The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.

Purpose: The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase III study examined the efficacy of the four-drug combination of bortezomib-melphalan- prednisone-thalidomide (VMPT) followed by maintenance with bortezomib- thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous stem-cell transplantation. Patients and Methods: A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival. Results: The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio [HR], 0.67; 95% CI, 0.50 to 0.90; P = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; P = .007). Complete response rates were 38% in the VMPT-VT group and 24% in the VMP group (P < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P = .77). Grade 3 to 4 neutropenia (38% v 28%; P = .02), cardiologic events (10% v 5%; P = .04), and thromboembolic events (5% v 2%; P = .08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. Conclusion: VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation. © 2010 by American Society of Clinical Oncology.

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This clinical trial was conducted to determine the safety and efficacy of bortezomib retreatment in patients with multiple myeloma (MM) who had previously responded to bortezomib. Patients with progressive MM who had previously tolerated bortezomib as a single agent or in combination with other drugs, with a minimum of partial response (PR; ≥50% M-protein reduction) for ≥4 months, who had not received intervening MM therapy, were retreated with bortezomib (days 1, 4, 8, and 11 of a 21-day cycle) with a starting dose being the dose at which the patient ended the initial treatment. Patients were allowed to receive bortezomib on retreatment in combination with dexamethasone, thalidomide, or doxorubicin. Thirty-two patients received bortezomib retreatment (most with added dexamethasone). The median treatment-free interval (last dose of initial bortezomib treatment to first dose of retreatment) was 9.9 (range 2.5-34.0) months. The median duration of retreatment was 2.8 (<1-7.9) months; median total duration of bortezomib treatment was 6.7 (2.5-19.8) months. Based on the investigators' assessment of best response, the overall response rate (complete plus PR) was 50%. The median time from start of retreatment to progressive disease (PD) was 6.6 (95% confidence interval: 5.1-9.6) months. Thirteen patients (41%) experienced PN; bortezomib-related SAEs were reported in four patients. Retreatment with bortezomib alone or in combination is effective and well tolerated in patients with MM who have responded to their initial bortezomib treatment. © 2009 Wiley-Liss, Inc.

PURPOSE:

Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.

PATIENTS AND METHODS:

We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).

RESULTS:

In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.

CONCLUSION:

Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

The aim of the study was to perform a meta-analysis of the efficacy and safety of (bortezomib plus lenalidomide/thalidomide)- vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. We searched electronic and printed sources for relevant articles published. Inclusion criteria was as follows: randomized controlled trials (RCT) of (bortezomib plus lenalidomide/thalidomide) vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. Two reviewers independently assessed potentially eligible studies and extracted relevant data. We retrieved five RCT studies including a total of 1,200 patients. Using the random-effects model to pool the five RCT with a statistically significant heterogeneity (P = 0.03; X² = 10.69; df = 4; I² = 63%), the weighted risk ratios of a complete response (CR) for (bortezomib plus lenalidomide/thalidomide)-containing regimens was 1.81 (P = 0.005; 95% CI.: 1.20-2.73). When we excluded the study by Cavo et al. (Lancet 376:2075-2085, 2010), the pooled risk ratio for CR was 1.59 (P < 0.0001, 95% CI.: 1.29-1.96) with no statistically significant heterogeneity (P = 0.54; X² = 2.14; df = 3; I² = 0%) among four RCT under the fixed effects mode. The pooled odds ratio for the main grade III/IV adverse events (the peripheral neuropathy, thrombotic events, and infections) were 1.76 (P = 0.32; 95% CI.: 0.58-5.31), 0.92 (P = 0.76, 95% CI.: 0.52-1.61), and 1.05 (P = 0.82, 95% CI.: 0.70-1.57), respectively. Our analysis showed (bortezomib plus lenalidomide/thalidomide)-containing regimens as induction treatment in newly diagnosed multiple myeloma improved CR but did not increase the risk of major adverse events (the peripheral neuropathy, thrombotic events, and infections).

OBJECTIVE:

To evaluate the efficacy and safety of bortezomib-based vs non-bortezomib-based post-transplantation therapy in patients with multiple myeloma.

METHODS:

Data of relevant randomized controlled trials assessing the effect of bortezomib as post-transplantation consolidation or maintenance therapy was obtained through a comprehensive search. The outcome measures included response rate, progression-free survival, overall survival, and adverse events (AEs). The hazard ratio (HR), Cochran-Mantel-Haenszel odds ratio (OR), and 95% confidence interval (95% CI) were applied to evaluate the effect of bortezomib in relation to the end points such as progression-free survival, overall survival, response rate, and AEs.

RESULTS:

Three randomized controlled trials comprising 1,518 participants were included in this study. Pooled ORs for the rates of overall response, and complete response and near complete response, were 1.85 and 1.75, respectively. Pooled HR for progression-free survival favored bortezomib-based therapy over non-bortezomib-based therapy (0.73, 95% CI.: 0.67-0.81), while no statistically significant difference could be found between the two groups regarding the pooled HR for 3-year overall survival. Moreover, incidence rates of overall adverse events and grade 3 and 4 peripheral neuropathy were similar in the bortezomib-based groups and the non-bortezomib-based groups (P=0.12 and P=0.41, respectively). The corresponding cumulative meta-analyses of the rates of overall response rate, complete response and near complete response, and grades 3 and 4 peripheral neuropathy supported the superiority of bortezomib-based maintenance therapy over consolidation therapy.

CONCLUSION:

Bortezomib-based therapy after autologous stem cell transplantation, with tolerable AEs, could obviously improve the response as well as the outcome of multiple myeloma patients, particularly when bortezomib was administered as maintenance therapy.

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RECORD STATUS:

None

CITATION:

National Institute for Health and Clinical Excellence. Bortezomib monotherapy for relapsed multiple myeloma. London: National Institute for Health and Clinical Excellence (NICE). Technology Appraisal Guidance 129. 2007

RECORD STATUS:

None

CITATION:

Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, Stephens M. Bortezomib for the treatment of multiple myeloma patients. Health Technology Assessment 2009; 13(Suppl 1 Article 5): 29-33