Correspondence
drugs, leaving only a small proportion requiring systemic
treatment. Our own experience with rFVIIa and reports in the
literature on the use of rFVIIa in treating this group of patients
involve small numbers of patients. Systematic data collection
as recommended by the international registry on rFVIIa and
congenital platelet disorders group (Poon & d’Orion, 2000) are
therefore important in providing useful information on dosing
regimes, efficiency and safety in these rare disorders.
Mohamed Kaleelrahman1
Adrian Minford2
Liakat Ali Parapia1
1
Haemophilia Centre, and 2Department of Paediatrics, Bradford
Teaching Hospitals NHS Trust, Bradford, UK.
E-mail: parapia@doctors.org.uk
Thalidomide in patients with multiple myeloma and renal
failure
Thalidomide, a derivate of glutamic acid, is increasingly used
in patients with multiple myeloma (MM) (Singhal et al, 1999).
It has proved to be active in up to one-third of patients with
refractory or relapsing MM. Renal failure is a frequent
complication of MM that is present in 50% of newly diagnosed
patients (Kyle et al, 2003). Data regarding thalidomide phar-
macokinetics and tolerance in patients with renal failure are
lacking. We report our early experience regarding the use of
thalidomide in seven patients with MM and variable degrees of
renal insufficiency.
Seven patients (three females and four males) diagnosed
with MM between 1996 and 2001 received treatment with
thalidomide (Laboratoire Laphal, Paris, France). Four patients
received a combination of steroids and thalidomide.
The main characteristics of these patients before and during
treatment are summarized in Table I. Patient 7 presented with
severe hyperkalaemia (>8 mmol/l) on two occasions during
therapy with 400 mg/d thalidomide. However, hyperkalaemia
recurred when the thalidomide dosage was tapered to 100 mg/d.
The measurement of thalidomide trough plasma concen-
tration using a high-performance liquid chromatography
method as described previously (Eriksson et al, 1992) was
performed in each patient on one to four occasions.
Thalidomide trough plasma level ranged from 0Æ39 lg/ml to
1Æ48 lg/ml. Serial plasma thalidomide concentration measure-
ments were performed in patient 2 during a haemodialysis
session (DiCEA, Baxter, France; cellulosic membrane, surface
area ¼ 1Æ70 m2, ultrafiltration coefficient: 12Æ5). Serum
thalidomide concentrations were 1Æ48 lg/ml at initiation of
dialysis and 1Æ1, 0Æ96, 1Æ06 and 0Æ68 lg/ml at 1, 2, 3 and 4 h of
96 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 90–102
References
Almeida, A.M., Khair, K., Hann, I. & Liesner, R. (2003) The use of
recombinant factor VIIa in children with inherited platelet function
disorders. British Journal of Haematology, 121, 477–481.
Poon, M.C. & d’Orion, R. (2000) Recombinant activated factor VII
(NovoSeven) treatment of platelet-related bleeding disorders.
International Registry on Recombinant Factor VIIa and Congenital
Platelet Disorders Group. Blood Coagulation Fibrinolysis, 11(Suppl.
1), S55–S68.
Keywords: recombinant factor VIIa, Bernard–Soulier syn-
drome, Glanzmann’s thrombasthenia, congenital platelet func-
tion disorders, platelet transfusion.
doi:10.1111/j.1365-2141.2004.04878.x
dialysis respectively. The thalidomide extraction coefficient
was 0Æ057 and the dialytic clearance was 1Æ73 ml/min.
Data regarding the pharmacokinetics of thalidomide are
particularly scarce due to the absence of a suitable intraven-
ous formulation and the withdrawal of this drug from clinical
practice for several decades. To our knowledge, no pharma-
cokinetics data of thalidomide have been reported previously
in patients with MM, either with or without renal failure.
A trough plasma thalidomide level of 0Æ8–1Æ5 lg/ml is
probably a suitable target in patients with MM who have renal
failure. However, there is no clear correlation between the dose
of thalidomide, its plasma concentration and the clinical
response in patients with MM (Kumar et al, 2003). Thus,
lower trough levels (around 0Æ5 lg/ml), as in patients 3 and 7,
may be acceptable particularly in the maintenance phase of
thalidomide treatment.
For plasma trough levels of 0Æ8–1Æ5 lg/ml, thalidomide
tolerance is fairly good in patients with renal failure. Minor
thalidomide toxic effects, mainly sedation, constipation, and
nausea, occur in virtually all treated patients and may subside
with time. Seven of eight patients in our series experienced
minor thalidomide toxicity. More serious complications such
as neutropenia and thromboembolic events were not
observed in our patients. However, as recently reported
(Harris et al, 2003), hyperkalaemia is a specific and serious
potential complication of thalidomide in patients with renal
failure. It usually occurs during the first few weeks of
treatment (as in patient 7) but may occur later during the
treatment with thalidomide. The mechanisms underlying the
thalidomide-associated hyperkalaemia remain unclear and
 Correspondence

Table I. Data regarding thalidomide use in seven patients with variable degrees of renal failure.

