Search

Summary Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m2 intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25–2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

Summary. Dexamethasone, a prototypic synthetic glucocorticoid, was added to cultures of human fetal liver and adult marrow cells to assess its effects on erythroid colony and burst formation. Dexamethasone decreased the number of fetal liver erythroid colonies and bursts formed in the presence of erythropoietin, and also decreased the number of cells per colony. The amount and type of haemoglobin produced per cell were unaffected by adding dexamethasone to the cultures. Dexamethasone inhibited the incorporation of 3H-thymidine into DNA in fetal liver cells stimulated with erythropoietin, supporting the hypothesis that dexamethasone inhibits the proliferation but not the differentiation of fetal liver CFU-E and BFU-E. In contrast, addition of dexamethasone to adult bone marrow cultures had a variable effect on erythroid colony and burst formation.

Bone marrow CFU-E and BFU-E from a patient with CDA-II formed erythroid colonies and bursts which contained multinucleated erythroblasts in vitro. Adherent cell depletion of the patient's marrow increased CFU-E derived colonies six-fold (98 +/- 17 v. 640 +/- 15 per 10(5) marrow cells plated) and co-culture of CDA-II marrow adherent cells with CSA-II adherent cell depleted marrow significantly suppressed erythroid colony formation. Similar adherent cell suppression of the patient's BFU-E also occurred. Adherent cell depletion of normal marrow did not increase CFU-E derived colony formation (488 +/- 63 v. 495 +/- 108) and decreased BFU-E derived burst formation. Addition of normal adherent cells to normal marrow increased erythroid colony and burst formation. Karyotype and chromosomal banding studies of the patient's multinucleated cells did not show chromosomal inversions, deletions or translocations.

Summary. To determine whether erythropoietin (Ep) is required only to trigger, or also to sustain the growth of erythroid progenitor (CFU-E) in vitro, the effect of limiting the time of exposure of sheep bone marrow CFU-E to Ep on erythroid colony (EC) formation was examined. Restricting the in vitro exposure of CFU-E to 2–24 h, either by brief preincubation with Ep or by neutralization of Ep present in culture with anti-Ep, resulted in a 70–90% reduction of EC formation, and the colonies that were produced were of a small size. In contrast, no inhibition of EC size or number occurred when CFU-E were exposed to Ep for more than 24 h. These results suggest that Ep also modulates the proliferative events subsequent to the initial triggering of CFU-E which lead to the formation of erythrocytes.