From June 25th – 30th in 2007, the International Myeloma Foundation presented the widely anticipated XIth International Myeloma Workshop. This workshop covered many issues about multiple myeloma, ranging from its genetics to treatment options and new novel approaches.
Multiple myeloma is a cancer affecting the plasma cells, which are located in our bone marrow. Plasma cells are an important part of our immune system, helping produce antibodies (also known as immunoglobulins) 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. Although patients benefit from treatment, there is no cure for multiple myeloma and many people eventually develop advanced, relapsing disease. Relapsed or refractory disease is referred to cases where you demonstrate a minor response or better to treatment, but then the disease progresses and you relapse, requiring further treatment. It can also refer to cases where your disease progresses within 60 days of your last therapy. The average survival can vary, ranging from a minimum of 6-7 months and responses to further treatment regimes are limited. This decrease in duration of response to treatments may be a result of your body becoming resistant to the drug treatment and possibly also changes in the course of the disease in your body. Some features that have been linked with a poorer prognosis include: particular chromosome deletions; high levels of a protein called beta 2 microglobulin; and low levels of a molecule called albumin. This has resulted in the development of new novel treatment therapies that aim to target the natural course of multiple myeloma and its environment. New treatments such as bortezomib (velcade) and bortezomib based combinations (including medications such as thalidomide and lenalidomide) have demonstrated exciting results in this area. Bortezomib (velcade) is an anticancer agent used to treat patients with multiple myeloma. It acts by inhibiting proteosomes, which are enzyme complexes located within cells, to break down old proteins and help regulate the cell function. In cancer cells, proteosomes may contribute to the excessive reproduction and survival of abnormal cells. Bortezomib works both directly on multiple myeloma cells to sensitise them to the effects of chemotherapy, and also on the surrounding bone cells to inhibit myeloma cell survival. Bortezomib and bortezomib based combinations in the treatment of relapsed / refractory mulitple myeloma Multiple studies have demonstrated the clinical effectiveness of treatment with bortezomib in patients with relapsed or refractory multiple myeloma. The SUMMIT study involved 202 patients with relapsed / refractory myeloma. Patients were administered bortezomib treatment on certain days of a 21 day treatment cycle. In cases where sub-optimal responses were observed, a steroid medication called dexamethasone was added. Patients who achieved complete or partial response after two treatment cycles had significantly longer survival rates. Additional outcomes that were assessed included quality of life, tiredness, pain and other disease symptoms, which were significantly improved with bortezomib treatment. After an average of 23 months follow-up, the overall survival was approximately 17 months and the average duration of response was 12.7 months. The CREST study was another randomised trial that studied the effects of bortezomib at different doses of 1.0 or 1.3mg/m2. Dexamethasone was also added for cases with sub-optimal response. At both doses of bortezomib, activity against the disease was achieved. Side effects were also lower in the group that received a lower dose of bortezomib. These results suggest that if patients are suffering from side effects or unable to tolerate the recommended treatment dose of 1.3mg/m2 of bortezomib, a dose of 1.0mg/m2 may also achieve comparable results. The APEX study was a larger study involving 669 patients with relapsed and relapsed / refractory multiple myeloma. The effectiveness and safety of bortezomib was compared against high dose dexamethasone. However, the trial was terminated early when an analysis of results performed during the study demonstrated the superiority of bortezomib over dexamethasone. This treatment advantage was seen in all areas of response rates, average time to progression and survival rates. Final results have confirmed these findings, with survival benefits being observed in patient follow-up at 6 months. A combination of multiple medications has been used to treat patients with multiple myeloma. Some of these agents include; bortezomib, cyclophosphamide and prednisolone, all of which have been used to treat patients with relapsed / refractory multiple myeloma. The combination of all three of these agents has demonstrated an 82% response rate in 50 eligible patients, and an average disease free survival of 12 months. Combination therapies involving newer novel medications used to target multiple myeloma include: bortezomib plus a special form of doxorubicin, known as pegylated liposomal doxorubicin (PLD), and thalidomide; and bortezomib, melphalan, prednisolone and thalidomide. One study demonstrated a response rate of 56% in 18 patients treated with the first combination of medications. These patients had already received multiple other treatments, yet 22% still gained complete response. The second regimen (bortezomib, melphalan, prednisolone and thalidomide) was studied in a trial that involved the administration of bortezomib on particular days of a 35-day cycle, with melphalan and prednisolone on days 1-5, and thalidomide given daily. The response rate in all 30 patients was 67%. Patients experiencing their first relapses showed an improved response compared to those who had multiple relapses. Lenalidomide has also been investigated in combination with bortezomib. A trial involving patients with relapsed / refractory multiple myeloma demonstrated that the combination was well tolerated, with responses in 39% of patients. Lenalidomide may represent an encouraging alternative treatment for resistant patients, as most of these study patients had already received prior thalidomide and bortezomib treatment. Further studies involving lenalidomide are currently underway. The novel treatment tanespimycin (HSP-90) has also