Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/GMMG-HD4 Trial
ABSTRACT We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM).
In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage.
Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003).
Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.
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- "After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; P = .002) . Moreover, bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma according to subgroup analysis . "
ABSTRACT: Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within bone marrow and extramedullary sites. It is one of the most common haematological malignancies; it accounts for 1.4% of all tumours and is responsible for 2% of cancer-related mortality. Over the last decades, the paradigm of MM therapy has changed dramatically - from the conventional combination of oral melphatan + prednisone, high-dose chemotherapy with stem cell (ASCT) support for younger patients to the present paradigm with the use of one (or more) of 3 major new targeted agents - the first-in class proteasome inhibitor bortezomib, the immunomodulatory drug thalidomide, and its more potent derivative lenalidomide. Their use as a part of initial therapy is associated with high overall response rates as well as high rates of complete response (CR), both for elderly patients unable to undergo ASCT and for younger patients treated prior to ASCT. Altogether, the advent of novel agents has resulted in a 50% improvement in median survival. Moreover, the development of new drug classes based on preclinical rationale and the introduction of next-generation agents are likely to further expand treatment options and improve outcomes for especially relapsed MM. This review highlights important historic landmarks as well as more recent events that have played an important role in the evolution of myeloma targeted therapy.06/2014; 10(16). DOI:10.1016/j.csbj.2014.05.005
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ABSTRACT: Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end-organ damage. In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard-risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months. After initial therapy, lenalidomide maintenance is considered for standard-risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in pateints with intermediate or high-risk myeloma. Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013.American Journal of Hematology 01/2011; 86(1):57-65. DOI:10.1002/ajh.21913 · 3.48 Impact Factor
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ABSTRACT: DISEASE OVERVIEW: Multiple myeloma accounts for ∼10% of all hematologic malignancies. DIAGNOSIS: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of end-organ damage felt to be related to the underlying plasma-cell disorder. RISK STRATIFICATION: Patients with 17p deletion, t(14;16), t(14;20), or high-risk gene expression profiling signature have high-risk myeloma. Patients with t(4;14) translocation, karyotypic deletion 13, or hypodiploidy are considered to have intermediate-risk disease. All others are considered to have standard-risk myeloma. RISK-ADAPTED THERAPY: Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). An alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. Intermediate-risk and high-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease, or with a bortezomib-based regimen if intermediate-risk or high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly subcutaneous dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. MANAGEMENT OF REFRACTORY DISEASE: Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib.American Journal of Hematology 01/2012; 87(1):78-88. DOI:10.1002/ajh.22237 · 3.48 Impact Factor