TH measurement

Immunological CrCl at the Starting dose of TH serum Impact of TH

Patient Gender/age characteristics of start of TH TH/maximal TH dose CrCl concentration on MM (duration
no. (years) serum (urine) (ml/min) dose of TH (mg/d) (mg/d) (ml/min) (lg/ml) of effect) Side-effects

1 M/66 IgG k (BJP+) 47 100/300 300 54 0Æ81 PR (1 year)* Constipation

300 55 0Æ85
2 M/71 IgG j (BJP+) 14 100/200 100 13 0Æ81 CR (5 months) Sedation
100 9 1Æ2
100 HD 1Æ48
3 M/77 IgG k AL 16 100/100 100 17 0Æ39 CR maintained Dizziness
amyloidosis (8 months)
4 F/65 IgA k (BJP+) 15 100/300 200 <10 0Æ89 MR (2 months)* Sedation
5 M/64 IgG k (BJP+) 19 200/200 100 HD 1Æ19 MR (4 months) –
6 F/59 IgG j (BJP+) 25 200/400 100 10 1Æ21 MR (5 months) Peripheral
neuropathy
7 F/57 Light chain j HD 200/400 200 HD 1Æ2/0Æ4 CR Severe
400 HD 2Æ1 Regression hyperkalaemia
100 HD 0Æ5 of plasmocytosis Sedation
100 HD 0Æ5 (5 months)* Myalgia
Peripheral
neuropathy

BJP, Bence–Jones protein; TH, thalidomide; CrCl, creatinine clearance; MM, multiple myeloma; HD, haemodialysis; CR, complete remission; PR,
partial response; MR, minor response.
*Died.
Complete haematological response was defined by the disappearance or a decrease >90% in the serum and/or urine monoclonal component.
Partial and minor response were defined by a decrease of 50–90% and 25–49% in the serum and/or urine monoclonal component respectively.

may be related to the lysis of MM cells or an extracellular chromatography: avoiding hydrolytic degradation. Journal of Chro-
shift of potassium. matography, 582, 211–216.
In conclusion, thalidomide is, in general, a safe treatment for Harris, E., Behrens, J., Samson, D., Rahemtulla, A., Russell, N.H. &
relapsing or refractory myeloma in patients with renal failure. Byrne, J.L. (2003) Use of thalidomide in patients with myeloma and
renal failure may be associated with unexplained hyperkalaemia.
However, clinicians must be aware of the risk of severe
British Journal of Haematology, 122, 160–161.
thalidomide-associated hyperkalaemia, especially in haemo-
Kumar, S., Gertz, M.A., Dispenzieri, A., Lacy, M.Q., Geyer, S.M.,
dialysed patients. Iturria, N.L., Fonseca, R., Hayman, S.R., Lust, J.A., Kyle, R.A.,
Fadi Fakhouri1 Greipp, P.R., Witzig, T.E. & Rajkumar, S.V. (2003) Response rate,
Houda Guerraoui1 durability of response, and survival after thalidomide therapy for
relapsed multiple myeloma. Mayo Clinic Proceedings, 78, 34–39.
Claire Presne2
Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispen-
Julie Peltier1
zieri, A., Fonseca, R., Rajkumar, S.V., Offord, J.R., Larson, D.R.,
Richard Delarue3 Plevak, M.E., Therneau, T.M. & Greipp, P.R. (2003) Review of 1027
Patrice Muret4 patients with newly diagnosed multiple myeloma. Mayo Clinic
Bertrand Knebelmann1 Proceedings, 78, 21–33.
1 Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P.,
Service de néphrologie, AP-HP, Hôpital Necker, Paris, 2Service de
Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M.,
néphrologie, Hôpital Sud, Amiens, 3Service d’hématologie, Hôpital
Zeddis, J. & Barlogie, B. (1999) Antitumor activity of thalidomide in
Necker, Paris, and 4Service de pharmacologie, Hôpital Jean Minjoz,
refractory multiple myeloma. The New England Journal of Medicine,
Besançon, France. E-mail: fadi.fakhouri@nck.ap-hop-paris.fr 341, 1565–1571.

References Keywords: thalidomide, multiple myeloma, pharmacokinetics,

renal failure.
Eriksson, T., Bjorkman, S., Fyge, A. & Ekberg, H. (1992) Determina-
tion of thalidomide in plasma and blood by high-performance liquid doi:10.1111/j.1365-2141.2004.04875.x

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 90–102 97