Bortezomib (Velcade) & Combination Therapies as First Line Treatment for Patients with Multiple Myeloma / in Untreated Myeloma Patients

During June 25th – 30th in 2007, the XIth International Myeloma Workshop was hosted by the distinguished International Myeloma Foundation in Kos Island, Greece. Many specialists and guest speakers gathered to discuss a wide range of issues surrounding multiple myeloma, such as it’s genetics, to treatment options and new therapeutic approaches. Promising new clinical data and the effectiveness of certain treatments in multiple myeloma were discussed and further explored.

Multiple myeloma is a cancer affecting the plasma cells, which are located in your bone marrow. Plasma cells are an important part of your immune system, helping produce antibodies to protect against infection. In multiple myeloma, abnormal plasma cells that do not work properly are produced. These plasma cells produce large quantities of abnormal antibodies, which cannot fight infections. Patients who suffer from multiple myeloma experience symptoms such as bone pain, abnormal fractures and kidney disease. Although patients benefit from treatment, there is no cure for multiple myeloma and many people eventually develop advanced, relapsing disease. Treatment combinations involving bortezomib (also known as Velcade) have been proven to be highly effective in both relapsing / remitting disease and also as first line treatment in newly diagnosed patients. New Agents Targeting Processes Behind Multiple Myeloma Bone Disease Bone cells called osteoclasts are responsible for the production of enzymes and factors that help absorb old bony tissue and allow new bone to be deposited. In multiple myeloma, there is an abnormal release of factors from malfunctioning osteoclast cells, which results in destruction of normal bone and allows tumour cells to develop and grow. As a consequence of these processes, you may experience unwanted and troublesome symptoms such as bone pain and more frequent fractures. Looking at factors underlying the disease process, there are increased interactions between the tumour cells and the cells which make up the supportive network found in your bone marrow. Specific factors and pathways have been identified – medications which target these pathways have been shown to provide considerable benefits for patients suffering from multiple myeloma. Results from a clinical study performed by Roodman et al support the role of a particular molecule called p62 in multiple myeloma – targeting this new, novel molecule should be investigated as part of the treatment of bony disease associated with multiple myeloma. Study of Genetics and Pharmacological Bortezomib activity in multiple myeloma Bortezomib is an anticancer agent used to treat patients with multiple myeloma. Bortezomib works by inhibiting proteosomes, which are enzyme complexes located within cells. They break down old proteins and help regulate the cell function. In cancer cells, proteosomes may contribute to the survival of abnormal cells. A study of bortezomib activity in multiple myeloma was performed by Mulligan et al, to investigate specific genes and pathways related to bortezomib efficacy in relapsed multiple myeloma. 264 samples were obtained from patients who were enrolled in clinical trials involving bortezomib. Genes associated with response to treatment or progressive disease after treatments with bortezomib were tested for. These genes were then compared with each other. Multiple genes were identified which were over-expressed in multiple myeloma patients – approximately 200 genes were over-expressed in response to treatment and 500 genes were over-expressed in progressive disease. In conclusion, this study demonstrates the many biological pathways expressed in multiple myeloma and the usefulness of genomics to connect pathways with treatment options such as bortezomib. Lenalidomide and / or Bortezomib in multiple myeloma: influence on osteoclast function If you suffer from multiple myeloma, you may experience symptoms such as bone pain and an increased risk of developing fractures. This is due to inappropriate activation of osteoclasts, and inhibition of cells called osteoblasts. As described above, osteoclasts are bone cells, which produce enzymes and factors that help absorb old bony tissue. Osteoblasts have an opposite function, producing and depositing the matrix needed for the formation of new bone. Normally, there is a balance between the activation and action of these cells, allowing the cycle of bone resorption and new bone formation to occur. In multiple myeloma, this balance is disrupted, and there is more osteoclastic activity occurring. Bortezomib has demonstrated exciting results in patients with multiple myeloma, with studies indicating that bortezomib works to inhibit abnormal osteoclast function. A study was conducted by Breitkreutz et al, to investigate the effects of drugs such as bortezomib and lenalidomide on osteoclast cells found within the body. Both patients with multiple myeloma and healthy volunteers took part in this study. Special types of cells were collected from participants and stimulated to induce the formation of osteoclasts. This was performed in the presence of lenalidomide or bortezomib. The study found that both agents inhibited osteoclast activity, directly reducing the rate of progression and development of bony lesions seen in multiple myeloma patients. Major growth and survival factors implicated in multiple myeloma were also studied – their secretion from osteoclasts was down-regulated with both bortezomib and lenalidomide. This subsequently reduces survival rates of multiple myeloma in the bone marrow. PETHEMA Trial of Alternating Bortezomib and Dexamethasone as an Induction Regimen Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM) The PETHEMA trial is one of the first studies that compared administration of bortezomib and dexamethasone on an alternating basis prior to autologous stem cell transplantation (this refers to stem cells that are collected from an individual and given back to that same individual). This trial recruited 40 patients with newly diagnosed multiple myeloma, who were under the age of 66 years. These patients were treated with bortezomib on days 1, 4, 8 and 11 and dexamethasone on days 1-4, 9-12 and 17-20. This was then followed by autologous stem cell transplantation with melphalan. The overall response rate was 82%, with 12% achieving complete remission and 10% achieving very good partial remission. In addition, observed responses occurred rapidly, with significant reductions achieved by the end of the first two cycles. Low toxicity rates were seen, with 25% of patients experiencing a mild alteration in sensation to the peripheral nerves and low platelet counts. In all study patients, stem cells were able to be successfully harvested