shown promising results in combination with bortezomib. Regardless of whether patients had been exposed to bortezomib before, response rates were achieved in 35% of patients. Patients with relapsed / refractory multiple myeloma present a significant medical challenge that needs to be tackled. Treatments such as bortezomib (both alone and in combination with other therapies) is a promising option for such patients, especially for older patients and patients with risk factors that may indicate more resistant disease. Newer treatments that can further improve responses in resistant patients are now being developed. Further studies are being conducted to evaluate the role of bortezomib in treatment of patients with light chain myeloma and advanced bone disease that has spread to other parts of the body. Frontline treatment of multiple myeloma – bortezomib’s role in multiple myeloma patients eligible for high-dose therapy Frontline treatment for patients with multiple myeloma, (over 70 years of age), involves high dose therapy (HDT) in addition to autologous stem-cell transplantation (ASCT – this refers to stem cells that are collected from an individual and given back to that same individual). This combination of treatments demonstrates greater benefits for patients in terms of improved overall response and complete response rates. Prior to receiving treatment with HDT and ASCT, patients can receive neoadjuvant chemotherapy to reduce the tumour burden (eg involving agents such as vincristine and doxorubicin). Neoadjuvant chemotherapy refers to the use of medications as a precursor to treat / shrink the primary cancer, so that additional treatments are more effective. However, these conventional agents have been linked with low complete response rates, thus leading to the research and development of other alternative agents. Bortezomib has been developed and studied in an aim to improve responses prior to treatment with HDT and ASCT, and also to improve overall survival. Bortezomib’s effectiveness has been investigated both as a single agent and also in combination with other agents. As a single agent, bortezomib has shown promising results and activity in patients with multiple myeloma. In combination, marked improvements in clinical outcomes, response rates and patient survival have been observed. Jagannath and his colleagues conducted a study in 49 newly diagnosed patients with multiple myeloma. The overall response, complete response and survival rates were measured with bortezomib treatment, with or without dexamethasone. Bortezomib was administered for up to six, three week cycles. Dexamethasone was added to patients achieving a sub-optimal response. The response rate was 88%, including 18% achieving complete / near-complete response and 20% having very good partial response. Side effects and toxicities were both expected and manageable. After a median follow-up period of 26.7 months, the estimated 2 year survival was 85%. A further 25 patients went on to receive HDT-ASCT, with an increased estimated 2 year post-transplant survival rate of 91%. Other study groups including the IFM and PETHEMA groups have also investigated the effects of bortezomib and dexamethasone regimens in patients with multiple myeloma. IFM conducted a study involving 48 patients, who were given four cycles of bortezomib plus dexamethasone. The response rate was 67%, with 21% achieving complete response and 10% with a very good partial response. 42 of these patients went on to receive treatment with HDT-ASCT. Post treatment response rates were 90%, with 33% gaining complete response and 21% a very good partial response. The PETHEMA group investigated a different course of therapy with bortezomib and dexamethasone. A study involving 40 patients who had recently been diagnosed with multiple myeloma was performed. Bortezomib and dexamethasone were administered in alternating cycles. The best response rate that was achieved was 67%, with 13% achieving complete response and 10% very good partial response. Side effects and toxicities were either mild or moderate. Half of these patients have received further treatment with HDT-ASCT and response rates three months after transplantation stand at 80%. As a result of the positive effects demonstrated from combination therapy with bortezomib plus dexamethasone, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Multiple Myeloma has added this combination as a first-line treatment option for patients proceeding to HDT-ASCT. The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has also been added to these guidelines as a result of its efficacy in clinical studies. The CALGB conducted another study involving 63 newly diagnosed multiple myeloma patients. These patients were given eight, three week cycles of bortezomib plus liposmal doxorubicin. The response rate observed in 29 patients who had completed the course of therapy was 79%, including a 28% complete response rate. Bortezomib in combination with thalidomide and dexamethasone (VTD) has also been studied. Bortezomib, thalidomide, and dexamethasone have been combined with cisplatin, doxorubicin, cyclophosphamide, and etoposide (VDT-PACE) in a study involving 12 patients. After two, five week treatment cycles, the overall response rate was 83%, including 17% with complete / near-complete response. Following HDT-ASCT and subsequent maintenance therapy with low-dose thalidomide and dexamethasone, the overall response rate was 100%. An important finding from these trials was that the use of bortezomib prior to HDT-ASCT treatment did not interfere with harvesting of stem cells needed for subsequent transplantation treatment. The use of these treatments has shown significant benefits in patients with multiple myeloma. High rates of complete / near-complete responses has been achieved with these agents. Not only has bortezomib and its combination therapies demonstrated efficacy in frontline treatment of myeloma, but in patients with poor prognostic factors, bortezomib has also appeared to be a hopeful alternative. Follow-up data and research is required to further investigate survival benefits and optimise the role of bortezomib as both frontline treatment and for relapsed / refractory patients with multiple myeloma.