From June 25th – 30th in 2007, the International Myeloma Foundation presented the widely anticipated XIth International Myeloma Workshop. This workshop provided comprehensive coverage of issues surrounding multiple myeloma, ranging from its genetics and microenvironment, to treatment options and novel approaches.
Multiple myeloma is the second most common haematological malignancy, characterised by excessive production of abnormal plasma cells and intact monoclonal immunoglobulins or Bence-Jones proteins. Advances in treatments have allowed many patients to experience an improved quality of life, yet there is still no cure for multiple myeloma. Many patients will eventually suffer from advanced, relapsing disease, with few treatment options to choose from. Relapsed / refractory disease is defined as patients who achieve a minor response or better, followed by relapse and then progress on salvage therapy, or those who experience disease progression within 60 days of their last therapy. Median survival rates can range from a minimum of 6-7 months and responses to any treatment regimes are limited.3This decrease in duration of response to treatment regimes reflects both emerging drug resistance and possibly also changes in the disease biology in individual patients. Although prognostic factors in refractory disease are still being comprehensively defined, features that have been linked with a poorer prognosis include those patients with; particular chromosome deletions (t(4;14) or t(14;16), deletion 17 or 13), hypodiploidy, high beta 2 microglobulin and low serum albumin.3This has resulted in the development of new novel treatment therapies that aim to target disease biology and tumour environment, to improve the prognosis of patients suffering from advanced stages of disease. Bortezomib (Velcade) and bortezomib based combinations (including thalidomide and lenalidomide) have demonstrated exciting results in this area. Bortezomib is now being referred to as a ‘paradigm of drug development’, where it was initially approved via an accelerated approval program for treatment of multiple myeloma in the relapsed and refractory patient group, before quickly gaining full approval in the relapsed setting.1,3Bortezomib is an antineoplastic agent which acts as a proteosome inhibitor. The effects of bortezomib are mediated through binding to the beta 5 subunit of the proteosome complex and also inhibition of a specific nuclear factor signalling pathway, to promote events such as myeloma cell apoptosis and decreased cytokine transcription and secretion. The nuclear factor (NF-κB) remains inactivated due to its binding with a particular inhibitory protein (IκB-α). Consequently the anti-apoptotic / growth response is overcome and myeloma cells may be more susceptible to stress. Resistant cells are now more sensitised and susceptible to the effects of combination chemotherapy with other agents.3Bortezomib and bortezomib based combinations in the treatment of relapsed / refractory mulitple myelomaMultiple trials have confirmed the clinical efficacy of bortezomib based treatment approaches in patients with relapsed or refractory multiple myeloma. The SUMMIT study involved 202 patients with relapsed / refractory myeloma. This was one of the first open label, Phase II trials to assess the effects of bortezomib on days 1,4,8 and 11 of a 21 day treatment cycle. In cases where sub-optimal responses were observed, dexamethasone was added. Patients who achieved complete or partial response after two treatment cycles had significantly longer survival rates, and those with complete or near-complete response demonstrated longer survival rates than those with partial response. Additional outcomes that were assessed included; quality of life, fatigue, pain and other disease symptoms, which significantly improved with bortezomib treatment. After a median of 23 months follow-up, average overall survival was 17 months and the median duration of response was 12.7 months.3The CREST study was another open label randomised trial that studied the effects of bortezomib at doses of 1.0 or 1.3mg/m2, administered on the same treatment cycle as above. Dexamethasone was also added for cases with suboptimal response. At both doses of bortezomib, disease activity was achieved. Side effects were also lower in the group that received a lower dose of bortezomib. These results suggest that in patients unable to tolerate the recommended treatment dose of 1.3mg/m2 of bortezomib, a dose of 1.0mg/m2 may also achieve acceptable results.3The APEX study was a randomised phase 3 trial involving 669 patients with relapsed and relapsed / refractory multiple myeloma where the efficacy and safety of bortezomib was compared against pulsed, high dose dexamethasone. The trial was terminated during an interim analysis that demonstrated the superiority of bortezomib over dexamethasone, in all areas of response rates, median time to progression and survival rates. Final results have confirmed these findings, with survival advantages being observed in patient follow-up at 6 months.3Combination therapies for multiple myeloma include bortezomib, cyclophosphamide and prednisolone, all of which have been used to treat patients with relapsed / refractory multiple myeloma. The combination of all three agents has demonstrated an 82% response rate in 50 eligible patients, and a median event free survival of 12 months. A recent phase 3 study has shown that the combination of bortezomib plus pegylated liposomal doxorubicin (PLD) was comparable to that achieved with bortezomib alone.3Combination therapies involving newer novel agents include bortezomib (velcade) plus PLD and thalidomide (VDT combination); and bortezomib (velcade), melphalan, prednisolone and thalidomide (VMPT). One study demonstrated a response rate of 56% in 18 patients treated with the VDT combination. These patients had already been heavily pre-treated, yet 22% still gained complete response. The VMPT regimen was studied in a phase I / II trial that involved the administration of bortezomib 1.3 mg/m2 on days 1, 4, 15 and 22 of a 35-day cycle, with melphalan 6 mg/m2 and prednisone 60 mg/m2 on days 1-5, and thalidomide 50 mg 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.3Lenalidomide has also been investigated in combination with bortezomib. A phase I trial involving patients with relapsed / refractory multiple myeloma demonstrated that the combination was well tolerated, with responses in 39% of patients, including 6% achieving complete response rates. Lenalidomide may represent an encouraging alternative treatment for resistant patients, as most of these study patients had already received prior thalidomide and bortezomib treatment. Phase II studies involving lenalidomide are currently underway. The novel treatment tanespimycin (HSP-90) has also shown promising results in combination with bortezomib. This combination not only evoked responses in those who had not been exposed to bortezomib before, but also achieved responses in those who had a history of previous exposure. 