From June 25th – 30th in 2007, the International Myeloma Foundation presented the 11th International Myeloma Workshop. This event was held on the beautiful and picturesque Kos Island in Greece. A wide range of guest speakers and distinguished medical doctors involved in areas of medicine such as the body’s blood and immune system, cancer and genetics were involved. This workshop covered many issues about multiple myeloma, ranging from it’s genetics to treatment options and new novel approaches. Debates were held, where speakers presented their opinions regarding treatment goals and what the future may hold for multiple myeloma patients.
Multiple myeloma is a cancer affecting the plasma cells, located in the 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. They occupy too much space in the bone marrow and stop other blood cells from being produced, such as red and white blood cells. The plasma cells from multiple myeloma also produce large quantities of abnormal antibodies, which cannot fight infection and can cause damage to the kidneys. Although patients benefit from treatment, there is no cure for multiple myeloma and many people eventually develop advanced, relapsing disease. Recent advances in treatment have helped decrease the occurrence and progression of disease, with combination therapies involving Velcade showing even more promising results than single agents alone. Velcade (also known as Bortezomib) is an anticancer agent used to treat patients with multiple myeloma. It is a relatively new treatment that has been approved as therapy for patients who have relapsed with multiple myeloma after two prior treatments and for those who have demonstrated resistance to their last treatment. It was approved for use, after discussions between the National Cancer Institute, the Food and Drug Administration (FDA) and the pharmaceutical company manufacturing the medication. There have been initial studies which showed a good response rate to Velcade, in patients who had demonstrated progression of disease on their most recent therapy and also those with relapsed multiple myeloma. Over the past few years, there have been further studies conducted, which evaluate the clinical benefits that Velcade offers, and also effects in combination with other therapies. Velcade is a proteosome inhibitor. Proteosomes are enzyme complexes located within cells, which 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. Velcade works both directly on multiple myeloma cells and also on the surrounding bone cells to inhibit myeloma cell survival. Combination Therapy – BCD (Bortezomib, Cyclophosphamide & Dexamethasone) for relapsing (recurring) Multiple Myeloma In patients with multiple myeloma, treatment with chemotherapy medication is often associated with high response rates. There is a complete remission rate of about 40%. Inevitably, all patients with myeloma that respond to treatment will require periods of treatment when the disease relapses, to prolong survival. A study was conducted by Delasalle and his team, involving 35 patients with multiple myeloma. This study compared the effects of combining Velcade with other medications that have activity against cancer cells. From December 2004 – 2006, an assessment was performed on treatment regimes composed of Velcade twice weekly for 4 infusions, Cyclophosphamide twice daily for 4 days and Dexamethasone on days 1-4, 9-12, 17-20. Partial remission was defined as a greater than 50% reduction of the abnormal proteins found in the serum and/or greater than 90% reduction of Bence Jones proteins (these are small proteins that can be found in the blood or urine, named after the English physician who first described them – Henry Bence Jones). Out of the 35 patients studied, partial remission was observed in 25 patients. The median remission time of these 25 patients with responsive disease was 6 months. Median survival of all patients was approximately 18 months. Remissions occurred in 14 out of 23 patients with myeloma that relapsed despite prior treatment with Thalidomide. Overall, the combined actions of Velcade and Cyclophosphamide were very effective in inducing remission in patients with relapsed disease. In addition, the tolerability and minimal side effects associated with this treatment regime promotes the usage of this combination of medications in patients with relapsing myeloma. Bortezomib, doxorubicin and dexamethasone (PAD) in advanced multiple myeloma A combination of therapy involving medications such as Velcade, Doxorubicin and Dexamethasone (PAD) has demonstrated encouraging results in patients with multiple myeloma. Sixty four patients with advanced and relapsed multiple myeloma were treated with this combination of PAD. Each cycle was repeated every month, with patients receiving an average of four treatment cycles. 67% of patients achieved at least a partial response to the combination, with 25% showing a very good partial response. From the start of treatment with PAD, the one year survival rate that was free from progression was 34%. The one year overall survival rate was 67%. In patients treated with PAD as a second line option, the one year survival rate free from progression was 57%. In conclusion, patients who are treated with combination therapies have demonstrated efficacy with these medications and response rates, despite being in the advanced and relapsing stages of disease. Bortezomib, Doxorubicin (Adriamycin) and Dexamethasone (PAD) in relapsed and refractory myeloma Other studies have also confirmed that triple therapy involving a combination of Velcade, Doxorubicin (Adriamycin) and Dexamethasone (PAD) is highly active in patients with multiple myeloma. A response rate of up to 95% has been reported. A study performed by Morris et al looked at patients previously treated with Vincristine, Adriamycin and Dexamethasone (VAD) or a similar regimen. Their aim was to see if this treatment was comparable to treatment with PAD. There were three main groups, each planned to recruit 23 patients. Group 1 was to consist of patients treated with Vincristine, Adriamycin and Dexamethasone (VAD) or a VAD-like regimen. These were patients who already had stem cell transplants. Group 2 would have similar patients but without previous transplant and Group 3 would consist of patients refractory (non-responsive) to VAD. To date, 30 patients have been enrolled. Response rates have been promising in both groups 1 and 2, with patients demonstrating improved responses when compared with their initial VAD or similar