post treatment. A high overall response rate after autologous stem cell transplantation was seen, with 90% response rates. In summary, this study has shown that alternating bortezomib and dexamethasone is an effective and safe therapeutic regime pre- stem cell transplantation in younger patients with multiple myeloma. Studies of Upfront Lenalidomide / Bortezomib / Dexamethasone / Doxorubicin in Multiple Myeloma A study was conducted by Richardson et al, to determine the maximum tolerated dose of lenalidomide, bortezomib and dexamethasone and the response rate seen in newly diagnosed multiple myeloma patients. To date, 10 patients have been enrolled in the study. Patients received bortezomib therapy on days 1, 4, 8, 11, lenalidomide on days 1-14, and dexamethasone on the days of / after bortezomib treatment. Depending on side effects and toxicities observed in patients, doses of medication were adjusted as necessary. Results from this study show that the combination of lenalidomide, bortezomib and dexamethasone is well tolerated and effective in newly diagnosed multiple myeloma patients. Enrolments are continuing, with 10 additional patients to be recruited to further investigate the maximum tolerated dose of combination therapy. Another study conducted by Jakubowiak et al also investigated the use of bortezomib, doxorubicin and dexamethasone in newly diagnosed multiple myeloma patients. Additionally, this trial presented follow-up data for these patients. 40 patients who had a measurable degree of disease requiring treatment, were involved. A treatment regimen consisting of bortezomib on days 1, 4, 8, and 11, doxorubicin on day 4, and dexamethasone on days 1-4 or on the days of bortezomib treatment, was administered for six 3-week cycles. After the completion of this treatment, most of these patients then proceeded to stem cell transplantation. 37 out of these 40 patients were then able to be analysed for their response rates. By the end of the treatment period, a partial response was observed in 89% patients, with a very good partial response in 50%. Complete and non-complete remission (decrease in disease activity) was seen in 37% of patients. In those patients remaining on maintenance therapy, very good partial response was seen in 53% of patients, whereas in patients who received stem cell transplantation, the response observed was 78%. In summary, the combination of bortezomib, doxorubicin and dexamethasone is highly active as part of the initial treatment of multiple myeloma. Subsequent stem cell transplantation in eligible patients is further associated with a high rate of response and improved survival. Frontline Bortezomib / Melphalan / Prednisone therapy in elderly MM patients Multiple myeloma affects a significant proportion of elderly patients, many of whom are not eligible for stem cell transplantation. Melphalan and prednisolone have been traditionally used as first line treatments in these patients. However, response rates are limited with these treatments. Some studies have shown that the combination of bortezomib with this traditional regime results in amplification of the effects against multiple myeloma cells with minimal side effects. A study was performed to compare the efficacy and safety of the combination of Bortezomib, melphalan and prednisolone in 60 untreated multiple myeloma patients, who were equal to or more than 65 years old. Patients received bortezomib on days 1, 4, 8, 11, 22, 25, 29 and 32 for four 6-week cycles, then on days 1, 8, 15, and 22 for five 5-week cycles. This was in addition to melphalan and prednisolone given on the first four days of each cycle. Factors such as the response rate, overall survival, time to progression of disease and the survival periods that were free of disease events were investigated. The triple combination of bortezomib, melphalan and prednisolone was compared with melphalan and prednisolone alone. In 53 patients, the response rate with triple combination therapy was 88%, with 32% achieving complete remission and 11% with non-complete remission. This response rate was higher in comparison to results obtained in previous studies of patients who were given melphalan and prednisolone alone. After an average follow-up period of 26 months, the approximate time to progression was 27.2 months. The treatment regimes were well tolerated, with an average treatment duration of 9 months. Following an extended period of study and observation, the combination of bortezomib, melphalan and prednisolone has been shown to produce superior effects in comparison to melphalan and prednisolone in elderly patients with multiple myeloma. Bortezomib, ascorbic acid and melphalan upfront therapy You may have heard about some concerns raised regarding side effects associated with steroid and thalidomide containing combination therapies for the treatment of multiple myeloma patients. Results are now available investigating the use of alternative agents such as melphalan and ascorbic acid with bortezomib in the treatment of patients with multiple myeloma. A recent study was conducted by Berenson et al, involving over 20 newly diagnosed patients with symptomatic multiple myeloma. A combination of bortezomib, oral ascorbic acid and melphalan was administered to these patients for 28 day cycles, up to a maximum of 8 cycles. Bortezomib was given to patients on days 1, 4, 8, and 11 (in the mornings) followed by a rest period for the rest of the month. Oral ascorbic acid and melphalan were both administered on days 1-4 (in the evenings) of each cycle. Groups of patients who experienced no disease progression then proceeded to treatment with bortezomib every other week until progressive disease recurred. 23 newly diagnosed multiple myeloma patients have taken part in the study, with results from 20 patients evaluated for response. A significant degree of response has occurred in 70% of patients and five patients (25%) achieving stable disease. In conclusion, the combination of bortezomib, melphalan and ascorbic acid administered for 28 day cycles in newly diagnosed multiple myeloma patients shows promising results with minimal side effects and toxicities. Multiple studies have confirmed the efficacy of bortezomib in the treatment of patients with relapsing / remitting multiple myeloma. Further research has been performed, suggesting that bortezomib holds an increasing role in first line treatment of newly diagnosed and untreated multiple myeloma patients. In combination with other medications such as dexamethasone, thalidomide and doxorubicin, patients have demonstrated high response rates, accompanied by limited side effects. To date, most of these combination treatment regimes have been well tolerated in both young and elderly patients, either as sole treatment or as pre-treatment prior to receiving further therapy with stem cell transplantation.