Lenalidomide in multiple myeloma

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1 For reprint orders, please contact Lenalidomide in multiple myeloma Expert Rev. Anticancer Ther. 9(11), (2009) Bhawna Sirohi and Ray Powles Author for correspondence Medical Oncology, Max Cancer Centre, Max Healthcare, New Delhi, , India Tel.: Fax: maxhealthcare.com Treatment options for patients have increased over the last few years, especially with the availability of novel agents for routine care and within clinical trials. Owing to the promising activity seen with lenalidomide in the relapsed/refractory setting, its use has now expanded to induction and maintenance therapy. It is generally well tolerated and the side effects, including hematological toxicity and thromboembolic complications, are usually easily managed. Although new treatments including lenalidomide have increased response rates, the survival has not been strongly impacted. This article will summarize recent data and ongoing clinical trials. Keywords: lenalidomide multiple myeloma targeted therapy Treatment for patients with multiple myeloma (MM) has changed considerably over the last two decades and now includes a sequence of treatments, including induction therapy, consolidation with high-dose (melphalan) chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in younger, fit patients, as well as maintenance chemotherapy [1]. The treatment for most MM patients today includes chemotherapy with or without one of the biological targeted agents, such as thalidomide, bortezomib or lenalidomide, either when they are newly diagnosed or at the time of relapse [2 4]. With these strategies, tailoring of sequential treatment for each individual patient and, most importantly, consideration of patient choice, patients can now expect a doubling of median survival and a 30% chance of surviving longer than 10 years. Therefore, the focus of treatment is shifting to long-term quality of life [5,6]. Lenalidomide (Revlimid ; Celgene, NJ, USA) is an oral derivative of thalidomide with proven efficacy against MM in clinical studies [7 10]. The mechanism of action of lenalidomide is complex in that it has a direct anti-tumor effect and inhibits the microenvironment support for tumor cells. Lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, anti-angiogenic and anti-osteoclastogenic effects and immunomodulatory activity [11]. As published previously, the immunomodulatory effects and in vivo anti-tumor activity of lenalidomide is similar to thalidomide, although with improved potency as seen by greater ability to stimulate T-cell proliferation, IL-2 and interferon production, and to inhibit tumor cell growth [11,12]. The toxicity profile of lenalidomide is more favorable than thalidomide with different side effects (less somnolence, constipation or peripheral neuropathy), although myelosuppression, not commonly seen with thalidomide, is often observed with lenalidomide. The Phase I II trials of lenalidomide in patients with refractory MM showed a partial response (PR) rate of 24 29%, with an additional 29% of patients who had not had a response to lenalidomide alone having a partial remission after the addition of pulsed doses of dexamethasone [10,13], thus providing the rationale for using lenalidomide in combination with dexamethasone. Lenalidomide has also been combined with melphalan prednisone (MP), and in a randomized trial MP thalidomide (MPT) was shown to be more effective than MP alone [14,15]. It has previously been shown that when bortezomib is combined with thalidomide and dexamethasone (VTD), at least 60% of patients attained a very good PR (VGPR) versus 25% of those who received thalidomide and dexamethasone alone (p < 0.001) [16]. VTD also overcame the potential effect of adverse cytogenetics on response, whereas combined thalidomide and dexamethasone did not. This was the rationale for combining lenalidomide with borte zomib and dexamethasone in a large multicenter Phase I/II study [17]. This article summarizes the current data on lenalidomide in patients with newly diagnosed and relapsed/refractory MM. Some of the ongoing studies of interest are summarized in a supplementary table found online [101] /ERA Expert Reviews Ltd ISSN