35% of patients demonstrated response rates, with 14% achieving complete / near-complete responses.3 Patients with relapsed / refractory multiple myeloma present a significant medical challenge that remains to be tackled. Bortezomib and its efficacy, both alone and in combination with other therapies, is a promising option for such patients, especially in older patients and those with poorer prognostic factors such as elevated beta 2 microglobulin and low serum albumin. Newer, novel treatments that can further improve responses in these patients are now being developed, guided by our understanding of gene expression and cellular signalling pathways. Further studies are being conducted to evaluate the role of bortezomib in treatment of patients with light chain myeloma and advanced, metastatic bone disease.3Frontline treatment of multiple myeloma – bortezomib’s role in multiple myeloma patients eligible for high-dose therapyFrontline treatment for patients with multiple myeloma, (over 70 years or age), involves high dose therapy (HDT) in addition to autologous stem-cell transplantation (ASCT). This combination of treatments demonstrates greater benefits for patients in terms of improved overall response and complete response rates. Some studies have also shown improved overall survival and a longer event free survival in patients who achieve complete / very good partial response rates, in comparison to other chemotherapeutic regimes. Prior to receiving treatment with HDT and ASCT, patients receive neoadjuvant therapy to reduce the tumour burden (eg involving chemotherapy agents such as vincristine and doxorubicin). 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 post induction responses and overall survival. Bortezomib has been investigated both as a single therapeutic agent and also in combination with other agents as induction therapy prior to treatment with HDT and ASCT. 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. These results are applicable to patients both following induction treatment and post transplantation.2Jagannath and his colleagues conducted a phase 2 study in 49 newly diagnosed patients with multiple myeloma. Overall response, complete response and survival rates were measured with bortezomib treatment +/- 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. Adverse events 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%.2 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 phase 2 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 and post transplantation response rates were 90%, with 33% complete response and 21% very good partial response. This group of researchers is now comparing this treatment combination with vincristine/ doxorubicin and dexamethasone prior to HDT-ASCT treatment.2The PETHEMA group investigated a different course of therapy with bortezomib and dexamethasone in a phase 2 study, involving 40 patients who had recently been diagnosed with multiple myeloma. The agents were administered in alternating cycles, starting with bortezomib for six cycles of treatment. The best response rate that was achieved was 67%, with 13% achieving complete response and 10% very good partial response. Toxicities were either mild or moderate, however 15% of patients experienced grade 3 neutropenia. Half of these patients have received further treatment with HDT-ASCT and response rates three months after transplantation stand at 80%, with 40% complete response and 20% very good partial response.2As a result of the 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 therapeutic 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. In one study, 21 patients were treated with four, three week cycles of PAD. The response rate was 95%, with 29% complete response / near complete response. Following HDT-ASCT in 18 patients, the overall complete / near-complete response rates increased to 57%.2The CALGB conducted another phase 2 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 28% complete response. The regime was well tolerated by most patients, with six patients having proceeded on to HDT-ASCT.2Bortezomib 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 phase 1 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%.2A noteworthy finding from these trials was that the use of bortezomib prior to HDT-ASCT treatment did not interfere or hamper with harvesting of stem cells needed for subsequent transplantation treatment. The time to engraftment was also not affected. The use of these treatments has shown significant benefits in patients with multiple myeloma, reflected in the high rates of complete / near-complete responses 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. Further follow-up data is required to quantify survival benefits and optimise the role of bortezomib in both frontline treatment and also for relapsed /refractory patients with multiple myeloma.2References
- FDA Approves Velcade for Multiple Myeloma Treatment, [online] 2003 [cited 5th November 2007]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2003/NEW00905.html
- Jagannath S. The role of bortezomib in myeloma patients eligible for high-dose therapy, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
- Richardson P, Schlossman R, Ghobrial I, et al. The treatment of relapsed and refractory myeloma: Focus on bortezomib and bortezomib-based combinations, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.