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Myelomas

New Drugs for Myeloma

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

Key Words. Bortezomib • Lenalidomide • Multiple myeloma • Thalidomide

Correspondence: Paul G. Richardson, M.D., Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Dana 1B02, Boston, Massachusetts 02115, USA. Telephone: 617-632-2104; Fax: 617-632-6624; e-mail: paul_richardson{at}dfci.harvard.edu

Received November 13, 2006; accepted for publication March 8, 2007.

	Learning Objectives

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
After completing this course, the reader will be able to:

1. Discuss the impact of novel agents on the treatment paradigm for multiple myeloma.
   
2. Explain the importance of combination regimens and in particular the ability to rechallenge patients with a combination of drugs that may each have been administered separately before.
   
3. Describe the toxicity profiles of the agents being used with a focus on key side effects and discuss the potential value of these agents in special populations, such as those with renal failure.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed and advanced multiple myeloma.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Multiple myeloma remains incurable with conventional treatments, with a median survival duration of 3–5 years [1–8]. The disease follows a relapsing course in the majority of patients, regardless of treatment regimen or initial response to treatment. Novel, more effective treatment approaches are required in order to improve outcomes and extend survival.

Recently, the management of patients with multiple myeloma has been transformed by the introduction and approval of three new agents. Bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceuticals Research and Development, L.L.C., Raritan, NJ) received full approval in 2005 for the treatment of patients who have received at least one prior therapy [9]; thalidomide (Thalomid®; Celgene Corp., Summit, NJ) in combination with dexamethasone was approved in early 2006 for the treatment of newly diagnosed multiple myeloma; and the thalidomide analogue lenalidomide (Revlimid®; Celgene Corp., Summit, NJ), also in combination with dexamethasone, has recently been approved for the treatment of patients who have received at least one prior therapy.

These three agents represent a new generation of therapies for multiple myeloma that both affect specific intracellular signaling pathways within the tumor cell and also target the tumor microenvironment. Bortezomib is a novel, first-in-class proteasome inhibitor that has antiproliferative, proapoptotic, antiangiogenic, and antitumor activity through inhibition of proteasomal degradation of numerous regulatory proteins [10–13]. In preclinical studies, bortezomib has demonstrated synergistic or additive antitumor activity with agents commonly used in the treatment of multiple myeloma, including doxorubicin, melphalan, and dexamethasone, as well as activity in myeloma cells resistant to these agents [14–16]. Thalidomide and lenalidomide also exhibit their antineoplastic activity in multiple myeloma through multiple mechanisms of action, including inhibition of angiogenesis, induction of apoptosis, immunomodulation, antiproliferative effects, inhibition of cytokine signaling, and stimulation of T-cell activity [17–22]. Preclinical studies have shown that both drugs induce apoptosis in myeloma cells resistant to melphalan, doxorubicin, and dexamethasone, and potentiate the activity of dexamethasone and bortezomib [23, 24].

Other novel targeted therapies are also being evaluated in preclinical and clinical studies, including arsenic trioxide [25–27], interleukin-1 receptor antagonists [28], cyclic depsipeptides [29], farnesyltransferase inhibitors [30], the p38 mitogen-activated protein kinase inhibitor SCIO-469 [31], histone deacetylase inhibitors [32], and heat-shock protein 90 inhibitors, including KOS-953 [33]. These agents have demonstrated antimyeloma activity in preclinical models and early-phase clinical studies; arsenic trioxide has been studied most extensively, both as monotherapy [25–27] and in combination with other agents [34–37]. Regimens incorporating bortezomib, thalidomide, lenalidomide, and these novel agents, together with commonly used conventional therapies, represent a promising future paradigm in the treatment of myeloma. At present, further investigation is required to assess the safety and activity of these novel agents and their combinations. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. Therefore, this review focuses on the extensive clinical data available on bortezomib, thalidomide, and lenalidomide in the treatment of patients with advanced and newly diagnosed multiple myeloma. Efficacy results from studies of each agent alone and in combination in the relapsed/refractory and frontline settings are reviewed; all response rates reported are based on the stringent European Group for Blood and Marrow Transplantation (EBMT) criteria [38], unless otherwise stated. The toxicity profiles of the agents are addressed, with a focus on the key toxicities, and the potential for use of these new agents in special populations is reviewed.

