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

Sonneveld, Pieter; Schmidt‐Wolf, Ingo G.H.; Holt, Bronno van der; Jarari, Laila el; Bertsch, Uta; Salwender, Hans; Zweegman, Sonja; Vellenga, Edo; Broyl, Annemiek; Blau, Igor Wolfgang; Weisel, Katja; Wittebol, Shulamiet; Bos, Gerard M.J.; Stevens‐Kroef, Marian; Scheid, Christof; Pfreundschuh, Michael; Hose, Dirk; Jauch, Anna; Velde, H Van der; Raymakers, Reinier; Schaafsma, M; Kersten, M. J.; Marwijk-Kooy, Marinus van; Duehrsen, Ulrich; Lindemann, Walter; Wijermans, Pierre W.; Lokhorst, Henk M.; Goldschmidt, Hartmut

doi:10.1200/jco.2011.39.6820

Cited by 743 publications

(704 citation statements)

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“…In one study, bortezomib administered every other week post-transplant produced better OS than thalidomide maintenance [103]. Although more studies are needed, bortezomib-based maintenance may be important for intermediateand high-risk patients.…”

Section: Post-transplant Maintenance Therapymentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe 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.Risk stratificationIn 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.Risk‐adapted initial therapyStandard‐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.Maintenance therapyAfter 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.Management of refractory diseasePatients 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. © 2013 Wiley Periodicals, Inc.

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Section: Post-transplant Maintenance Therapymentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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“…Per protocol, one or two cycles of highdose melphalan were planned. In patients who received single ASCT, the 5-year OS was 55% in both PAD and VAD arms (P=0.39), while in those who received tandem ASCT the 5-year OS was 70% with PAD and 55% with VAD (P=0.07), thus suggesting an advantage with the tandem option (13). Yet, P-values were not significant and results were derived from a subgroup analysis.…”

mentioning

confidence: 88%

“…Better results were achieved with three-drug combinations including thalidomide or bortezomib plus conventional chemotherapeutic agents, such as doxorubicin and cyclophosphamide (13,19,20).…”

Section: Induction Regimensmentioning

confidence: 99%

“…Similarly, bortezomib plus dexamethasone (VD) showed an ORR of 78% in comparison with 63% with VAD (P<0.001) (16). Two randomized phase III trials evaluated a short course of lenalidomide and dexamethasone (Rd) as induction before ASCT, showing an ORR of 76%, including 29% of patients achieving at least a VGPR (17,18).Better results were achieved with three-drug combinations including thalidomide or bortezomib plus conventional chemotherapeutic agents, such as doxorubicin and cyclophosphamide (13,19,20).A significant improvement in ORR in comparison with VAD was reported with doxorubicin in combination with thalidomide-dexamethasone (TAD) (88% vs 79%, P=0.005) (19) and doxorubicin in combination with bortezomib and dexamethasone (PAD) (78% vs 54%, P<0.001) (13).Cyclophosphamide in combination with thalidomide-dexamethasone (CTD) significantly enhanced the ORR in comparison with cyclophosphamide-VAD (83% vs 71%, P<0.0001) (20).The three-drug combination bortezomib-thalidomide-dexamethasone (VTD) was compared with TD and multi-agent chemotherapy (21,22). A significant improvement in the CR rate was detected with VTD compared with TD (35% vs 14%, P=0.0001) and with multi-agent chemotherapy (35% vs 21%, P=0.01) (21).…”

mentioning

confidence: 99%

“…Yet, P-values were not significant and results were derived from a subgroup analysis. In addition, patients were not randomized to receive either tandem or single ASCT, but the choice was dependent on country practice (13). Post-ASCT consolidation with bortezomib and IMiDs is currently under evaluation.…”

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confidence: 99%

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The Role of Pre-Transplant Induction Regimens and Autologous Stem Cell Transplantation in the Era of Novel Targeted Agents

Gay

Cavallo

Palumbo

2015

Drugs

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Outcome of patients with multiple myeloma (MM) has greatly improved with the use of autologous stem cell transplantation (ASCT) and new agents, such as immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib). When compared to conventional chemotherapy, high-dose melphalan with ASCT significantly improved response rates and progression-free survival, while overall survival benefit was not consistent across all trials. ASCT is considered the standard treatment for patients who are younger than 65 years and who do not have limiting comorbidities. New, effective agents have been introduced as part of induction, consolidation and maintenance treatments within ASCT and in combinations with chemotherapy for patients not eligible for ASCT. The remarkable results obtained with these regimens are questioning the role of ASCT for newly diagnosed MM patients. This article aims to delineate the role of ASCT in the era of novel agents based on the results of recent clinical trials. 1.IntroductionAutologous stem cell transplantation (ASCT) is the standard treatment for newly diagnosed multiple myeloma (MM) patients younger than 65 years and/or eligible for high-dose chemotherapy. Before the introduction of novel agents, such as immunomodulatory drugs (IMiDs; thalidomide and lenalidomide) and proteasome inhibitors (bortezomib), high-dose melphalan with ASCT significantly improved response rates and progression-free survival (PFS) in comparison with conventional chemotherapy, with conflicting results in terms of overall survival (OS) (1-4).Newer agents were later incorporated both in the transplant and non-transplant settings, and significantly improved patient outcome (5). The depth and the duration of response obtained with these new approaches correlated with a PFS benefit and, in several studies, also with an OS improvement. This was evident in both young patients receiving ASCT, and elderly patients receiving conventional chemotherapy in combination with new agents (6-10). It has been suggested that the optimal treatment strategy should aim at achieving sustained complete response (CR) (11).Yet, long-term control of the disease has been shown also in patients not achieving high-quality responses, which may reflect changes in host immune status or a clonal heterogeneity of the disease at diagnosis. Thus patients may also benefit from a less intensive treatment, that can be able to control, if not eradicate, the disease. The remarkable results obtained in the non-transplant setting questioned the role of ASCT for newly diagnosed MM patients. On the other hand, there is increasing evidence that the selective pressure of treatment may be responsible for emergence of different MM sub-clones leading to drug resistance at more advanced stages (12). If this will be confirmed, it could be reasonable to give the most effective and intensive treatment, that is ASCT, at the early phases of disease, when the probability of reaching long-lasting remissions is higher.This article aims to deline...

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