Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial

Abdelkefi, Abderrahman; Ladeb, Saloua; Torjman, Lamia; Othman, Tarek Ben; Lakhal, Amel; Romdhane, Neïla Ben; Omri, Halima El; Elloumi, Moez; Belaaj, Hatem; Jeddi, Ramzi; Aissaouï, Lamia; Ksouri, Habib; Hassen, Assia Ben; Msadek, F.; Saâd, Ali; Hsaïri, Mohamed; Boukef, K.; Amouri, Ahlem; Louzir, Hechmi; Dellagi, Koussay; Abdeladhim, Abdeladhim Ben

doi:10.1182/blood-2007-07-101212

Cited by 114 publications

(70 citation statements)

References 34 publications

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“…VTD [25][26][27] In contrast, TT2 used thalidomide from the outset of treatment. 3 Despite drug discontinuation resulting from cumulative toxicity in approximately 80% of patients 2 years into protocol therapy, an OS benefit was first detected in patients exhibiting CA.…”

Section: Discussionmentioning

confidence: 99%

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy

Rhee

Szymonifka

Anaissie

et al. 2010

Blood

100

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The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio ‫؍‬ 6.44; P < .001), whereas PMDD of both IntroductionThe superiority of Total Therapy 3 (TT3) 1,2 to Total Therapy 2 (TT2) 3 was limited to the approximately 85% of patients presenting with gene expression profiling (GEP)-defined lowrisk myeloma. 4,5 As a consequence of shortened induction before and consolidation after melphalan-based tandem transplantations in TT3 versus TT2, the compliance with intended protocol steps was improved which, along with the incorporation of bortezomib, affected prognosis favorably. 6 TT3 applied 2 cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone; 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide) as induction before and, at reduced doses, as consolidation after melphalan-based tandem transplantation. Thalidomide and dexamethasone were given at 50 mg/day and 20 mg/day for 4 days every 28 days to "bridge" drug-free intervals between induction cycles, whereas thalidomide dosing was 100 mg/day with dexamethasone 20 mg/day for 4 days every 28 days between transplantations and consolidation cycles. Maintenance therapy comprised VTD (bortezomib [V], thalidomide [T], and dexamethasone [D]) in year 1 and TD without V in years 2 and 3.Here, we examined whether cumulative dosing of VTD components and their premature drug discontinuation (PMDD) impacted overall survival (OS), event-free survival (EFS), time to next therapy (TNT), and postrelapse survival (PRS) in the context of baseline variables and completion of second transplantation and both cycles of consolidation therapy. MethodsTrial details have been reported previously. 1,2,4,5 Briefly, TT3 accrued 303 newly diagnosed patients with symptomatic or progressive myeloma between February 2004 and July 2006. GEP analysis of CD138-enriched plasma cells was performed in a subset of 275 patients. 7 GEP parameters considered included risk designation (high vs low), 4 molecular subgroups (hyperdiploidy, low bone disease, CCND1 without CD-1 and with CD20 coexpression, MAF/MAFB, MMSET/FGFR3, myeloid, proliferation), 8 and delTP53 status. 9,1...

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Section: Discussionmentioning

confidence: 99%

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy

Rhee

Szymonifka

Anaissie

et al. 2010

Blood

100

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“…In this context, maintenance therapy after HDM/auto-SCT and tandem HDM/auto-SCT for patients who do not achieve a CR after first transplantation may be options worth investigating in patients with MIDD. Indeed, maintenance therapy using new therapeutic agents like thalidomide [23][24][25] and tandem HDM/auto-SCT 26 have both been shown to increase the rate of complete hematologic remission, prolong time to disease progression and overall survival in patients with multiple myeloma. Although it remains an open question, in our opinion, it is likely that these approaches aiming at achieving a durable complete hematologic remission may be of special benefit to these patients.…”

Section: Discussionmentioning

confidence: 99%

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

Hassoun

Flombaum

D’Agati

et al. 2008

Bone Marrow Transplant

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“…[42][43][44] Likewise, the benefit of tandem transplants may be limited to patients failing to achieve at least a 90% reduction of tumor burden after the initial induction and first high-dose therapy consolidation. 42,43 Second, the use of post-transplant maintenance with thalidomide may abrogate the benefits of a second autograft as demonstrated by Abdelkafi et al 45 The use of second autologous transplants as salvage therapy for some patients has been shown to result in long disease-free intervals in patients with long remission after their first autograft. 46 The committee recognized that the role of tandem transplantation will need to be reevaluated in the era of IMID's and proteosome inhibitors.…”

Section: Issues In Stem Cell Collectionmentioning

confidence: 99%

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)

Giralt

Stadtmauer

Harousseau³

et al. 2009

Leukemia

212

165

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Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial

Cited by 114 publications

References 34 publications

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)

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