	BORTEZOMIB

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Activity in Relapsed and/or Refractory Multiple Myeloma
Bortezomib with or without dexamethasone was shown to be active in two phase II studies in patients with relapsed/refractory multiple myeloma—SUMMIT (Study of Multiple Myeloma Managed with proteasome Inhibition Therapy, [39]) and CREST (Clinical response and efficacy study of bortezomib in the treatment of relapsing myeloma, [40]) (Table 1) [34, 39–67]. The international, randomized phase III Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial in patients with relapsed multiple myeloma following 1–3 prior therapies showed that single-agent bortezomib provides a significantly longer time to progression (TTP), higher response rate, and superior survival compared with high-dose dexamethasone [43]. Bortezomib is the only single agent to date that has been shown to provide a survival benefit in the setting of relapsed multiple myeloma; in an updated analysis of the APEX trial after extended follow-up (median, 22 months), the median overall survival (OS) time was 29.8 months with bortezomib versus 23.7 months with dexamethasone. This 6-month benefit was seen despite >62% of dexamethasone patients crossing over to receive bortezomib [42]. Overall response (43%) and complete response (complete response/near complete response [CR/nCR], 15%) rates with bortezomib were also higher in the updated analysis than at initial analysis [42]. Results from the APEX trial also indicate that bortezomib is more active when used earlier in the relapsed setting, with TTP, duration of response (DOR), and OS appearing to be longer and response rate higher among patients with only one prior therapy compared with those with two or three prior therapies [43].

An important aspect of the phase I study of bortezomib plus liposomal doxorubicin was that responses were seen in 8 of 13 patients who had progressive disease (PD), stable disease (SD), or an initial response followed by PD or SD with a previous anthracycline-based regimen [48], suggesting that the combination of bortezomib plus doxorubicin may overcome resistance. This is supported by the results from a study of bortezomib, liposomal doxorubicin, and thalidomide, in which responses were seen despite prior failure of regimens containing bortezomib, doxorubicin, or thalidomide [70]. The overall response rate was 65%, including a 23% CR/nCR rate (Southwest Oncology Group [SWOG] criteria) [70]. Similarly, a response rate of 63%, including a 25% CR/nCR rate, was seen with a regimen comprising bortezomib, doxorubicin, thalidomide, and dexamethasone, despite use of these agents in previous therapies [68]. The addition of liposomal doxorubicin to bortezomib, thalidomide, and dexamethasone has also been shown to produce a higher response rate (74% versus 50%; CR/nCR rate, 33% versus 17%) and longer median progression-free survival (PFS) and OS times than with the triplet regimen [69]. Responses were seen despite patients having previously received bortezomib, doxorubicin, thalidomide, and dexamethasone [69]. This superior activity may reflect the synergistic activity seen with bortezomib and doxorubicin in preclinical studies [15, 16].

Bortezomib and melphalan combination regimens have also been shown to be active [53, 54, 71, 72]. In a dose-escalation study of bortezomib plus oral melphalan, the response rate was 47% (including a 15% CR/nCR rate), with responses seen in five of six (83%) patients at the maximum-tolerated dose [53]. Similarly, results from a dose-escalation study of bortezomib plus low-dose i.v. melphalan showed a response rate of 43%, rising to 52% with the addition of dexamethasone for patients with suboptimal response [54]. Activity appeared greatest in patients receiving the highest melphalan dose [54]. The addition of thalidomide, along with dexamethasone or prednisone, appears to increase the activity of the combination regimen, with response rates of 66% (37% CR/nCR rate) [72] and 67% (17% CR/nCR rate) [71] for the dexamethasone- and prednisone-containing regimens, respectively.

