Mohamad A Hussein
Myeloma Research Program
Cleveland Clinic Myeloma Research
Multiple myeloma is a malignant process characterised by a clonal B-cell tumour of slowly proliferating plasma cells within the bone marrow.(1) Until recently, therapy for multiple myeloma has focused on the use of chemotherapy in different forms and combinations (including in an intensified manner) in the hope of eliminating or reducing the tumour burden.(2) Chemotherapy administered in a traditional fashion or in high doses in different forms and schedules positively yet minimally impacted on overall survival rates in multiple myeloma.(3,4) The reintroduction of thalidomide in the 1990s has resulted in a change in the therapeutic paradigm, mainly because of the studies that were carried out to understand the pathophysiology and the biology of the disease.(5) Over the past few years new agents have been introduced to the therapeutic armamentarium, and others are being actively studied.
Proteasome inhibitors were introduced into clinical trials for haematological malignancies based on the central role of nuclear factor κB (NFκB) in cell division. NFκB is a protein central to the pathophysiology of multiple myeloma. The Rel/NFκB family of proteins are inducible dimeric transcription factors that recognise and bind a common sequence motif in nuclear DNA.(6–9) NFκB, the major transcription factor in this family, is a p50/RelA heterodimer (p50/p65) present in the cytoplasm of almost all cells.(9,10) NFκB regulates cell growth and apoptosis, as well as the expression of various cytokines, adhesion molecules and their receptors.(11) In the cytoplasm, NFκB is normally bound to its inhibitor IκB.(9) When cells are stimulated (eg, by cytokines, stress or chemotherapy), signalling cascades are triggered that lead to the activation of the IκB kinase, a heterodimeric protein kinase that catalyses IκB phosphorylation.(7) IκB is then degraded by the proteasome pathway, releasing free active NFκB. When activated (ie, released from IκB), NFκB translocates to the nucleus and binds to promoter regions of several target genes, thereby triggering their transcription. This leads to increased expression of various cytokines, chemokines, adhesion molecules and cyclin D that promote cell growth and survival.(7) NFκB activation also leads to increased expression of adhesion molecules such as intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 by multiple myeloma cells, thus facilitating the binding of the myeloma cells to stroma in turn causing NFκB-mediated upregulation of IL-6 secretion by stromal cells, which contributes to drug resistance.(12,13) Therefore, treatment strategies targeting NFκB, the malignant cell/stroma interaction and the complex cytokine network could result in regulating the growth and development of the myeloma cell.
Bortezomib (N-pyrazine carbonyl-l-phenyl‑alanine-l-leucine boronic acid; previously known as PS-341 or MLN-341), a boronic acid dipeptide, is a specific inhibitor of the proteasome pathway.(14,15) Bortezomib inhibits the proteasome pathway in a rapid and reversible manner by binding directly with the 20S proteasome complex and blocking its enzymatic activity. The proteasome pathway is important for the activation of NFκB, as it regulates the degradation of the NFκB inhibitor, IκB.(16,17) Several effects of bortezomib, including the induction of apoptosis in the malignant plasma cell, appear to be mediated through inhibition of NFκB. Bortezomib prevents the degradation of IκB and thereby inhibits NFκB activation.(6)
Based on its preclinical and phase I activity in multiple myeloma,(18) a phase II study (SUMMIT) of bortezomib was initiated in patients with relapsed and refractory multiple myeloma.(14) The dose established for bortezomib in the treatment of relapsed, refractory myeloma is 1.3mg/m(2) given twice weekly on days 1, 4, 8, and 11 every 21 days.(14) Dexamethasone (20mg the day of and after each bortezomib dose) was permitted if progressive disease was observed after two cycles or with stable disease after four cycles. A total of 202 heavily pretreated patients were enrolled. Of the 202 patients entered, 193 were evaluable for response. The overall response rate (complete response [CR] + partial response [PR] + minimal response [MR]) was 35% (67 of 193 patients). Seven patients (4%) achieved CR, and 12 (6%) had a near-CR (myeloma protein undetectable by electrophoresis but immunofixation positive). An additional 34 patients (18%) had a PR, and 14 (7%) achieved MR.(14) The median time to disease progression for bortezomib as a single agent was seven months, compared with three months reported for the patients’ previous therapy (p=0.01). In a landmark analysis, patients who achieved CR or PR by the end of the second cycle survived significantly longer than those achieving other types of response. Drug-related adverse events of any grade, occurring in ≥25% of patients, included nausea (55%), diarrhoea (44%), fatigue (41%), thrombocytopenia (40%), peripheral neuropathy (31%), vomiting (27%) and anorexia (25%). The most significant and common clinical adverse events were neuropathy at 12% and gastrointestinal toxicity in the form of nausea and diarrhoea; experience shows that gastrointestinal toxicity is probably a reflection of autonomic neuropathy.