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SIR, We would like to thank the authors for their comments on our recent review article ‘evolving treatment strategies for myeloma’. Although very rare, the occasional patient may present
with a pyrexia of unknown origin (PUO), arising presumably from cytokines released by the myeloma plasma cells. While we agree this is possible, it should not be the first conclusion as the
immunosuppressed myeloma patient is at great risk of infection. These patients represent a difficult diagnostic challenge and need to be screened for active infection and treated with
antibiotics where appropriate. The only clear proof that the temperature is related to the myeloma is that it will resolve when antimyeloma treatment is initiated. However, it is important
not to delay the initiation of treatment, which may be detrimental to the patient. Therefore, we totally agree that once active infection had been ruled out in a newly diagnosed patient with
a PUO, chemotherapy should be initiated promptly. The antitumour role of bisphosphonates in myeloma is intriguing especially with the highly potent third-generation compounds such as
zoledronic acid, which are now in routine use. To date, their antimyeloma effect has only been shown in cell lines and mouse models. The apoptotic action of sodium clodronate is clearly
different from that of zoledronic acid. Clodronate is metabolised to a number of ATP analogues, which are resistant to hydrolysis and therefore accumulate within the cell resulting in the
inhibition of important metabolic enzymes, such as phosphatases and pyrophosphatases, whereas zoledronic acid inhibits the mevalonate pathway leading to an inhibition of the prenylation of
small GTPases important in cell signalling, such as RAS. While these and other effects such as inhibition of _γδ_ T cells are clearly demonstratable _in vitro_, their relevance _in vivo_ is
less clear. Dose levels in this setting are lower, and the drugs rapidly leave the circulation and become fixed in the bone; thus, it has to be postulated that bisphosphonates are
concentrated in proximity to osteoclasts and can reach doses that are able to kill them. The relevance of this mechanism to myeloma plasma cells rather than osteoclasts is less certain.
However, what is clear is that the direct inhibition of bone resorption and the resulting change in the pattern of cytokines produced can inhibit positive feedback loops important in
maintaining survival of the myeloma clone. Available data from numerous clinical trials only support the effect of bisphosphonates in inhibiting bone resorption and reducing skeletal-related
events, and we believe that no conclusion regarding their _in vivo_ antimyeloma effect can be drawn at present. We agree in view of the dramatic effects on skeletal-related events that all
patients should receive a bisphosphonate; however, whether this should be a first- or third-generation derivative is unclear. We eagerly await the results of the current large Medical
Research Council randomised phase III trial, which compares oral sodium clodronate with intravenous zoledronic acid in order to determine whether there is any differential antimyeloma effect
in patients. CHANGE HISTORY * _ 16 NOVEMBER 2011 This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication _ AUTHOR
INFORMATION AUTHORS AND AFFILIATIONS * Royal Marsden Hospital and Institute of Cancer Research, SM2 5PT, Downs Road, Surrey, UK G J Morgan & F E Davies Authors * G J Morgan View author
publications You can also search for this author inPubMed Google Scholar * F E Davies View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING
AUTHOR Correspondence to G J Morgan. RIGHTS AND PERMISSIONS From twelve months after its original publication, this work is licensed under the Creative Commons
Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Reprints and permissions ABOUT THIS
ARTICLE CITE THIS ARTICLE Morgan, G., Davies, F. Reply to letters on review ‘Evolving treatment strategies for myeloma’. _Br J Cancer_ 93, 269 (2005). https://doi.org/10.1038/sj.bjc.6602695
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