Background We conducted a randomized trial of the treatment of multiple myeloma with high-dose chemotherapy followed by either one or two successive autologous stem-cell transplantations. Methods At the time of diagnosis, 399 previously untreated patients under the age of 60 years were randomly assigned to receive a single or double transplant. Results A complete or a very good partial response was achieved by 42 percent of patients in the single-transplant group and 50 percent of patients in the double-transplant group (P=0.10). The probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group (P=0.03). The estimated overall seven-year survival rate was 21 percent in the single-transplant group and 42 percent in the double-transplant group (P=0.01). Among patients who did not have a very good partial response within three months after one transplantation, the probability of surviving seven years was 11 p...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa032290

Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma

Purpose We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and Methods In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stemcell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m 2 (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. Results Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P .001) and bortezomib maintenance (34% v 49%; P .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12v22 months; HR, 0.47; 95% CI, 0.26 to 0.86;P.01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P .003). Conclusion Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS. J Clin Oncol 30:2946-2955. © 2012 by American Society of Clinical Oncology

/pdf/bortezomib-induction-and-maintenance-treatment-in-patients-3w2hh581g7.pdf

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

Multiple myeloma plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. A clinically relevant aspect of the interactions of multiple myeloma plasma cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. This process is only partially supported by factors such as vascular endothelial growth factor, fibroblast growth factor-2 and metalloproteinases, which are directly secreted by the tumor cells. In fact, the presence in the bone marrow microenvironment of cytokines, in particular interleukin-6, as a consequence of plasma cell-stromal cell interactions, induces the production and secretion of angiogenic factors by other cells present in the bone microenvironment, thus contributing to the angiogenic switch during the progression of the disease. Near angiogenesis vasculogenesis occur in the bone marrow of myeloma patients and contribute to the vascular three formation. In the bone marrow of myeloma patients haematopoietic stem cells are recruited and induced to differentiate into endothelial cells by the angiogenic cytokines present in the microenvironment. Myeloma plasma cells also induce angiogenesis indirectly via recruitment and activation of stromal inflammatory cells (i.e.: macrophages and mast cells) to secrete their own angiogenic factors. They are recruited and activated by tumor plasma cells through the secretion of fibroblast growth factor-2, interleukin-8, and other chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete their angiogenic factors: fibroblast growth factor-2, vascular endothelial growth factor, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, which contribute to enhance the tumor neovascularization. Finally, myeloma macrophages when exposed to vascular endothelial growth factor and fibroblast growth factor-2 secreted by plasma cells shows vasculogenic ability and acquire endothelial cell markers and transform into cells functionally and phenotypically similar to paired bone marrow endothelial cells. So they participate to the formation of the bone marrow capillary network (vasculogenic mimicry).

Bone marrow angiogenesis and progression in multiple myeloma

Bortezomib, as a single agent and in combination with dexamethasone, was examined as first-line treatment in 32 consecutive patients with untreated symptomatic multiple myeloma. Patients received bortezomib 1.3 mg/m(2) for a maximum of six 3-week cycles; oral dexamethasone 40 mg was added if a less than partial response (PR) was achieved after two cycles or a less than complete response (CR) was achieved after four cycles. The response rate (CR + PR) was 88%, with undetectable paraprotein (CR) in 6%, and detectable by immunofixation only in 19% [near (n)CR]. All 32 patients completed the first two cycles of bortezomib alone, of whom 3% achieved CR, 9% nCR, and 28% PR. Ten patients received single-agent bortezomib on study, and dexamethasone was added in 22, leading to 15 improved responses. The most common adverse events >/=grade 2 included sensory neuropathy (31%), constipation (28%), myalgia (28%) and fatigue (25%). Sensory neuropathy grade 2 or 3 was reversible within a median of 3 months in five of 10 patients. Bortezomib treatment did not affect stem cell mobilization in eight or transplantation in six patients. Bortezomib alone or in combination with dexamethasone is an effective induction therapy with a high CR and nCR rate and manageable toxicities in previously untreated patients with myeloma.

Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma.

Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma.

We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mg and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32–65 years; Durie & Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity.

/pdf/vincristine-doxorubicin-and-dexamethasone-vad-administered-552kul22b4.pdf

Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first‐line treatment in untreated multiple myeloma

Intensive Versus Double Intensive Therapy in Untreated Multiple Myeloma: Updated Analysis of the Randomized Phase III Study HOVON 24 MM.

https://repub.eur.nl/pub/8236/12456509.pdf

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study.

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Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first‐line treatment in untreated multiple myeloma

Intensive Versus Double Intensive Therapy in Untreated Multiple Myeloma: Updated Analysis of the Randomized Phase III Study HOVON 24 MM.

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study.