Thalidomide in multiple myeloma: current status and future prospects (2002)

Thalidomide was introduced in Europe during the 1950s as a sedative agent and was found to be particularly effective at alleviating the symptoms of morning sickness. As is widely known, it was subsequently withdrawn in 1961 after its teratogenic properties were recognized, in particular, its ability to cause phocomelia. Damage to the fetus occurs early in pregnancy (from d 28–42 post conception) and the limb bud abnormalities are thought to be due to inhibition of normal vessel formation. Since that time, thalidomide's immunomodulatory effects have been recognized and it has been used, in a cautious and restricted manner, in the treatment of such disparate disorders as Behcet's disease, erythema nodosum leprosum, human immunodeficiency virus-associated oral ulceration and chronic graft-versus-host disease. More recently, the drug has been tested in a variety of solid and haematological malignancies, and has shown remarkable efficacy in patients with advanced multiple myeloma. Indeed, the use of thalidomide is arguably the most significant advance in the treatment of myeloma since the introduction of high-dose melphalan and autologous stem cell transplantation nearly 20 years ago. Many tumours require new vessel formation in order to support their continued growth (Folkman, 1974; Holmgren et al, 1995) and various lines of evidence suggest that neoangiogenesis is also important in the pathogenesis of myeloma. Myeloma bone marrow shows increased microvascularity and its density correlates with the clinical aggressiveness of plasma cell neoplasms (Vacca et al, 1994). Furthermore, the density of bone marrow vascularity has important prognostic implications such that patients with extensive vascularity have reduced overall survival (OS) (24 months) compared with patients with less extensive vascularity (53 months) (Rajkumar et al, 2000a). In addition, myeloma cells secrete a variety of angiogenic factors and their level of secretion is again correlated with activity of disease (Bellamy et al, 1999; Vacca et al, 1999). Thalidomide has proven anti-angiogenic activity as it can inhibit angiogenesis induced by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) (D'Amato et al, 1994), although there was no significant reduction in microvascular density or in the plasma levels of VEGF or bFGF following treatment with thalidomide (Singhal et al, 1999; Neben et al, 2001). The exact mechanism whereby this effect is achieved remains uncertain, although it is known that thalidomide analogues impair VEGF-induced mitogen-activated protein kinase (MAPK) signalling pathways (Lentzsch et al, 2000). Indeed, thalidomide was first tested in myeloma because of its known anti-angiogenic activity. Although thalidomide is known to interfere with angiogenesis, it possesses other potential mechanisms of action. Furthermore, a number of thalidomide analogues have been developed that possess distinct spectra of biological activities. The two major classes of analogue are known as ‘selected cytokine inhibitory drugs’ or SelCIDs and ‘immunomodulatory drugs’ or IMiDs. The former are phosphodiesterase type 4 inhibitors and result primarily in reduced tumour necrosis factor α (TNFα) production, whereas the latter do not inhibit phosphodiesterase type 4 but stimulate T-cell proliferation and the production of interleukin 2 (IL-2) and interferon-γ (IFN-γ) (Corral et al, 1999). Thalidomide can directly inhibit the growth and survival of myeloma cells, perhaps by oxidative damage to DNA mediated by free radicals (Parman et al, 1999). The drug can certainly directly induce apoptosis even in drug-resistant myeloma cells (Hideshima et al, 2000). IMiD 1 induces apoptosis in myeloma cells in a similar fashion to dexamethasone by activating related adhesion focal tyrosine kinase (RAFTK) (Hideshima et al, 2000). Both dexamethasone and IMiD 1-induced apoptosis are abrogated by exogeneous IL-6 (Hideshima et al, 2000). In addition, thalidomide modulates cell adhesion molecule expression, so it may well interfere with the mutually stimulatory interactions between myeloma cells and the bone marrow microenvironment (Geitz et al, 1996). Importantly, the drug and its analogues also interfere with TNFα production (Moreira et al, 1993; Turk et al, 1996; Corral et al, 1999) and with DNA binding of nuclear factor-κB (NF-κB), so abrogating normal inflammatory cytokine production (Payvandi et al, 2000). Finally, thalidomide has direct stimulatory effects on both T and natural killer (NK) cells (Haslett et al, 1998; Davies et al, 2001). It seems probable that