Bortezomib has also been studied in combination with thalidomide and dexamethasone [73], and lenalidomide plus dexamethasone, in patients with suboptimal response to the doublet combination [74]. The response rates with these regimens were 55% (16% CR/nCR rate) [73] and 52% (10% CR/nCR rate) [74], respectively, indicating that these agents can be administered in combination with promising activity, and supporting the notion of dual apoptotic signaling. The median event-free survival (EFS) and OS times with bortezomib, thalidomide, and dexamethasone were 9 months and 22 months, respectively. However, these were shorter in patients who had received prior thalidomide [73], suggesting that the combination may be more active if used in advance of other thalidomide-containing regimens. The response rate in the study of bortezomib plus lenalidomide is especially encouraging as nearly all patients had received prior thalidomide, half had received bortezomib, and approximately 10% had received prior lenalidomide [74].

Activity in Previously Untreated Multiple Myeloma
Bortezomib-based therapies have demonstrated encouraging activity in 13 studies in the frontline setting, both as induction therapy prior to stem cell transplantation (SCT) and as therapy for patients not proceeding to, or not eligible for, SCT (Table 1 [34, 39–67] and Table 2 [68–79]). These studies, in more than 700 patients, have shown high response rates, and consistently high CR/nCR rates that are greater than those seen with standard induction regimens and conventional therapies. Bortezomib has been studied as a single agent in the frontline setting [59, 60]. In one phase II study in patients eligible for SCT, the response rate was 40%, with a 10% CR/nCR rate. This CR/nCR rate is substantial for a single-agent therapy in the frontline setting [59]. Notable activity has also been demonstrated in patients with high-risk multiple myeloma (elevated ß₂-microglobulin, high plasma cell labeling index, or chromosome 13 deletion) [60].

Regimens containing bortezomib plus doxorubicin are also demonstrating substantial activity. The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has been investigated as induction therapy prior to SCT [65, 66]. In 21 patients, the response rate to PAD was 95%, including a 29% CR/nCR rate, prior to SCT [65]. Eighteen patients underwent transplant. The response rate in all 21 patients remained at 95%, but the CR/nCR rate was higher at 57% [65]. This high CR/nCR rate is important because CR status following SCT is associated with a longer OS time [82–85], as is CR status following non-SCT therapy [86]. Similar results were obtained with a reduced-dose PAD regimen. In 19 evaluable patients, the response rate was 89%, including a 16% CR/nCR rate; 13 patients subsequently underwent SCT, and the response rate post-SCT was 100%, with a 54% CR/nCR rate [66]. The PAD regimen is currently being compared with vincristine, doxorubicin, and dexamethasone (VAD) as induction therapy prior to SCT in an international phase III trial. The use of liposomal doxorubicin instead of doxorubicin in the PAD regimen is also being investigated. In 21 evaluable patients, the response rate was 81% with a 29% CR/nCR rate, the same as with PAD [51]. A similar response rate of 80% with a 13% CR/nCR rate has been reported in a Cancer and Leukemia Group B study of bortezomib plus liposomal doxorubicin [67].

The doublet regimen of bortezomib plus dexamethasone has been investigated as induction therapy in three trials [62–64]. In a phase II study by the Intergroupe Francophone du Myélome (IFM), the combination produced a response rate of 67%, including a 21% CR/nCR rate, prior to SCT in 48 evaluable patients [63]. Among 42 patients who proceeded to SCT, the post-SCT response rate was 90%, with a 33% CR/nCR rate [63]. Similarly, substantial activity was reported in another study in which potential candidates for SCT received bortezomib alone initially, with dexamethasone added for suboptimal response [62]. In 48 evaluable patients, the response rate was 90%, with a 19% CR/nCR rate; 23 patients proceeded to SCT. The 1-year OS rate in those going on to SCT was 100% [62]. Preliminary results from an IFM phase III study of bortezomib plus dexamethasone compared with VAD as induction therapy prior to SCT showed a higher postinduction response rate (82% versus 67%) and CR/nCR rate (20% versus 9%) with bortezomib plus dexamethasone. In addition, among evaluable patients who had undergone a single SCT, a greater proportion of the patients who had received induction with bortezomib plus dexamethasone, compared with VAD, achieved a very good partial response (VGPR) or better (78% versus 55%), obviating the need for a second SCT [64].