(19) In a randomised phase III study of 669 relapsed/refractory multiple myeloma patients who had been treated with one to three prior therapies, patients were assigned to receive bortezomib (327 patients) as outlined above versus dexamethasone (330 patients) 40mg per oral on days 1–4, 9–12, 17–20 once a week during five weeks for four cycles followed by 40mg per oral days 1–4 every 28 days for three cycles.(20) The primary endpoint was time to progression (TTP) using EBMT (European Group for Blood and Marrow Transplantation) criteria for progressive disease. The interim analysis, presented at ASCO 2004, showed that 254 progressive disease events had occurred. Patients receiving bortezomib demonstrated a highly significant benefit in TTP. Median TTP was 5.7 months (95% CI: 5.0, 7.9) on bortezomib and 3.6 months (95% CI: 3.2, 4.8) on dexamethasone (p<0.0001, log-rank test). Overall survival was longer on bortezomib (p=0.038, log-rank test), with 13 deaths on bortezomib and 24 on dexamethasone. However, at the time of the report, the median overall survival was not reached in either arm. The exact position of bortezomib in the management of multiple myeloma and its future development await larger studies and longer follow-up in both newly diagnosed and relapsed refractory myeloma patients. Moreover, because of its toxicity profile, especially past the first few cycles of therapy and the need to have the agent for maintaining the response achieved (TTP in patients who have received one to three chemotherapeutic regimens is 5.7 months vs 3.6 months with dexamethasone(20)), its use in new tolerable dosages and schedules as well as in combination therapy needs to be urgently explored.
Immune modulators: thalidomide
Immune modulators are another class of agents. The first compound to have been discovered in this class is thalidomide. Thalidomide and its analogues appear to have a broad spectrum of activities and may act as antimyeloma agents through several mechanisms.(21) Thalidomide may have a direct effect on the multiple myeloma cell and/or bone marrow (BM) stromal cell through free radical-mediated oxidative DNA damage, which may play a role in the teratogenicity of thalidomide.(22) Another probable target for thalidomide is its ability to interfere with the adhesion of multiple myeloma cells to BM stromal cells, which both triggers the secretion of cytokines that augment multiple myeloma cell survival(23–25) and confers drug resistance.(27) Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor 2 (bFGF-2) are secreted by multiple myeloma and/or BM stromal cells may play a role both in tumour cell growth and survival, as well as BM angiogenesis.(28,29) The activity of thalidomide could directly and/or indirectly decrease the different angiogenic factors supporting the multiple myeloma environments. This multifaceted activity of thalidomide makes it an attractive agent to use as a single agent or in combination therapy in the treatment of diseases such as multiple myeloma, which has a complex tumour microenvironment. Thalidomide and its role in the management of multiple myeloma have been reviewed.(19)
Supportive care is a critical aspect in the management of multiple myeloma, as the disease tends to damage more than one organ with the haematological system and the skeletal system being the most common targets. Relative to the skeletal system, in addition to the medical management,(30) the treatment of spine (the skeletal organ most commonly affected by multiple myeloma) pain should focus not only on the management of the pain but also on the treatment of the compression fractures, to prevent deformities and their consequences.(31) In a nonrandomised trial, kyphoplasty has shown a significant positive impact on the management of pain, as well as the ability to restore the lost height in a significant number of patients.(31) Other areas that deserve close follow-up and management are the hypercoagulable states associated with the disease or therapy for the disease.(32) The increased incidence of hypercoagulable state events associated with immune modulator chemotherapy combination regimens can be managed with the use of low-dose aspirin.(33) The use of aspirin (81mg a day) was not associated with any increased incidence of complications and might add a survival advantage that is not related to the prevention of the hypercoagulable events.(33) Anaemia is another common presenting feature of multiple myeloma, and its treatment should be managed aggressively.(34,35) The use of erythropoietin therapy appears to be associated with a survival advantage in in-vitro systems, as well as in multiple myeloma patients.(36–38)
Recent advances in the management of multiple myeloma are related to the discovery of new biological agents which, alone or in combination with traditional therapy, have improved response rates. It remains to be determined whether such improvements in response rates will translate into a survival advantage.(39) The SWOG (SouthWest Oncology Group) observations that the quality of response does not translate into a survival advantage should be viewed with caution, as these studies were carried out when none of the current biological agents was in use. Supportive care not only appears to be beneficial, as it relates to quality of life, but also might have an impact on overall survival. Studies are underway to address such issues, especially as they relate to the use of erythropoietin therapy.
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