some or all of these mechanisms of action are relevant to the efficacy of thalidomide and its analogues in myeloma. Further clarification of the precise effects of thalidomide and similar agents is likely to be provided by analysis of the differential effects of thalidomide and its analogues. Whatever its exact mechanism of action, thalidomide has impressive activity in myeloma, as first reported by Singhal et al (1999). In this pivotal study, 84 patients were treated with thalidomide at a starting dose of 200 mg/d, increasing in 200 mg increments every 2 weeks to a maximum dose of 800 mg/d. All patients had progressive disease and over 90% had received at least one high-dose procedure. Two thirds of the patients tolerated 600 mg/d but only half were able to take the maximum 800 mg dose. The total response rate was 32%, as defined by a fall in paraprotein level of at least 25%. Responses were associated with a reduction in bone marrow (BM) infiltration by malignant plasma cells and increases in haemoglobin levels. However, there was no clear correlation between responses and any reduction in BM microvascularity. In responders, a reduction in paraprotein level (> 25%) was achieved within 2 months in 78% of patients. Response rates were inversely correlated with the plasma cell labelling index (PCLI). For patients with a PCLI < 0·2% the response rate was 48%, whereas only 9% of those with a PCLI > 0·2% responded. Approximately one-third of the patients experienced side-effects, mainly somnolence, constipation and fatigue. These adverse events were classified as World Health Organization Grade 3–4 in < 10% of cases and were related to the dose taken. After 12 months of therapy, 44% of the patients had shown evidence of progression. The 12 month event-free survival (EFS) was 22% and the 12 month OS was 58%. This report has been updated (Barlogie et al, 2001a), at which time 169 patients had been treated, with an overall response rate of 36%. Responses were more frequent in patients with a low PCLI and normal cytogenetics. Overall, the 2 year EFS and OS were 20% and 48%, respectively, with superior outcomes for those patients who actually responded to thalidomide (EFS 34% and OS 69%). However, 62% of patients showed evidence of disease progression and were withdrawn from the study. Thromboembolic events occurred in less than 5% of patients. Similar findings in smaller series of patients have been reported by others (Juliusson et al, 2000; Grosbois et al, 2001; Oakervee et al, 2001; Rajkumar et al, 2001a). Overall, approximately 30–45% of patients with relapsed or refractory disease have achieved a partial response in these studies, so confirming the activity of thalidomide as a single agent in advanced myeloma (see Table I). (A) Response to thalidomide alone in relapsed/refractory disease. (B) Response to thalidomide alone in untreated, asymptomatic disease. The optimal dose of thalidomide has yet to be defined. Barlogie et al (2001a) have suggested that there is evidence of a dose–response effect with higher response rates being observed in those patients who receive more than 42 g of thalidomide within the first 3 months (54%vs 21% response rate, P = 0·001). In contrast, other investigators have observed similar response rates with doses varying from 50 to 200 mg/d (Durie & Stepan, 2001; Wechalekar et al, 2001). Similarly, when utilizing an escalating dose regimen, responses are usually first observed when patients are taking only 200 mg/d (Oakervee et al, 2001). Therefore, the optimal thalidomide dose remains uncertain and this issue can only be resolved by appropriate prospective clinical trials. Thalidomide has been used alone in untreated, asymptomatic patients (dose 100–400 mg/d) with a response rate of 36% and a median duration of response of greater than 12 months (Weber et al, unpublished observations, Eighth International Myeloma Workshop, 2001) with other groups reporting similar results (Rajkumar et al, 2001b). Certain of the thalidomide analogues demonstrate enhanced in vitro activities that might predict superior clinical anti-tumour efficacy. In addition, these analogues do not have the teratogenic effects of thalidomide and it is also hoped that they will have a better side-effect profile than the parent drug. IMiD 3 (CC-5013, Celgene Corporation, Warren, NJ, USA) is among the most promising analogues in vitro and displays significantly increased potency in inhibiting TNF-α production, following lipopolysaccharide stimulation of peripheral blood mononuclear cells (PBMC). Likewise, CC5013 is 50–2000 times more active than thalidomide at stimulating T-cell