Bortezomib in combination with thalidomide and dexamethasone is also active in the frontline setting. The response rate in a single-center study of 38 patients was 92%, including an 18% CR rate; importantly, responses were achieved rapidly, eliminating the need for further therapy prior to SCT [77]. In total, 26 patients proceeded to SCT, following which the response rate in all 38 patients was 100%, including a 34% CR rate [77]. This triplet regimen has also been investigated as induction therapy prior to SCT in combination with cisplatin, doxorubicin, cyclophosphamide, and etoposide—the VDT-PACE regimen [78, 79]. VDT-PACE is being employed as induction therapy prior to tandem transplants in the Total Therapy 3 approach; the addition of bortezomib to the previous Total Therapy 2 plus thalidomide approach appears to result in a higher CR rate, higher yield of stem cells, and faster completion of transplants [79].

These results suggest that bortezomib-based combination regimens could provide a valuable treatment option in the frontline setting. Importantly, use of bortezomib-based induction regimens does not impair stem cell mobilization and harvesting prior to SCT, and neutrophil and platelet engraftment is prompt following SCT [62–66, 78, 79, 87]. The higher CR/nCR rates associated with bortezomib-based induction may potentially result in superior clinical outcomes with SCT.

Key Side Effects of Bortezomib
The safety profile of bortezomib in the relapsed setting has been well characterized and is generally manageable, with prolonged exposure in some patients shown to be well tolerated. In an extension study of the SUMMIT and CREST trials, no new or cumulative toxicities were reported [88]. Importantly, no additive toxicities were reported in the studies of bortezomib-based combination regimens. Similarly, in frontline studies, the toxicities associated with bortezomib alone and in combination were generally predictable and manageable, with no unexpected adverse events reported.

The most common toxicities associated with bortezomib treatment include fatigue, gastrointestinal events, and peripheral neuropathy, with the most commonly reported grade 3 toxicities being peripheral neuropathy, thrombocytopenia, neutropenia, and anemia. Bortezomib-related peripheral neuropathy is an important and dose-limiting toxicity. Based on findings from the SUMMIT and CREST studies, specific management guidelines were developed [89] and subsequently tested in the APEX study. In the APEX study, bortezomib-related peripheral neuropathy was shown to be reversible in the majority of patients [90]. Similarly, in the SUMMIT and CREST trials it was shown to resolve or improve in 71% of patients with grade 3 peripheral neuropathy and/or neuropathy requiring discontinuation [89]. Comparable results have been observed in the frontline setting [59, 65].

The hematologic toxicities associated with bortezomib have also been well characterized and shown to be generally predictable and manageable. Bortezomib-related thrombocytopenia and neutropenia are transient and cyclical; in patients experiencing thrombocytopenia, platelet counts decrease and recover predictably during each bortezomib treatment cycle with no evidence of cumulative toxicity [91, 92]. Notably, despite a higher incidence of grade 3 thrombocytopenia with bortezomib compared with dexamethasone in the APEX trial, the incidence of significant bleeding events, including grade 3 bleeding events, serious bleeding, and cerebral hemorrhage, was similar between the two arms [91]. Not surprisingly, patients with low platelet counts at baseline (<70 x 10⁹/l) have been shown to be at a higher risk for grade 3 thrombocytopenia, and so bortezomib use in such patients warrants caution but is feasible and can be effective [92].

