Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.
OBJECTIVE
To determine the progression-free survival at 12 weeks, to evaluate the toxic effects, and to analyze the biological activity of thalidomide in patients with relapsed multiple myeloma (MM) after high-dose chemotherapy and stem cell transplantation.


METHODS
From 1999 to 2001, we performed a multicenter prospective phase 2 study in patients with MM that relapsed after high-dose chemotherapy and stem cell transplantation to evaluate the efficacy of oral thalidomide, with dose escalation from 200 to 600 mg/d over 12 weeks and a subsequent maintenance phase of 200 mg/d for up to 1 year. Outcome was correlated with serum and plasma levels of vascular endothelial growth factor and serum levels of tumor necrosis factor alpha, soluble intercellular adhesion molecule 1, interferon gamma, interleukin (IL) 2, and IL-6 during treatment.


RESULTS
Thirty patients were treated (19 men and 11 women; median age, 58 years). The median number of prior therapies was 5, and the median duration from diagnosis of MM to study enrollment was 4.3 years. The 12-week progression-free survival rate was 67% (95% confidence interval [CI], 48%-86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28%-60%) with a median duration of 6 months. Attributable toxicities included constipation, fatigue, rash, and neuropathy, which was dose limiting in 8 patients (27%). Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Although responses were observed with lower doses, possibly eliminating the need to escalate the dose, responses were also seen in patients who completed the dose escalation. Some patients had disease progression while receiving the maintenance dose of 200 mg/d. Analysis of biomarker assays did not identify any biomarker associated with greater response, but a significant increase in levels of soluble intercellular adhesion molecule 1, IL-2, and interferon gamma was seen with thalidomide therapy.


CONCLUSIONS
The optimal thalidomide dose varies, and adverse effects can be dose limiting. The dose of thalidomide therapy should be based on the individual patient to ensure that it is well tolerated and that a response is achieved.
Richardson
Paul
P
Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Mass 02115, USA. paul_richardson@dfci.harvard.edu
Schlossman
Robert
R
Jagannath
Sundar
S
Alsina
Melissa
M
Desikan
Raman
R
Blood
Emily
E
Weller
Edie
E
Mitsiades
Constantine
C
Hideshima
Teru
T
Davies
Faith
F
Doss
Deborah
D
Freeman
Andrea
A
Bosch
Joan
J
Patin
John
J
Knight
Robert
R
Zeldis
Jerome
J
Dalton
William
W
Anderson
Kenneth
K
D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D011446:Prospective Studies; D012008:Recurrence; D033581:Stem Cell Transplantation; D013792:Thalidomide / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D013792:Thalidomide; D007371:Interferon-gamma