proliferation and 50–100 times more active in augmenting the production of IL-2 and IFN-γ following T-cell receptor (TCR) ligation of PBMC and T cells respectively (Corral et al, 1999). Furthermore, the IMiDs display a greater ability than thalidomide in inhibiting myeloma cell DNA synthesis in vitro (Hideshima et al, 2000). For all these reasons, CC5013 and similar compounds (e.g. CC4047) are being investigated in early-phase clinical studies. Two phase I, dose-escalating studies have recently been reported (Richardson et al, 2001; Zangari et al, 2001a). Somnolence, constipation and neuropathy were not observed, although myelosuppression appears to be a problem and a single case of thromboembolism occurred. Although these are not primarily efficacy studies, it is encouraging to note that 12/19 evaluable patients in the Dana Farber study (Richardson et al, 2001) showed at least a 25% paraprotein reduction. On the basis of these results, phase II/III trials are being designed. The activity of thalidomide as a single agent in advanced myeloma, along with in vitro evidence of synergistic effects, has prompted investigation of the combination of thalidomide with dexamethasone. In one such study from the MD Anderson Cancer Center, 44 evaluable patients with relapsed or refractory disease were initially treated with thalidomide alone and 25% achieved a partial response (PR) (Weber et al, 1999). Thalidomide was started at 200 mg/d, increasing every 2 weeks to a maximum of 800 mg/d. Of note, all responses were observed with doses less than or equal to 400 mg/d. Of the 26 non-responders, approximately 35% went on to show a response to the combination of thalidomide with pulsed dexamethasone, suggesting synergy between these two agents in the clinical setting (Table IIA). Two similar small studies have been reported, although there were differences in the thalidomide dose (100 mg rising to 600 mg and 100 mg at a fixed dose respectively) and in the exact pulsed dexamethasone regimen (Palumbo et al, 2001; Tosi et al, 2001) (results summarized in Table II). PR rates of 26% and 48% were observed respectively. In the latter study, thalidomide/dexamethasone-treated patients were compared with pair-mates treated with melphalan and prednisolone. Similar response rates were observed but with reduced toxicity. In none of these three studies was an excess of thromboembolic events reported. (A) Response to thalidomide and dexamethasone in relapsed/refractory disease. (B) Response to thalidomide and dexamethasone in newly diagnosed or untreated disease. These results in patients with advanced myeloma have prompted the investigation of this combination in newly diagnosed patients (Table IIB). A major potential advantage of this regimen is that it obviates the need for a long-term central venous catheter with its associated risks of infection and line-related thrombosis. Rajkumar et al (2001c) from the Mayo Clinic have reported on the first 50 patients with active myeloma treated in this manner. Thalidomide was initially escalated up to 800 mg/d but after the occurrence of unexpected, severe skin rashes in two of the first seven treated patients, the dose was fixed at 200 mg. The observed PR rate was 64%, which was comparable to VAD (vincristine, adriamycin, dexamethasone)-like regimens. thromboembolism was in 10% of patients, a significantly higher than that observed with this regimen in patients with relapsed disease. This phase study has the to a study for patients with newly diagnosed myeloma in which patients receive pulsed dexamethasone with or thalidomide at 200 mg/d with the of to high-dose melphalan and stem cell after 4 months of have been encouraging the efficacy of thalidomide with dexamethasone and of patients with advanced myeloma achieved a PR to the combination of dexamethasone and thalidomide et al, 2000). patients were on pulsed dexamethasone and thalidomide with no progression observed after a median of In a study, 42 patients with advanced disease were treated with and and 78% achieved at least a PR et al, 2000). excess of events was reported in study. A study in treated patients the efficacy of pulsed and dexamethasone with the of the side-effect profile associated with responses were in patients et al, 2001) (Table The study in treated patients, who had not received a has been at The of for (Barlogie et al, et al, 2001). were initially treated with two of dexamethasone and thalidomide with and cells were in all patients at least a who were to or of The of this study was to for in disease. The 2 year EFS and OS in the and groups were and respectively. The number of thromboembolic events