Bortezomib (Velcade) & Combination Therapies as First Line Treatment for Multiple Myeloma

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, ranging from its genetics and microenvironment, to treatment options and novel approaches. Promising new clinical data and the effectiveness of certain treatments in multiple myeloma were discussed and further explored.

Multiple myeloma is a common haematological malignancy, characterised by abnormal plasma cells and inappropriate immune function, with signs and symptoms experienced due to disease pathology such as bony destruction, pathological fractures and impaired renal function. There are multiple therapies for the treatment of multiple myeloma, to provide symptomatic relief and help retard disease progression. Recent advances in treatment have helped decrease the occurrence and progression of disease, with combination therapies involving bortezomib showing positive results. Not only have these results been demonstrated in patients with relapsing / remitting myeloma – bortezomib combination therapy has also proven to be highly effective in untreated patients and as first line treatment in newly diagnosed patients. New Agents Targeting Myeloma Bone Disease Pathology There is an abnormal release of growth factors from inappropriately functioning osteoclasts, which leads to tumour growth and bone destruction. This often results in distressing symptoms for patients, with bony pain being one of the most difficult pains to treat. In relation to disease processes and underlying pathology, there is an increase in interactions between tumour and marrow stromal cells, resulting in release of factors such as RANKL and interleukin 6, MCP-1 and TNF alpha. A signalling pathway known as the NF-kappaB pathway plays a significant role in these processes – inhibition of this pathway should have considerable benefits for patients suffering from multiple myeloma. P62 is a member of this signalling pathway, thus inhibition of p62 expression / activity is postulated to have effects against processes such as bony destruction and various production of factors which are involved in tumour-stromal interactions. Results from a study performed by Roodman et al support the role of p62 in multiple myeloma and its potential as a new, novel molecule to target for the treatment of bony disease associated with multiple myeloma. ⁹ Pharmacogenomics study of Bortezomib activity in multiple myeloma As part of the development process in creating bortezomib for the treatment of multiple myeloma, pharmacogenetic gene expression profiling (GEP) of pre-treated tumour biopsies was performed. This was done with a view to identifying predictive classifiers of response in clinical trials and also to further define biological pathways related to drug sensitivity. A pharmacogenomics 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 Phase 2 or 3 trials involving bortezomib. Genes associated with response or progressive disease after treatments with bortezomib were tested for. These genes were then compared and multiple differentially expressed genes were identified – approximately 200 genes were over-expressed in response to treatment and 500 genes were over-expressed in progressive disease. Response associated genes included: TRADD, TANK and CFLAR (signalling molecules) whereas progressive disease associated genes involved: NRAS (oncogenes), DAP3 and CTAG (cancer antigens). Investigative tools were then used to further extend these findings, identifying activation of NFKB and adhesion as response related, whereas mitochondrial pathways and protein synthesis were related to progressive disease. In particular, these pathways were linked to bortezomib and not to dexamethasone. In conclusion, this study demonstrates the multitude and range of biological pathways expressed in multiple myeloma and the usefulness of genomics to connect pathways with treatment such as bortezomib. ⁷ Lenalidomide and / or Bortezomib in multiple myeloma: influence on osteoclast function Symptoms of bone pain, skeletal and pathological fractures experienced with multiple myeloma are due to inappropriate and accelerated osteoclast activation, as well as osteoblast inhibition. Bortezomib has demonstrated exciting results in patients with multiple myeloma, with studies indicating that bortezomib has strong inhibitory effects on osteoclast function. A study was conducted by Breitkreutz et al, to investigate the effects of drugs such as bortezomib and lenalidomide on human osteoclast function. Both patients with multiple myeloma and healthy volunteers took part in this study. Peripheral blood mononuclear cells (PBMC) were collected from participants and stimulated with the receptor activator of NFkappa-B ligand (RANKL) and M-CSF to induce osteoclast formation. This was performed in the presence of lenalidomide or bortezomib. The study found that both agents inhibited osteoclast differentiation and activity, directly reducing the rate of progression and development of osteolytic bony lesions. Major growth and survival factors implicated in multiple myeloma were also studied – their secretion from osteoclasts was down-regulated with both bortezomib and lenalidomide, which subsequently reduces survival rates of multiple myeloma in the bone marrow. ⁴ Another study investigating the effects of bortezomib on osteoclast activity was performed by Boissy et al, which involved continuous and intermittent treatment of osteoclasts with various concentrations of bortezomib. Results showed that continuous treatment of osteoclast cultures with bortezomib at concentrations of 4nM and higher was highly toxic to osteoclasts and monocytes. In comparison, a 3 hour pulse treatment with bortezomib followed by a 3 day culture without bortezomib was not toxic to both osteoclasts and monocytes, even at high concentrations. However, this pulse period was highly toxic to myeloma cells. These results suggest that bortezomib temporarily inhibits osteoclast activity both in vitro and in vivo. ³ PETHEMA Trial of Alternating Bortezomib and Dexamethasone as Induction Regimen Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): Efficacy and Clinical Implications of Tumor Response Kinetics 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 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 82% of reduction in the M-protein achieved by the end of the first two cycles. This decrease in the M-protein was not significantly different with dexamethasone and with bortezomib. Low toxicity rates were seen, with 25% of patients experiencing a mild peripheral neuropathy and low grade thrombocytopenia. 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. ¹⁰ Phase 1 / 2 Studies of Upfront Lenalidomide / Bortezomib / Dexamethasone / Doxorubicin in Multiple Myeloma A phase 1/2 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, appropriate dose escalation was carried out. Results from this study show that the combination of lenalidomide, bortezomib and dexamethasone is well tolerated and efficacious in newly diagnosed multiple myeloma patients. There have been no dose limiting toxicities observed to date, however dexamethasone dose reduction has been required in most patients later in the treatment regime. Enrolments are continuing, with 10 additional patients to be recruited to further investigate the maximum tolerated dose of combination therapy. ⁸ Another study conducted by Jakubowiak et al presented updated results of a phase II clinical trial involving bortezomib, doxorubicin and dexamethasone in newly diagnosed multiple myeloma patients. This trial also 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 evaluable for response. ⁵ By the end of the studied treatment regime, a partial response was observed in 89% patients, with a very good partial response in 50%. Complete and non-complete remission 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 very good partial 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. ⁵ 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 employed as first line treatments in these patients, but complete and sought after responses are not commonly seen. Some pre-clinical studies have shown that the combination of bortezomib with this traditional regime results in significant in-vitro synergy with minimal side effects, in patients with relapsed / refractory multiple myeloma. A phase 1/2 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 and the event-free survival with the triple combination of bortezomib, melphalan and prednisolone were compared with melphalan and prednisolone alone. In 53 patients who were suitable for evaluation, 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 a median follow-up period of 26 months, the median 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 is clearly superior in comparison to melphalan and prednisolone in elderly patients with multiple myeloma. This is an important finding, providing an additional option of treatment for these patients, who are ineligible for stem cell transplantation. ⁶ Bortezomib, ascorbic acid and melphalan upfront therapy There have been concerns raised about steroid and thalidomide containing combination therapies for the treatment of multiple myeloma patients. Results are now available that support the use of alternative agents such as melphalan and ascorbic acid with bortezomib in the treatment of patients with multiple myeloma. A recent phase II 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. Certain groups of patients without 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. ² Efficacy and safety of liposomal doxorubicin, bortezomib and dexamethasone in the treatment of previously untreated multiple myeloma patients: Impact of the cytogenetic profile Bortezomib in addition to liposomal doxorubicin, which is used as first line treatment in patients with multiple myeloma has demonstrated increased response rates compared to conventional therapy. In one particular study, the combination of pulsed dexamethasone was added to further investigate response rates. Newly diagnosed multiple myeloma patients, who were also eligible for further treatment with autologous stem cell transplant were involved in a phase 2 clinical trial conducted by Belch et al. 56 patients were involved, who were given three to four 21-day cycles of combination induction therapy involving bortezomib on days 1, 4, 8, 11, liposomal doxorubicin on day 4 and pulsed dexamethasone on certain days, depending on the treatment cycle and rapidity of remission achieved. Subsequently, these patients were then followed up after engraftment to determine response rates and time to progression of disease. In 44 evaluable patients out of the original 50, the best response post-induction of treatment was 95%, with 20.4% achieving a combination of complete and non-complete remission. The average time taken to achieve the best response post-induction of therapy was 55 days. Importantly, in the 29 patients who have gone on to receive transplantations, stem cell collection was not compromised post-induction therapy. In the group of patients for which cytogenetic data is currently available (approximately 50% patients), an overall response rate of 100% was observed. From these results, we can see that the response achieved with the combination of bortezomib, doxorubicin and dexamethasone as first line treatment of patients with multiple myeloma is independent of the cytogenetic profile, with limited side effects. ¹ Multiple clinical trials 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, studies show that there is a high response rate, accompanied by limited side effects. Furthermore, trials have investigated response rates with non steroid / non thalidomide containing preparations in newly diagnosed patients, to minimise toxic 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. References