	THALIDOMIDE

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Activity in Relapsed or Refractory Multiple Myeloma
Thalidomide has been widely used in patients with relapsed or refractory multiple myeloma for a number of years, following the initial report of single-agent activity in 1999 [93], and more recent developments in the frontline setting have confirmed its efficacy. Table 3 [94–116] summarizes a number of key studies and recent reports; specifically, response rates of 25%–48% by paraprotein reduction have been reported with single-agent thalidomide in patients with relapsed or refractory multiple myeloma [93, 94, 117–119]. A recent systematic review of phase II studies calculated an overall response rate of 29% [120]. The response rate has been shown to be substantially higher when thalidomide is combined with dexamethasone and cyclophosphamide [121]. For example, thalidomide plus dexamethasone has been proven to be effective in relapsed/refractory multiple myeloma [95, 122–125], with response rates of 42%–72% (CR/nCR rates not available; various response criteria), while the addition of cyclophosphamide (the CTD regimen) has resulted in response rates of 57%–83%, with CR/nCR rates of 2%–17% (various response criteria) [96, 126–128]. The combination of thalidomide plus liposomal doxorubicin and dexamethasone has recently been shown to be very active, with a response rate of 76%, including a 32% CR/nCR rate [98]. The addition of vincristine to this regimen has also been studied, producing a response rate of 76%, with a 20% CR rate [99], although concerns regarding cumulative neurotoxicity remain. Other combinations are listed in Table 2 and Table 3.

The addition of thalidomide to MP has also been investigated in two important randomized trials [115, 116]. In an IFM study in patients aged 65–75 years with newly diagnosed multiple myeloma, patients were randomized to receive standard MP, melphalan (100 mg/m²)-based autologous SCT or oral melphalan, prednisone, and thalidomide (MPT) for up to 72 weeks [116]. There was a significant OS benefit seen with the thalidomide-based regimen compared with the other two treatments, and both the response rate and CR/nCR rate were higher with the triplet than with MP. The authors suggested that MPT should therefore be considered the reference treatment for newly diagnosed multiple myeloma patients ineligible for high-dose therapy [116]. The superiority of MPT compared with MP alone has also been confirmed in a similar phase III study by the Italian Multiple Myeloma Network [115].

Thalidomide has also been incorporated into more extensive combination regimens as induction therapy prior to SCT. In the Total Therapy 2 approach, the addition of thalidomide to induction therapy and its use in consolidation and maintenance therapy resulted in a significantly higher rate of CR compared with patients not receiving thalidomide (62% versus 43%), and a significantly greater 5-year EFS rate (56% versus 44%). However, no difference was seen in the 5-year OS rate; the authors indicated that this was partially a result of a higher failure rate with salvage therapy and a shorter survival after relapse [114], which was possibly a consequence of a high proportion of patients in each arm (75% in the thalidomide arm, 83% in the control arm) receiving thalidomide-based salvage therapy after relapse. In a phase III study comparing the VAD regimen with thalidomide plus doxorubicin and dexamethasone (the TAD regimen) as induction therapy prior to SCT in patients aged 65 years, preliminary data showed TAD to produce a statistically greater response rate prior to SCT compared with VAD (80% versus 63%) [110]. Another combination regimen offering promising results is thalidomide plus vincristine, liposomal doxorubicin, and dexamethasone, the T-VAD-Doxil regimen [111]. Data from an interim analysis of a phase III study comparing T-VAD-Doxil with VAD-Doxil have shown that the addition of thalidomide results in a significantly greater response rate (81% versus 66%) [112].