2 Sirohi & Powles Relapsed/refractory myeloma Table 1 summarizes some of the studies using lenalidomide in patients with relapsed/refractory MM. Lenalidomide with or without steroids In two prospective, randomized (lenalidomide dexamethasone vs dexamethasone plus placebo), double-blind, placebo-controlled Phase III clinical studies in the USA and Canada (n = 353) and Europe, Israel and Australia (n = 351; MM-009 and MM-010), it was shown that lenalidomide dexamethasone led to significantly higher overall response rate (ORR), complete response (CR), longer time to progression (TTP) and overall survival (OS), compared with placebo plus dexamethasone in patients with relapsed or refractory MM [18,19]. In both of these studies, the patients were not steroid-naive, the studies only required that the patient not be refractory to steroids. The CR plus VGPR rate was 24%. As lenalidomide is an analog of thalidomide, there have been valid concerns about using it in patients who have progressed on or relapsed after receiving thalidomide. Data pooled from the MM-009 and MM-010 Phase III clinical trials assessed the efficacy of lenalidomide dexamethasone in patients with prior thalidomide exposure. Of 704 patients, 39% were thalidomide exposed. In patients who received lenalidomide dexamethasone, the ORR was higher in thalidomide-naive versus -exposed patients (p = 0.04), with longer median TTP (p = 0.04) and progressionfree survival (PFS) (p = 0.02). Hence, lenalidomide has a substantial response rate among thalidomide-exposed patients, even if it is less than in thalidomide-naive patients. Previous exposure to thalidomide did not affect survival in lenalidomide dexamethasonetreated patients, and thalidomide-naive and -exposed patients had similar toxicities [20]. Lenalidomide plus chemotherapy with or without other biologics &/or steroids Lenalidomide cyclophosphamide dexamethasone/prednisolone Lenalidomide, cyclophosphamide and dexamethasone/prednisolone is increasingly being used as a regimen for patients with relapsed/refractory and newly diagnosed patients with MM [21]. As shown by Morgan et al. in a study of 21 patients, the ORR of 65% appears to be superior to lenalidomide alone (17 23%) or in combination with dexamethasone (48 51%) [10,18,19,21]. The optimal dosing schedule for this regimen is yet to be defined, although an attempt was recently made within a Phase I study to determine the maximum tolerated dose (MTD) and toxicity of cyclophosphamide when used in combination with lenalidomide and dexamethasone for patients with relapsed/refractory myeloma. This study showed that oral cyclophosphamide 600 mg on days 1 and 8 of a 28-day cycle is well tolerated in combination with lenalidomide and dexamethasone. The combination is a highly effective therapy (36% CR or VGPR; 81% ORR) for relapsed/refractory myeloma [22]. The majority of patients achieved a maximal response during the first four courses of treatment. Lenalidomide adriamycin dexamethasone To further improve the effectiveness of lenalidomide, the German Myeloma Study Group evaluated lenalidomide in conjunction with adriamycin and dexamethasone (RAD) for the treatment of patients with refractory/relapsed myeloma [23] in a Phase I/II trial based on the observation that vincristine adriamycin dexamethasone (VAD) with continuous adriamycin infusion was effective in cases resistant to alkylating agents [24]. Patients (n = 69) received oral lenalidomide on days 1 21; intravenous adriamycin as continuous infusion over 96 h starting on day 1 of the cycle; and oral dexamethasone on days Table 1. Results of studies using lenalidomide in relapsed/refractory myeloma. Treatment Lenalidomide dexamethasone Lenalidomide dexamethasone Patients (n) CR (%) ORR (%) PFS (months) OS (months) Grade 3/4 VTE (%) Grade 3/4 neutropenia (%) Grade 3/4 thrombocytopenia (%) NR [19] [18] CPR * [77] CRD CRD [21] RAD year (88%) Lenalidomide bortezomib RMPT year (50%) 1-year (90%) Ref. [22] [23] 0 * [27] ORR = CR plus near CR plus PR. * Thromboprophylaxis. CPR: Cyclophosphamide, Revlimid, prednisone; CR: Complete response; CRD: Cyclophosphamide, revlimid, dexamethasone; NR: Not reported; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; RAD: Revlimid, adriamycin, dexamethasone; RMPT: Revlimid, melphalan, prednisone, thalidomide; VTE: Venous thromboembolism. [25] 1560 Expert Rev. Anticancer Ther. 9(11), (2009)

