Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/GMMG-HD4 Trial

Erasmus Medical Center, Rotterdam, the Netherlands.
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2012; 30(24):2946-55. DOI: 10.1200/JCO.2011.39.6820
Source: PubMed


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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    • "VTD was also superior in a Spanish study associated with thalidomide maintenance (12). The addiction of doxorubicin to bortezomib–dexamethasone (PAD) was superior to VAD followed by ASCT and thalidomide maintenance, with a median PFS of 35 vs. 28 months, respectively (13). "
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    ABSTRACT: Multiple myeloma survival has significantly improved in the latest years due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib, and lenalidomide together with autologous stem-cell transplantation has considerably increased complete remission rate and progression-free survival resulting ultimately in prolonged survival in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to further implement responses. Finally, a number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, making the future of myeloma patients brighter.
    Full-text · Article · Sep 2014 · Frontiers in Oncology
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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) [13]. 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 [14]. "
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    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.
    Preview · Article · Jun 2014 · Computational and Structural Biotechnology Journal
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    • "More recently, novel agents have been assessed as consolidation therapy post-ASCT 9. Cavo and al. confirmed these findings, showing an increased CR rate from 49% to 61% after consolidation, and a prolonged PFS, with two cycles of VTd compared to 2 cycles of Td, but in the context of a tandem ASCT procedure upfront 8. Other studies have been conducted since, and found similar results in terms of improved quality of response and prolonged PFS after consolidation with immunomodulatory drugs or bortezomib based associations. Upgraded rates of CR and CR-nCR have indeed been reported with post-ASCT use of monotherapy with bortezomib or lenalidomide 13, 14, or VTd as consolidation 8-10. The consolidation strategy remains however a matter of debate in the field of myeloma upfront in transplant eligible patients. "
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    ABSTRACT: The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.
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