1. Belch A, Reece D, Bahlis N, et al. Efficacy and safety of liposomal doxorubicin [DOXIL/CAELYX], bortezomib [VELCADE] and dexamethasone in the treatment of previously untreated multiple myeloma patients: Impact of cytogenetic profile, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
2. Berenson J, Woytowitz D, Flam M, et al. Bortezomib + ascorbic acid + melphalan upfront therapy, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
3. Boissy P, Lund T, Andersen T L, et al. Intermittent treatment wih bortezomib inhibits transiently osteoclast resorptive activity, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
4. Breitkreutz I, Raab M S, Vallet S, et al. Lenalidomide and bortezomib in multiple myeloma: influence on osteoclast, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
5. Jakubowiak A, Al-Zoubi A, Kendall T, et al. Combination therapy with bortezomib (Velcade), Doxil, and dexamethasone(VDD) in newly diagnosed myeloma: updated results of phase II clinical trial, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
6. Mateos M V, Hernandez J M, Hernandez M T, et al. Frontline VMP in elderly MM patients: extended follow-up, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
7. Mulligan G, Pradines J, Roels S, Pharmacogenomics study of bortezomib activity in myeloma,11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
8. Richardson R G, Jagannath S, Raje N S, et al. Phase 1/2 study of upfront rev/vel/dex in mm: early results, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
9. Roodman G D, Kurihara N, Hiruma Y. New Agents Targeting Myeloma Bone Disease, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.
10. Rosinol L, Oriol A, Mateos M V, et al. Final Results of a Phase II PETHEMA Trial of Alternating Bortezomib and Dexamethasone as Induction Regimen Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): Efficacy and Clinical Implications of Tumor Response Kinetics, 11th International Myeloma Workshop, Kos, Greece, June 25-30 2007.