Key Side Effects of Thalidomide
The most common adverse events associated with thalidomide treatment are constipation, fatigue, somnolence, and peripheral neuropathy [93, 117]. The key grade 3 toxicities associated with thalidomide plus dexamethasone therapy include deep venous thrombosis, peripheral neuropathy, and weakness [106, 107]. Venous thromboembolism is a common complication in cancer patients, but therapy with thalidomide in combination appears to increase the risk for thrombosis substantially [106, 130, 131]. For management of this risk, prophylaxis with therapeutic doses of warfarin or low molecular weight heparin (LMWH) should be used [131, 132]; aspirin may reduce the risk for venous thromboembolic events [133], but it has been suggested that this should be reserved for patients unable or unwilling to take warfarin or LMWH [132].

Peripheral neuropathy is a common adverse event with thalidomide therapy that often limits the dose and duration of treatment [130, 134]. In a retrospective analysis of a phase II Mayo Clinic trial of thalidomide in myeloma, 56% of patients were identified as having developed symptoms of peripheral neuropathy. These symptoms improved in 27% of patients with or without dose reduction or after discontinuing treatment, remained stable in 52%, and worsened in 15% [134]. In a second study, the incidence of peripheral neuropathy increased from 38% at 6 months to 73% at 12 months, with 81% of responding patients developing peripheral neuropathy [135]. To minimize the risk for neurotoxicity, the authors suggested that therapy should usually be limited to 6 months or less [135].

Because of the toxicity profile of thalidomide, its analogue lenalidomide was developed with the aim of improving the clinical efficacy of thalidomide while offering a better safety profile.

	LENALIDOMIDE

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Activity in Relapsed or Refractory Multiple Myeloma
Results from phase I and II studies have shown lenalidomide to have significant and durable single-agent activity in the relapsed setting (Table 4) [136–144], with responses seen in 14%–29% of patients [136–138]. Activity has been shown to increase markedly when lenalidomide is combined with dexamethasone. Two randomized phase III trials have demonstrated that the combination regimen provides greater efficacy than with dexamethasone alone [139, 140]. In the North American phase III trial [139], the response rate was greater with lenalidomide plus dexamethasone than with dexamethasone alone (59% versus 21%), as was the CR rate (13% versus <1%). The median TTP (11.1 months versus 4.7 months) and median OS time (29.6 months versus 20.2 months) were also longer with lenalidomide plus dexamethasone than with dexamethasone alone. These findings were corroborated by results from an identical European phase III trial [140]. In that study, the observed response rate was again 59% with lenalidomide plus dexamethasone, compared with 24% for dexamethasone alone, and the CR/nCR rates were 17% and 4%, respectively [140]. Again, the median TTP and OS time were longer with lenalidomide plus dexamethasone than with dexamethasone alone [140]. Interestingly, results from a pooled analysis of the two phase III trials indicate that the response rate to lenalidomide plus dexamethasone is slightly lower in patients who have received prior thalidomide therapy than in those who have had no prior thalidomide (53% versus 63%), and the median TTP is significantly shorter (8.5 versus 14.2 months) [145], although the activity of the regimen even in patients with prior thalidomide exposure is remarkable.

Activity in Previously Untreated Multiple Myeloma
The results of a phase II trial have shown that lenalidomide plus dexamethasone has promising activity in the frontline setting. The response rate in 31 evaluable patients was 91%, including a 38% CR/nCR rate [143]. Based on these findings, two cooperative groups are currently assessing lenalidomide plus dexamethasone as frontline therapy for multiple myeloma patients in randomized phase III trials. Mirroring the therapeutic approach taken with bortezomib and thalidomide, lenalidomide is also being assessed in combination with MP in elderly patients with newly diagnosed multiple myeloma. Preliminary results show that the combination produces a response rate of 85% after a median of seven treatment cycles, including a 17% CR/nCR rate [144].

