Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

Morgan, Gareth J.; Davies, Faith E.; Gregory, Walter M.; Bell, Sue; Szubert, Alex J.; Coy, Nuria Navarro; Cook, Gordon; Feyler, Sylvia; Johnson, Peter; Rudin, C.; Drayson, Mark T.; Owen, Roger G.; Ross, Fiona; Russell, Nigel H.; Jackson, Graham; Child, J. Anthony

doi:10.3324/haematol.2011.043372

Cited by 149 publications

(127 citation statements)

References 33 publications

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“…The benefit conferred by thalidomide combinations in induction was confirmed by the Myeloma IX and Total Therapy 2 trials (Morgan et al, 2012;Barlogie et al, 2006b). The IFM 2005-01 trial demonstrated that bortezomib and dexamethasone was also superior to VAD, increasing the pre-ASCT response rate to 79% from 63%, (Harousseau et al, 2010), and a similar improvement with bortezomib-based induction was observed in the HOVON65/GMMGHD4 trial (Sonneveld et al, 2012).…”

Section: Novel Agent Inductionmentioning

confidence: 89%

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

Maybury

Cook

Pratt

et al. 2016

Biology of Blood and Marrow Transplantation

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SummaryConsolidation with high dose chemotherapy and autologous stem cell transplantation (ASCT) is the standard of care for transplant eligible patients with multiple myeloma, based on randomised trials showing improved progression free survival with autologous transplantation following combination chemotherapy induction. These trials were performed before novel agents were introduced, and subsequently combinations of immunomodulatory drugs (IMiDs) and proteasome inhibitors as induction therapy have significantly improved rates and depth of response. Ongoing randomised trials are testing whether conventional autologous transplantation continues to improve responses following novel agent induction. While these results are awaited, it is important to review strategies for improving outcomes following ASCT. Conditioning prior to ASCT with higher doses of melphalan, and combinations of melphalan with other agents, including radiopharmaceuticals have been explored. Tandem ASCT, consolidation and maintenance therapy following ASCT have been investigated in phase III trials. Experimental cellular therapies using ex vivo primed dendritic cells , ex vivo expanded autologous lymphocytes, KIR-mismatched allogeneic NK cells, and genetically modified T cells are also in phase I trials to augment ASCT. This review summarises these strategies and highlights the importance of exploring strategies to augment ASCT even in the era of novel agent induction.

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Section: Novel Agent Inductionmentioning

confidence: 89%

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

Maybury

Cook

Pratt

et al. 2016

Biology of Blood and Marrow Transplantation

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“…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%

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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“…It should be noted that LEN and THAL are not currently approved for use as frontline therapy under the Japanese medical insurance system. Data from phase III studies describing outcomes in response to regimens containing novel agents are summarized in Table 2 [5][6][7][8][9][10][11][12][13].…”

Section: Induction Therapy In Patients Eligible For Autologous Stem Cmentioning

confidence: 99%

Current approaches for the treatment of multiple myeloma

2013

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The development of novel therapeutic agents over the past decade, including the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, lenalidomide and thalidomide, has resulted in improved outcomes for patients with multiple myeloma. However, there is still considerable controversy as to which regimen should be used as first-line therapy, which patients should be considered for autologous or allogeneic transplantation, and how consolidation or maintenance therapy is used in patients that have a good response to first-line therapy. The present paper will review clinical evidence from previous and ongoing studies to explore issues related to these questions.

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Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

Cited by 149 publications

References 33 publications

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

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

Current approaches for the treatment of multiple myeloma

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