Bortezomib in combination with conventional chemotherapeutic agents for multiple myeloma compared with bortezomib alone.
BACKGROUND
Recent studies have demonstrated synergy between bortezomib and a number of conventional cytotoxic agents. This study examined whether or not the speed of the response, progression and safety from a combination treatment of bortezomib with common chemotherapeutic drugs is superior to bortezomib monotherapy.


METHODS
Fifty-seven patients with relapsed, refractory multiple myeloma (MM) who had received at least two cycles of treatment including bortezomib were enrolled in this study. The median age was 56 (35-79) years and 49.1% were male. Thirty-two patients were treated with bortezomib alone and 25 were treated with chemotherapeutic agents that were given in combination with bortezomib. The monoclonal immunoglobulin (mIg) or free light chain (FLC) concentrations were determined in the sera before and after two cycles of bortezomib treatment. The adverse events were assessed and graded according to the NCI Common Toxicity Criteria (version 2.0).


RESULTS
Thirty-one of the 57 patients (54.4%) attained an early objective response (EOR) after the second bortezomib treatment, defined as a >/=50% decrease in the serum mIg or FLC concentration. Improvements in the response were observed when common chemotherapeutic agents were added to bortezomib monotherapy. In patients who received bortezomib combined with chemotherapeutic agents, 19 out of 25 patients (76%) showed an EOR, whereas 12 out of 32 patients (37.5%) given bortezomib monotherapy achieved an EOR after the second cycle of bortezomib treatment (P = 0.004); the median decrease from the baseline in the paraprotein level was 74.6 +/- 5.9 and 39.7 +/- 4.2%, respectively (P = 0.003). A statistically significant elevation of serum lactic dehydrogenase (P = 0.007) and alkaline phosphatase (P = 0.027) from baseline within two cycles of bortezomib treatment was observed in responding patients. With the combination treatment, peripheral neuropathy of >/=Grade II occurred in 12 out of 25 patients (48%) compared with 12 of 32 (37.5%) in those given bortezomib alone (P = 0.589). The median time to progression of disease was similar in the two groups (359 +/- 43.5 versus 365 +/- 103.5, P = 0.688). The multivariate Cox regression model showed that a high serum albumin and low beta2-microglobulin are favorable factors for the progression-free survival following bortezomib treatment.


CONCLUSIONS
Bortezomib in combination with common chemotherapeutic agents is more active in the treatment of relapsed, refractory MM than with bortezomib alone. However, more effective post-bortezomib treatment is needed to reduce the rate of disease progression particularly in patients with high tumor burden.
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000069286:Bortezomib; D018572:Disease-Free Survival; D004586:Electrophoresis; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood; D045022:Lactate Dehydrogenases / Q000097:blood; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D012008:Recurrence
D001897:Boronic Acids; D007147:Immunoglobulin Light Chains; D011719:Pyrazines; D000069286:Bortezomib; D045022:Lactate Dehydrogenases; D000469:Alkaline Phosphatase