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Multiple Myeloma to the editor: Kyle and Rajkumar state in their review article (Oct. 28 issue)1 that use of bisphosphonates for the prevention of skeletal-related events and the treatment of hypercalcemia in patients with multiple myeloma may be complicated by osteonecrosis of the jaw. Although in some clinical case series in the literature, osteonecrosis of the jaw has been reported in association with the use of bisphosphonates, there was no denominator in these studies that corresponded to all the patients who received bisphosphonates, with or without this complication.2,3 Moreover, multiple risk factors for avascular necrosis of the jaw, particularly the use of corticosteroids in patients with multiple myeloma or other cancers, should not be discarded as possible causative factors. Kadri Altundag, M.D. Hacettepe University Institute of Oncology 06100 Ankara, Turkey
[email protected]
thalidomide neuropathy, tests of sensory-nerve action potentials and sural-nerve biopsies would need to be considered before a neuropathy could be ruled out.4 Colin L. Crawford, M.R.C.P. Imperial College of Medicine London W6 8RF, United Kingdom
[email protected] 1. Crawford CL. Thalidomide-induced neuropathy. Mayo Clin
Proc 2002;77:1395. 2. LeQuesne PM. Neuropathy due to drugs. In: Dyck PJ, Thomas
PK, Griffin JW, Low PA, Podulso JF, eds. Peripheral neuropathy. 3rd ed. Philadelphia: W.B. Saunders, 1993:1571-81. 3. Richardson P, Schlossman RL, Weller E, et al. Immunomodularity drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:3063-7. 4. Fullerton PM, O’Sullivan DJ. Thalidomide neuropathy: a clinical electrophysiological and histological follow-up. J Neurol Neurosurg Psychiatry 1968;31:543-51.
to the editor: Kyle and Rajkumar, in their review
Ozden Altundag, M.D. Ozlem Gundeslioglu, M.D. 8181 Fannin Street Houston, TX 77054 1. Kyle AR, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;
351:1860-73. 2. Lugassy G, Shaham R, Nemets A, Ben-Dor D, Nehlieli O. Severe
osteomyelitis of the jaw in long-term survivors of multiple myeloma: a new clinical entity. Am J Med 2004;117:440-1. 3. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
of contemporary therapies for multiple myeloma, highlight the importance of the disturbance of the ratio of receptor activator of nuclear factor-kB ligand (RANKL) to osteoprotegerin in the development of bone disease. The authors attribute this disturbance to increased production of RANKL by osteoblasts, as Pearse et al. described.1 However, there is growing evidence suggesting that myeloma cells themselves can express RANKL,2 that expression of RANKL on myeloma cells is related to osteolytic bone disease,3,4 and that myeloma cells (primary myeloma cells as well as cell lines) can stimulate osteoclast formation directly, bypassing the stromal and osteoblastic pathway of osteoclastic stimulation.4,5 It is not clear whether myelomacell expression of RANKL alone or in combination with other molecules, such as macrophage inflammatory protein-1a, are the crucial factors leading to osteolytic bone disease. What is clear from animal models is that interruption of the interaction between RANKL and RANK can lead to a reduction in myeloma cell growth,1 making these molecules attractive targets for therapeutic intervention.
to the editor: Kyle and Rajkumar mention that a neuropathy that is often painful develops in 30 percent of patients given bortezomib. However, thalidomide also causes a neuropathy in 50 to 80 percent of patients.1 When thalidomide was used as a sedative, recovery from the neuropathy occurred in only 25 percent of patients and, in some cases, not until three years after the drug was stopped.2 It would be unfortunate if patients with multiple myeloma, toward the end of their lives, sustained severe pain as a result of thalidomide neuropathy, Hans G. Schneider, M.D. because the drug caused “persistent, painful pares- John Sentry, Ph.D. thesias [that] were distressing and disabling.”2 Alfred Pathology Service In discussing the use of CC-5013, the authors Melbourne, VIC 3004, Australia state that common adverse effects, such as neuropathy, were not observed. However, leg cramps oc- 1. Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone decurred in 40 percent of patients given the drug.3 struction and promote tumor progression. Proc Natl Acad Sci U S A Because leg cramps are a common symptom of 2001;98:11581-6.