was not reported as being Although these outcomes were no it is to from this study as of patients in the over to the because of to levels of Furthermore, only of patients were actually the investigators able to that is an regimen for treated myeloma patients but that high-dose is for disease These impressive results observed in patients with advanced disease have the of studies the combination of thalidomide with in newly diagnosed patients with myeloma. The such study again is being at The of for are treated with and with or thalidomide (Barlogie et al, 2001b). This study is and results are with Two studies are being by the Myeloma the combination of thalidomide with for high-dose melphalan is to be appropriate are for the at mg with of early that to thalidomide might interfere with stem cell et al, patients are treated initially with a single of VAD to a first stem cell receive VAD and thalidomide to maximum a stem cell and with high-dose melphalan and stem cell utilizing the Of the 12 patients so treated, stem cells at the first and at the (Oakervee et al, The who had disease at the time, whereas the single who to for a time had been treated with oral melphalan and adriamycin, Therefore, it appears that not interfere with stem cell Of note, patients achieved at least a events have been three line-related and one A study is the combination of melphalan and with thalidomide in patients for high-dose is not to be patients have been treated untreated, with an overall PR However, untreated patients developed (Oakervee et al, This was to be more than and the study was to the of patients. in advanced disease has been to thalidomide with dexamethasone and patients with were treated on this regimen et al, unpublished observations, Eighth International Myeloma Workshop, 2001). Of evaluable patients, had at least a PR and achieved The use of thalidomide in a variety of has been associated with a low but of although neuropathy continued to be as the most potential adverse However, as has been with its use in myeloma, has as the single most important of thalidomide in this Although has been observed with the use of thalidomide as a single agent in the treatment of patients with advanced myeloma, has been less than Similarly, an rate of has not been reported with the use of thalidomide in combination with a variety of in patients with relapsed myeloma. However, an of has been observed when thalidomide is with for newly diagnosed patients with myeloma. Rajkumar et al (2001c) reported a 10% of when the combination of thalidomide with dexamethasone as therapy, which was higher than that observed when the regimen was used in relapsed or refractory patients. This is to the rate with regimens. Of more is a report by et al of a of when the regimen was used as for newly diagnosed patients. This thalidomide (100 mg rising to 200 peripheral and pulsed dexamethasone. Of the all were limb two were and all occurred early in the treatment These findings the investigators to this phase study evidence has from investigators at The of for compared the of among patients to the of thalidomide with in their study et al, 2001b). 100 patients so the of was in the no thalidomide and in the thalidomide = All of occurred within the first three of All 100 patients had central venous in In the 50 patients not was related in one case and in In contrast, for the 50 patients was related in three cases and in Therefore, it is clear that the major in is for This that the combination of thalidomide with in newly diagnosed patients with myeloma results in a no has been found to be of in this of patients et al, 2000). In particular, the levels of protein protein and the of protein factor and have been found to with increased of in patients thalidomide et al, although only small of patients have been to similar groups of patients being treated with thalidomide the of to the regimen in an increased rate et al, In an analysis of the reporting varying rates of were found when thalidomide was used in in patients with a variety of rates were and respectively, when thalidomide was used in combination with dexamethasone and with et al, 2001) (see Table It can be that the use of thalidomide with in patients with newly diagnosed myeloma a significant of This appears to be greater than that associated with the use of thalidomide as a single agent or when with in patients with relapsed disease. In addition, the major of occurs early on in treatment when the tumour is It seems that it is the combination of and disease that is particularly in myeloma. In this it is of potential that only patients treated to on the has developed (Oakervee et al, On this patients are treated with an of VAD with a stem cell to It is that the level of tumour from this the of when thalidomide is subsequently a number of patients need to be treated with in order to any with myeloma have multiple factors for such as increased plasma infection and et al, Indeed, in an analysis of patients, was in of patients and was more in this of patients than in those P = is by a number of the response & which are found in myeloma patients. All such patients be for appropriate and from suggest that is effective in the rate to in patients thalidomide with Furthermore, such combination treatment can be continued in patients with has been studies will be to is the most effective and the groups of patients who will most This is a major potential problem with thalidomide as neuropathy can be the drug is not It is that patients are during the first months of that they the drug significant or However, the of neuropathy in patients with myeloma is as neuropathy and other symptoms are likely to be in any (e.g. or Certain which have been primarily with the use of thalidomide in chronic inflammatory disorders in & 1994), are for patients with myeloma. For it has been that studies be for g This to the for every d in patients with myeloma, which is both and The by the is more and the and that the drug be there are symptoms of peripheral In addition, it is that be at the to and be However, for the who therapy, treatment not be be in the of symptoms not the use of thalidomide the potential of are as symptoms the drug can be may a those most at of As thalidomide was first introduced as a sedative it is to be that is a The of appears to with continued at a dose and can be by taking the drug in the the drug is approximately 3–4 to any effect is for the following This is a This can be a significant problem particularly when doses over 400 mg are taken. the use of and can usually this particularly remains the most and adverse following thalidomide be to that patients are of this and that the drug is not to of after of the potential risks and the drug is to be to such be with the use of two of and pregnancy to myeloma, the of will be so that these risks will not be patients be to the drug in a and to any drug to the be to use their is of as it is not known thalidomide is in This has been reported as a study has suggested that patients treated with thalidomide are at increased of and clinical et al, 2000). This has been most when in escalating doses with high-dose dexamethasone (Rajkumar et al, but has been on when used as a single This has been reported as a Thalidomide has significant activity both as a single agent and in combination with other in patients with and advanced myeloma. However, major Indeed, the optimal dose is uncertain, as is its in following high-dose The potential of thalidomide with dexamethasone as for newly diagnosed patients with myeloma is being investigated by and results are with Similarly, the combination of thalidomide with is of uncertain All these need to be in prospective clinical trials the precise of thalidomide can be Thalidomide has a significant side-effect profile but is tolerated by the of patients. A of patients need to treatment because of the of peripheral as both and are of this potential the drug can be damage seems for studies in this has as the most adverse associated with the particularly when thalidomide is used in combination with dexamethasone as for newly diagnosed patients. It is hoped that clinical and will the mechanisms that result in a and better effective the and the use of thalidomide is a major advance in the clinical of myeloma. Indeed, thalidomide a new for in that it primarily as a agent than as a drug. A series of new agents also show in myeloma and angiogenesis inhibitors and In order to the of thalidomide and other new agents it is that they are tested in the of prospective clinical trials. Thalidomide is an appropriate for patients with relapsed or refractory disease. not to thalidomide alone may to the combination of dexamethasone and It is not to the appropriate dose of However, the of patients will at doses of mg or less and most patients are to doses greater than 600 mg. Thalidomide alone or in combination with dexamethasone only be to newly diagnosed patients in the of a clinical is an increased of in patients treated with thalidomide in combination with dexamethasone or other which in groups and with The mechanism of is and at it is not to studies are not for patients with myeloma, but clinical is to The of and in the is by an International Myeloma Oakervee is the of an by the of The of