Key Side Effects of Lenalidomide
Data suggest that lenalidomide is better tolerated than thalidomide in several aspects of its toxicity profile; it does not usually cause clinically significant somnolence, constipation, or neuropathy, although myelosuppression is greater [22]. The most common grade 3 toxicities with lenalidomide are myelosuppression, mainly neutropenia and thrombocytopenia, which are manageable with dose reduction and growth factor support [136, 137]. The safety profile of the combination of lenalidomide plus dexamethasone is also as expected (with neutropenia, thrombocytopenia, anemia, and peripheral neuropathy reported); however, as seen with thalidomide, the risk for thromboembolic events is notably elevated in both the relapsed setting (5%–18%, 23% with concomitant erythropoietin) [139, 140, 145, 146] and the frontline setting [147]. Recently reported preliminary data from a randomized phase III study of lenalidomide plus high-dose or low-dose dexamethasone in newly diagnosed patients suggest that rates of toxicities were higher in patients receiving the high-dose dexamethasone combination, notably grade 3 thromboembolic events (18% versus 5%) [148]. Importantly, studies have also shown a greater risk for deep vein thrombosis in patients with prior thalidomide exposure [145]. The combination of lenalidomide plus vincristine, liposomal doxorubicin, and dexamethasone resulted in a 9% rate of venous thromboembolic events [142]. It will be interesting to see whether the combination of lenalidomide plus doxorubicin and dexamethasone [141] is also associated with a higher incidence of deep vein thrombosis, similar to that seen with thalidomide–doxorubicin combination therapy [149]. Further study of this aspect of the safety profile and establishment of optimal antithrombotic prophylaxis strategies [131, 146, 147, 150] are warranted.

	SPECIAL POPULATIONS

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Patients with Renal Dysfunction
Approximately 30% of multiple myeloma patients have renal dysfunction (serum creatinine 1.5 mg/dl) at presentation [151, 152]. An analysis of SUMMIT and CREST patients with impaired renal function indicated that renal function has little impact on response rate to bortezomib treatment and, as in the overall population, toxicities are manageable [153]. Furthermore, a National Cancer Institute prospective pharmacologic trial in adult cancer patients showed that bortezomib clearance is independent of renal function, and the standard 1.3 mg/m² dose appeared well tolerated in patients with mild to moderate renal dysfunction; accrual is continuing for patients with more severe renal dysfunction or requiring dialysis [154]. The results of a retrospective, multicenter analysis of 24 myeloma patients with severe renal dysfunction requiring dialysis showed high, durable response and CR rates with bortezomib and bortezomib-based combinations [155]. In both this and another small study, bortezomib-based therapy has been shown to reverse renal dysfunction in some patients, eliminating the need for dialysis or sparing patients from imminent dialysis [155, 156]. Thalidomide alone or in combination with dexamethasone has also been shown to reverse renal dysfunction in some patients with relapsed or refractory multiple myeloma [157], although the reversibility of dialysis-dependent renal failure may be limited [157]. As seen with bortezomib-based regimens, the toxicity profile of thalidomide with or without dexamethasone is comparable to that in patients with normal renal function [157]. However, thalidomide treatment has been associated with a risk for severe and potentially fatal hyperkalemia, particularly in patients undergoing hemodialysis [158, 159]. Lenalidomide has not yet been extensively studied in patients with renal dysfunction, because it is actively excreted via the kidneys and the risk for toxicities is therefore expected to be greater. In fact, patients with serum creatinine >2.5 mg/dl were excluded from two phase III studies of lenalidomide plus dexamethasone in relapsed multiple myeloma, and the drug was held in those who developed renal insufficiency while on study [160]. Nevertheless, dose-reduced lenalidomide in combination with dexamethasone has been used in such settings, with anecdotal reports of successful outcome.