therapy. Response rates in group 3 have been mixed, with some patients remaining relatively refractory but others obtaining complete responses. Doxil + Velcade in Patients Who Have Had Previously Treated Myeloma and Prior Stem Cell Treatment A recent randomised trial has been conducted in patients with multiple myeloma comparing Doxil (a reformulated version of Doxorubicin) + Velcade to treatment with Velcade alone. Results showed that there was a delayed period to progression with the combination of Doxil + Velcade treatment. A particular group of patients were randomised to receive a combination of Doxil on day 4 and Velcade on days 1, 4, 8, 11 versus Velcade alone for up to eight 21-day cycles. Treatment with both Doxil + Velcade resulted in a significantly longer time to disease progression, increased duration of response, and higher overall response rates. The safety profile was also similar between the two groups of patients. Doxil + Velcade in Previously Treated High Risk Myeloma Another study conducted in patients with advanced multiple myeloma also evaluated the effects of Doxil and Velcade versus Velcade treatment alone. A clinical trial was performed in patients who had multiple myeloma with poor prognostic factors including: an elevated serum protein (called beta-2 microglobulin) or presence of disease that was non-responsive to initial treatment. Patients who had received at least one prior treatment with other agents were randomized to receive Doxil on day 4 and Velcade on days 1,4,8, and 11 versus Velcade alone, for up to eight 21-day cycles, or at least 2 cycles beyond complete remission or optimal response. Patients who demonstrated disease progression or unacceptable toxicities /side effects from treatment were removed from this trial. A significant improvement was seen in the time to disease progression with the combination of Doxil and Velcade in high risk patients. This combination even produced an improved time to disease progression that was similar to patients with a better initial prognosis. Complete and partial response rates were also higher with combination therapy. Overall, this study concludes that the combination of Doxil and Velcade versus Velcade offers advantages such as improved time to progression and also a better prognosis in higher risk patients groups. Bortezomib, Doxorubicin and Dexamethasone (PAD) combination therapy followed by additional Thalidomide and Dexamethasone (TD) treatment The effectiveness of additional treatment after combination PAD therapy has been further investigated, in an attempt to further rescue those patients with relapsed multiple myeloma. In a particular clinical trial performed by Lee and others, PAD followed by Thalidomide and Dexamethasone (TD) was administered to a select group of patients. The primary goal was to analyse it’s efficacy and safety profiles. Patients enrolled in the study were to be given 6 cycles of PAD, (Velcade on days 1, 4, 8 and 11, Doxorubicin on days 1-4, Dexamethasone on days 1-4) every 21 days. Patients showing response to 6 cycles of PAD went on to receive 12 cycles of TD (Thalidomide days 1-28 and Dexamethasone days 1-4, every 28 days). On the other hand, in patients with progression during PAD therapy, the regimen was changed to 12 cycles of a higher dose of Thalidomide (days 1-28) combined with the same regime of Dexamethasone. This study aimed to recruit 35 patients up until October 2007; preliminary results have been reported involving 25 patients. After two cycles of PAD, 14 patients showed some response, with 4 complete remissions. Overall response rates to 6 cycles of PAD was 84%, with 32% achieving complete remissions. Five out of 11 patients with TD showed further improvement of their response status with 2 attaining complete remission. In summary, the overall response to PAD followed by TD was 90%: with complete remission in 42%, non complete remission in 11%, very good partial remission in 5% and partial remission in 32%. After assessment of the safety profile in 24 patients, the most common side effect in the blood system was thrombocytopenia (low platelet counts). The sensory nerves were also affected in some cases. We can therefore conclude that PAD followed by TD in patients with relapsed multiple myeloma is effective and tolerable in most patients. Administration of Bortezomib, Melphalan and Dexamethasone in previously treated myeloma patients Questions still remain regarding the optimal dosage and combination of medications for the best treatment of multiple myeloma. Many medications including Velcade, steroid therapy, Doxorubicin and Vincristine have been shown to provide remarkable results in patients who have relapsing, advanced disease. In an attempt to answer this clinical question, a study was developed based on a protocol with six monthly courses of Velcade, Dexamethasone and Melphalan. To date, 21 patients with advanced multiple myeloma have been enrolled, with an average age of 64.5 years. All patients had already been treated with an average of two previous lines of treatment, including bone marrow transplant in seven patients and Velcade (alone or in combination) in five patients. These patients were also not eligible for bone marrow transplants. This study is still in progress – to date, the toxicity and efficacy has been evaluated for the first four cycles of treatment. After the first cycle, toxicity involving the blood system has been observed in 38% of patients. By the fourth cycle, this toxicity was seen in over half of all enrolled patients. Four patients have been removed from the study due to significant toxicity from treatment cycles. Five patients have achieved a very good partial remission (myeloma protein not detectable), 5 patients have a partial remission (reduction of myeloma protein > 50%) while two other patients have demonstrated a reduction of the myeloma protein, but with increase of bone marrow plasma cells. Two patients were in stable disease, one was in progression and two are not yet evaluated. Overall, there is no doubt that administration of Velcade, Melphalan, and Dexamethasone is a highly effective treatment for patients with advanced disease, even demonstrating additional benefits in those that have already been treated with many other therapies. However, toxicity to the blood stream is a major limiting factor. With future research and studies, optimising the dosage of these drugs to minimise side effects should be possible, to allow more people with multiple myeloma to receive these effective therapies.