Phase 2 Study of Pegylated Liposomal Doxorubicin, Vincristine, Decreased-Frequency Dexamethasone, and Thalidomide in Newly Diagnosed and Relapsed-Refractory Multiple Myeloma

Hussein, Mohamad A.; Baz, Rachid; Srkalović, Gordan; Agrawal, Neeraj; Suppiah, Revathi; Hsi, Eric D.; Andrèsen, Steven; Karam, Mary Ann; Reed, Janice; Faiman, Beth; Kelly, Megan; Walker, Esteban

doi:10.4065/81.7.889

Cited by 100 publications

(64 citation statements)

References 28 publications

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“…Such high CR and !VGPR rates are important, because it has been demonstrated that CR rates and a !VGPR rates, both postinduction and post-ASCT, are prognostic for improved outcomes. 8,[22][23][24][25][26][27] To date, this is the largest study, with the longest follow-up, to assess BTD induction therapy. The 25-month follow-up allowed an analysis of post-ASCT outcomes to assess the impact of the response and CR rates achieved; and, to our knowledge, this is the first study to report time-to-events data after BTD induction.…”

Section: Discussionmentioning

confidence: 99%

“…The 25-month follow-up allowed an analysis of post-ASCT outcomes to assess the impact of the response and CR rates achieved; and, to our knowledge, this is the first study to report time-to-events data after BTD induction. Reflecting the association between CR and !VGPR rates and improved outcomes, 8,[22][23][24][25][26][27] the time-to-events data were promising. In addition, analysis of OS post-transplantation according to response to BTD induction therapy suggested a trend toward improved survival in patients who achieved a !VGPR compared with those who did not, although the small number of patients who did not proceed to HDT-ASCT limits interpretation of this result.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…The activity of regimens incorporating thalidomide, pegylated liposomal doxorubicin, and dexamethasone is also strongly supported by studies including both untreated patients, as well as those with relapsed/refractory disease, showing comparable response rates. 50 These combinations will require additional, longer-term follow-up, and in some cases larger and/or randomized phase III trials, to determine their proper place in our algorithm for treatment of nontransplant patients with multiple myeloma.…”

Section: Regimens Not Based On Mpmentioning

confidence: 99%

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Orłowski¹

2006

Hematology

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Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient's disease. Such a risk-and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.Using the diagnostic criteria recommended by the International Working Group, patients with multiple myeloma are classified as having either asymptomatic or symptomatic (Table 1) disease. 1 The latter population, generally considered candidates for a chemotherapy-based intervention, are then further divided into those who either are or are not eligible for high-dose chemotherapy followed by stem cell rescue. 2 Criteria that are weighed to help make this second distinction have generally included age, performance status, and co-morbid medical conditions. 2 There is some variability in these parameters and how they are applied, since studies examining stem cell transplantation have used different criteria. In regard to age, for example, which is the most objective of these measures, initial studies tended to enroll patients younger than 65 years of age, 3 while more recent studies suggest that transplant is safe in at least some who are over the age of 70 (for example 4,5 ). On the other hand, data suggesting that patients with poor-risk chromosomal features have a short time to progression after autologous transplantation have led to suggestions that even younger patients with these abnormalities may not be candidates for standard approaches. Nonetheless, as little as two years ago, there was general agreement that the standard of care for patients who were not eligible for transplantation and yet needed chemotherapy was melphalan

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“…Low-dose ASA (81 mg daily) has been shown to be feasible in this setting. 5,35 Prophylactic dose enoxaparin (40 mg subcutaneously once daily) has been used without excessive complications during the period of profound cytopenias following stem cell transplant, 65 suggesting it may be considered in thrombocytopenic MM patients, particularly if the duration of thrombocytopenia is expected to be short. *addition of ASA 81 mg/day decreased the incidence to 18% **addition of enoxaparin 40 mg/day decreased the incidence to 24% Abbreviations: CTX, cyclophosphamide; DOX, doxorubicin; DEX, dexamethasone; THAL, thalidomide; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/relapsed multiple myeloma; TEE, thromboembolic event Occasionally, patients with MM will develop new thrombocytopenia while on enoxaparin prophylaxis.…”

Section: Patients With Disease-related Thrombocytopenia And/or Renal mentioning

confidence: 99%

“…As shown in Table 2, in phase II studies evaluating thalidomide plus anthracycline-containing chemotherapy regimens without thromboprophylaxis, incidences of 10% to 58% have been reported. 5,[33][34][35] The study with the highest reported incidence of TEE was a large phase II trial evaluating DVd-T in both RRMM and NDMM patients in which 58% of patients developed TEE prior to amendment of the protocol mandating low-dose aspirin thromboprophylaxis. As will be discussed in more detail below, the addition of ASA reduced the incidence of TEE by approximately two-thirds.…”

Section: Thalidomide Plus Cytotoxic Chemotherapymentioning

confidence: 99%

Thrombotic Complications of Myeloma Therapy

Zonder

2006

Hematology

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Patients with multiple myeloma are at relatively high baseline risk of developing thromboembolic events (TEE), usually deep vein thromboses. There are numerous contributing factors, among them certain treatment regimens that include thalidomide or related compounds such as lenalidomide combined with glucocorticoids and/or cytotoxic chemotherapy. The risk of developing TEE appears to be particularly high when these immunomodulatory agents are combined with anthracyclines as treatment of newly-diagnosed disease. Up-front combinations including thalidomide plus pulse dexamethasone and/or alkylating agents are associated with an intermediate risk, whereas the same regimens for relapsed/refractory myeloma seem to be associated with the lowest risk. Several different thromboprophylaxis strategies have been effective in lowering the risk of developing clots: daily aspirin (81-325 mg/day), full-intensity warfarin (INR 2-3), and prophylactic enoxaparin (40 mg SQ daily). Low, fixed-dose warfarin may also reduce the risk of TEE, but the data on this are disputable. None of these TEE prevention strategies have been prospectively compared head-to-head, so the choice often reflects physician and/or patient preferences. The available evidence upon which one might make such a decision is reviewed here.Individuals with multiple myeloma (MM) are at increased risk for developing thromboembolic events (TEE) compared to the general population. 1 The exact incidence is difficult to determine since reported TEE rates likely vary according to the level of diagnostic vigilance. For example, in one retrospective chart review at the Cleveland Clinic, which has an established imaging algorithm for evaluating patients with MM and monoclonal gammopathy of uncertain significance who have symptoms of a possible TEE, the reported rate was approximately 10%.1 In contrast, the rates documented in patients treated with melphalan-prednisone or dexamethasone as part of large multicenter studies without uniform algorithms for documenting TEE were 5% and 3%, respectively.2,3 It is likely the actual background incidence falls in the 5-10% range. Factors that have been suggested as contributory to the risk of TEE in people with MM include newly diagnosed disease status 4 ; immobility due to pain and/or surgery; indwelling central venous catheters; extrinsic venous compression by plasmacytomas; acquired abnormalities in platelet function, 5 clotting factors, 6 and the coagulation cascade 7-9 ; the presence of inherited factors such as Factor V Leiden; and treatment with immunomodulatory agents including thalidomide and lenalidomide. The risk of developing TEE during therapy with combination regimens containing thalidomide and lenalidomide will be discussed, followed by recommendations on prevention and treatment.

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Phase 2 Study of Pegylated Liposomal Doxorubicin, Vincristine, Decreased-Frequency Dexamethasone, and Thalidomide in Newly Diagnosed and Relapsed-Refractory Multiple Myeloma

Cited by 100 publications

References 28 publications

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

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

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Thrombotic Complications of Myeloma Therapy

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