Elderly and High-Risk Patients
Bortezomib alone and in combination [56, 61, 161], thalidomide plus dexamethasone [105, 108, 113, 115, 116, 130], and lenalidomide plus dexamethasone [160] have been shown to be active and usually well tolerated in elderly (aged 65 years) patients with multiple myeloma. In a subgroup analysis of the APEX trial, bortezomib resulted in a longer TTP and higher response rate than with dexamethasone in patients aged 65 years, with comparable incidences of serious adverse events and slightly higher incidences of grade 3 and 4 adverse events [161], and a multivariate analysis of the SUMMIT trial demonstrated that age did not affect TTP, DOR, or OS [162]. In a phase III trial of thalidomide plus dexamethasone in patients with newly diagnosed multiple myeloma [106], no differences in efficacy and safety were observed in patients aged 65 years compared with younger patients [130]. However, in relapsed/refractory multiple myeloma, age exceeding 65 has been shown to be predictive of inferior outcome with thalidomide in terms of OS and response rate [163]. No differences in efficacy were observed between patients aged 65 years and younger patients in two phase III trials of lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma patients; however, patients aged 65 years were more likely to experience diarrhea, fatigue, pulmonary embolism, and syncope [160].

Bortezomib has also been shown to be active and well tolerated in other patients with high-risk factors. In subgroup analyses of the APEX trial, bortezomib therapy resulted in a longer TTP and higher response rate than with dexamethasone in patients with more than one line of prior therapy, patients with high ß₂-microglobulin, or patients refractory to prior treatment [161]. As with age, International Staging System stage II/III disease and the number/type of previous therapies did not affect TTP, DOR, or OS in a multivariate analysis of the SUMMIT trial [162]. Bortezomib also appeared to overcome the adverse impact of chromosome 13 deletion on survival and response in the SUMMIT and APEX trials and other studies [44, 164, 165]. In a phase II study of thalidomide in relapsed/refractory multiple myeloma, ß₂-microglobulin level and response to previous therapy did not affect response rate, but elevated ß₂-microglobulin at baseline was shown by multivariate analysis to be predictive of a shorter PFS, but not OS, time [163]. In addition, in one study of thalidomide plus dexamethasone in the relapsed setting, the regimen was shown to be superior to conventional chemotherapy in terms of the median PFS and OS times in patients who had received one prior line of therapy, but comparable in patients who had received two or more lines of therapy [95]. Finally, in a pooled analysis of two phase III studies in the relapsed setting, lenalidomide plus dexamethasone has been shown to produce a higher response rate and longer TTP and OS time than with dexamethasone alone in patients who had received more than one prior line of therapy [166], reflecting the promising results seen in the overall study populations.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
Studies of bortezomib, thalidomide, and lenalidomide have demonstrated promising activity in the treatment of relapsed/refractory and newly diagnosed multiple myeloma. Bortezomib alone and in combination is associated with high response rates and consistently high rates of CR, with a generally predictable and manageable toxicity profile. Substantial activity has also been seen with thalidomide-based regimens, notably thalidomide plus dexamethasone, in both advanced and newly diagnosed disease. The thalidomide analogue lenalidomide has shown activity in clinical trials, notably in combination with dexamethasone, and some aspects of its toxicity profile appear to be milder than with thalidomide. Treatments involving these agents currently represent the most promising strategies for improving patient outcome, although no conclusions can be drawn from the available data regarding the most beneficial combinations or the order in which these agents should be used in a patient's course of treatment. Further clinical investigation, including the results from ongoing phase III studies, should help establish the optimal use and sequence of these therapies in the frontline and relapsed settings, in combination with both conventional and investigational agents for the treatment of multiple myeloma.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
P.G.R. is on the advisory board and the speakers bureau for Celgene and Millennium. K.A. has acted as a consultant for and received research support from Millennium, Celgene, Novartis, and Gentium. C.M. has acted as a consultant for Millennium, Novartis, Merck, and Bristol-Myers. R.S. is on the speakers bureau for Celgene and Millennium. N.M. has been on the advisory board and speakers bureau for Celgene, Millennium, and Novartis.

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 
The authors would like to thank Steve Hill, medical writer, and Rosemary Washbrook, medical editor, of Gardiner-Caldwell London for assistance in drafting the manuscript.

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Top Learning Objectives Abstract Introduction Bortezomib Thalidomide Lenalidomide Special Populations Conclusions Disclosure of Potential... Acknowledgments References

 

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