. [4] Pitz CCM, Lokhorst HM, Hoekstra JBL. Fever as presenting symptom of multiple myeloma. Neth J Med 1998;53:256–9. [5] Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine 1961;40:1–30. [6] Daeninck PJ, Williams GJ, Rubinger M, Johnston JB. Multiple myeloma presenting clinically as lymphoma. Leuk Lymph 1997;28:195–201. [7] Di Stasi M, Cavanna L, Paties C et al. Anaplastic myeloma as extramedullary relapse of multiple myeloma in remission. Acta Haematol 1986;76:202–7. [8] Foucar K, Raber M, Foucar E et al. Anaplastic myeloma with massive extramedullary involvement. Cancer 1983;51:166–74. [9] Barlogie B, Smallwood L, Smith T, Alexanian R. High serum levels of lactic deshydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 1989;110:521–5. [10] Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin caused by multiple myeloma. Arch Intern Med 2002;162:1305–9. [11] Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997;350:575–80. [12] Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997;24:291–302. [13] Larson EB, Featherstone HJ, Petersdorf RG. Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970–1980. Medicine 1982;61:269–92. [14] Jacobson DR, Zolla-Pazner S. Immunosuppression and infection in multiple myeloma. Semin Oncol 1986;13:282–90. [15] Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med 1982;96:47–50. [16] Burton CH, Fairham SA, Millet B et al. Unusual aetiology of persistent back pain in a patient with multiple myeloma: infectious discitis. J Clin Pathol 1998;51:633–4. [17] Brown M, Battle Jr. JD. The effect of urography on renal function in patients with multiple myeloma. Can Med Assoc J 1964;91:786–90. [18] Dinarello CA, Bunn PA. Fever. Semin Oncol 1997;24:288–98.
O. Lambotte et al. / European Journal of Internal Medicine 14 (2003) 94–97 [19] Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Curr Opin Hematol 1998;5:42–8. [20] Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998;91:3–21. [21] Bataille R, Jourdan M, Zhang XG, Klein B. Serum levels of Interleukin 6, a potent myeloma cell growth factor, as a reflection of disease severity in plasma cell dyscrasias. J Clin Invest 1989;84:2008–11. [22] Wierzbowska A, Urbanska-Rys H, Robak T. Circulating IL-6-type
97
cytokines and sIL-6R in patients with multiple myeloma. Br J Haematol 1999;105:412–9. [23] Emile C, Fermand JP, Danon F. Interleukin-6 serum levels in patients with multiple myeloma. Br J Haematol 1994;86:439–40. [24] Asaoku H, Kawano M, Iwato K et al. Decrease in BSF-2 / IL-6 response in advanced cases of multiple myeloma. Blood 1988;72:429–32. [25] Carter A, Merchav S, Silvian-Draxler I, Tatarsky I. The role of interleukin-1 and tumour necrosis factor-alpha in human multiple myeloma. Br J Haematol 1990;74:424–31.