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2. Sezer O, Heider U, Jakob C, Eucker J, Possinger K. Human bone
marrow myeloma cells express RANKL. J Clin Oncol 2002;20:353-4. 3. Heider U, Langelotz C, Jakob C, et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003;9:1436-40. 4. Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 2003;63:5438-45. 5. Lai FPL, Cole-Sinclair M, Cheng M, et al. Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation. Br J Haematol 2004;126:192-201.
the authors reply: Dr. Altundag and colleagues
raise an important point concerning the recent reports of osteonecrosis of the jaw in patients with multiple myeloma who have received intravenous bisphosphonates.1 Durie and colleagues recently reported that in a Web-based survey, osteonecrosis of the jaw developed in 46 of 812 patients (5.7 percent) with multiple myeloma.2 The incidence of this complication was most closely correlated with bisphosphonate therapy and the duration of such treatment. Although this report has major epidemiologic shortcomings and does not allow one to determine the precise frequency of osteonecrosis of the jaw with bisphosphonate use, it does demonstrate its existence. It is important to be alert for this possible complication. We believe that it is prudent to advise patients to avoid dental procedures while they are taking intravenous bisphosphonates. Bisphosphonates have a proven benefit in patients with multiple myeloma, but we must learn the most effective way to use them. Further studies are needed to determine the duration and dosage of bisphosphonate therapy for multiple myeloma. We share Dr. Crawford’s concern about the development of peripheral neuropathy with thalidomide treatment. Neuropathy with thalidomide increases with the dose and duration of therapy. Fortunately, symptoms are typically mild; severe, disabling neuropathy (National Cancer Institute
toxicity criteria, grade 3 or higher) occurs in less than 10 percent of patients.3,4 The dose of thalidomide used to treat myeloma has been reduced greatly over the past five years to reduce the incidence and severity of complications, including neuropathy. In most cases, symptoms of neuropathy can be managed by dose adjustments and supportive care.4 Analogues of thalidomide, such as CC-5013, appear to have lower-grade, nonhematologic toxic effects than thalidomide, but we agree that more studies and longer follow-up are needed to determine the frequency of complications such as neuropathy. Drs. Schneider and Sentry point out that myeloma cells can themselves express RANKL and stimulate osteoclast formation, leading to osteolytic bone disease. We agree, but there is debate about whether the amount of RANKL produced by myeloma cells is sufficient to induce osteoclast formation.5 Interruption of the interaction between RANKL and RANK may also lead to reduction in myeloma cell growth, thus making these molecules attractive as targets for therapeutic intervention. Robert A. Kyle, M.D. S. Vincent Rajkumar, M.D. Mayo Clinic Rochester, MN 55905
[email protected] Dr. Kyle reports having received consulting fees from Favrille. 1. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteone-
crosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34. 2. Durie BGM, Katz M, McCoy J, Crowley J. Osteonecrosis of the jaws in myeloma: time dependent correlation with Aredia and Zometa use. Blood 2004;104:216a. abstract. 3. Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492-4. 4. Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol 2003;1:194-205. 5. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655-64.
Getting the Lead Out to the editor: The description accompanying the Images in Clinical Medicine by Shen and Hirschtick (Nov. 4 issue)1 contains two errors that I believe are errors in the understanding of plumbism, rather than purely typographical errors. First, there are two references to the serum lead level, one level of
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143.5 µg per deciliter and one of 116 µg per deciliter. Lead levels are measured in whole blood, not serum, because the lead is in the erythrocytes and not in the serum. Second, the normal blood level is 0, not less than 10 µg, as stated in the text. The currently acceptable lead level, according to the Cen-
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