Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities

Barlogie, Bart; Pineda‐Roman, Mauricio; Rhee, Frits van; Haessler, Jeff; Anaissie, Elias; Hollmig, Klaus; Alsayed, Yazan; Waheed, Sarah; Petty, Nathan; Epstein, Joshua; Shaughnessy, John D.; Tricot, Guido; Zangari, Maurizio; Zeldis, Jerome B.; Barer, Sol; Crowley, John

doi:10.1182/blood-2008-03-145235

Cited by 216 publications

(185 citation statements)

References 27 publications

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“…Unexpectedly, reanalysis after a long follow up of a median 72 months showed a significant prolongation of survival with thalidomide in the subgroup of patients with abnormal cytogenetics defined by metaphase karyotyping, but not in the entire patient cohort. 28 Both maintenance treatments were well tolerated with grade 1 hematologic toxicity seen in up to 15% of patients. Non-hematologic toxicity was more common in patients on Thal-IFN.…”

Section: Discussionmentioning

confidence: 94%

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Ludwig¹,

Adam²,

Tóthová³

et al. 2010

Haematologica

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BackgroundThalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Design and MethodsOf 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. ResultsThalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). ConclusionsThalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).Key words: thalidomide, thalidomide-interferon, progression-free survival, overall survival. Haematologica 2010;95(9):1548-1554. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, and Zojer N.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

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Section: Discussionmentioning

confidence: 94%

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Ludwig¹,

Adam²,

Tóthová³

et al. 2010

Haematologica

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“…[30][31][32] Despite the small number of patients in our series with high-risk cytogenetics (n ¼ 9) among those who proceeded to ASCT, PFS and OS appeared shorter in patients who had high-risk cytogenetics compared with those who had low-risk cytogenetics. On the basis of results produced with other thalidomide-containing regimens in patients with highrisk cytogenetics, 33,34 it is possible, and represents a testable hypothesis, that patients with high-risk cytogenetics may have benefited from a longer duration of BTD therapy either before ASCT 13 or as maintenance or consolidation therapy once they were in remission.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

Kaufman

Nooka

Vrana³

et al. 2010

Cancer

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BACKGROUND: This single-center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT). METHODS: Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3-week cycles of bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte-colony-stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria. RESULTS: Review of medical records identified 44 eligible patients (34 patients who were treated in the front-line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (!VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front-line patients, the ORR was 94%, which included a 56% !VGPR rate (24% sCR/CR). The median CD34-positive stem cell collection was 10.67 Â 10 6 /kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% !VGPR rate (53% sCR/CR). Among all 44 patients, the median progression-free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2-year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis. CONCLUSIONS: BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long-term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010;116:3143-51.

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“…In one study, maintenance with prednisone every other day improved PFS and OS, (38) yet, in another study, no benefit was seen with single agent dexamethasone. (39) Data are therefore insufficient to recommend corticosteroids maintenance therapy.In six different randomized trials, thalidomide maintenance was used post-ASCT: thalidomidebased maintenance arm was compared with alpha-interferon, dexamethasone, pamidronate, prednisone, or observation in the different trials (19,35,(42)(43)(44)(45). A recent meta-analysis showed a reduced risk of progression (HR 0.64, P<0.001) and death (HR 73, P=0.002) with thalidomide maintenance (46).…”

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confidence: 99%

“…These data show that intensification with bortezomib and/or IMiDs improves response rates, and the improvement was mainly seen in patients with sensitive disease. The total therapy (TT) study evaluated the impact of the addition of thalidomide (TT2) or bortezomib (TT3) to a multi-agent chemotherapy and high-dose melphalan program supported by double ASCT (35). In this TT study, novel agents were administered both in the pre-transplant and in the post-transplant settings.…”

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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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Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities

Cited by 216 publications

References 27 publications

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

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

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