3 Lenalidomide in multiple myeloma Drug Profile 1 4 and Cycles were repeated every 4 weeks for a maximum of six cycles. The MTD of this regimen was lenalidomide 25 mg once daily for 21 days in conjunction with doxorubicin 9 mg/m 2 and pegfilgrastim on day 6. In total, 74% of patients attained CR or VGPR at this dose level. Neutropenia occurred more frequently in elderly patients, defined as 65 years and older (25 vs 50%). Severe infections occurred in 10.5% of patients. The impressive response rates have to be interpreted with caution owing to the small number of patients (n = 47 at the MTD dose level) [23]. Lenalidomide bortezomib In a Phase I study, lenalidomide bortezomib with or without dexamethasone was well tolerated and resulted in an ORR of 58% in relapsed and/or refractory MM patients [25]. A recent Phase II study has evaluated the efficacy and safety of lenalidomide bortezomib dexamethasone (RVD). Patients received bortezomib 1.0 mg/m 2 (days 1, 4, 8, 11), lenalidomide 15 mg (days 1 14) and dexamethasone 40 or 20 mg (cycles 1 4/5 8) on days of/after bortezomib dosing. Of the 64 patients enrolled, the ORR was 86%, including 24% CR/near-CR (ncr) [26]. Toxicities were manageable and consisted mainly of grade 1 and 2 myelosuppression. Lenalidomide melphalan prednisolone thalidomide In a Phase II clinical trial in patients with relapsed/refractory myeloma with 44 patients, lenalidomide was administered at 10 mg/day on days 1 21, oral melphalan at 0.18 mg/kg on days 1 4 and oral prednisone at 2 mg/kg on days 1 4. Thalidomide was administered at 50 mg/day (arm A) or 100 mg/day (arm B) on days 1 28 [27]. Each course was repeated every 28 days for a total of six courses. Aspirin 100 mg/day was given as a prophylaxis for thrombosis. Maintenance therapy included lenalidomide alone at 10 mg/day on days After a median of two courses, 76% achieved at least PR, including 30% VGPR. Among patients who received thalidomide 100 mg, the PR rate was 93.3% (including VGPR 46.7%) compared with 64.7% of those administered thalidomide 50 mg. Initial results showed that lenalidomide melphalan prednisolone thalidomide is an effective salvage therapy with a high proportion of responses. Toxicities were manageable and no thromboembolic complications were reported [27]. Lenalidomide liposomal doxorubicin vincristine dexamethasone A Phase I/II study on 62 patients showed intravenous liposomal doxorubicin 40 mg/m 2 and intravenous vincristine 2 mg on day 1, dexamethasone 40 mg orally on days 1 4 (DVd), and lenalidomide on days 1 21 in a 28-day cycle was well tolerated. The MTD of lenalidomide was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. The ORR was 75%, with 29% of patients achieving a CR/nCR [28]. Newly diagnosed myeloma Novel agents are initially tested at the time of relapse or progression and if found to be effective, will subsequently be tested early on (i.e., during induction treatment). Early use of these novel agents is associated with high response rates, although long-term data on their use compared with standard therapy are lacking. Lenalidomide with or without steroids Treatment with lenalidomide plus dexamethasone in newly diagnosed myeloma patients is increasingly being used [29]. Rajkumar et al. reported on 34 patients and showed that 31 patients achieved an objective response, including 6% attaining a CR and 32% meeting the criteria for both VGPR and ncr with an ORR of 91% [29]. This study showed that this combination is very active, with a manageable side-effect profile. The Eastern Cooperative Oncology Group (ECOG) group has reported on a Phase III trial of lenalidomide plus high (standard)- dose dexamethasone (40 mg days 1 4, 9 12 and orally every 28 days [RD]) versus lenalidomide plus low-dose dexamethasone (i.e., dexamethasone 40 mg days 1, 8, 15 and 22 orally every 28 days [Rd]) in newly diagnosed MM [30]. The dose of lenalidomide was 25 mg. Of the 445 patients enrolled, major grade 3 or higher toxicities, including deep vein thrombosis/pulmonary embolism (DVT/PE) and infections, were significantly higher in the RD arm. The OS at the second preplanned interim ana lysis was significantly superior with lenalidomide plus lowdose dexamethasone (p < 0.001; 1-year survival: 96% [Rd] vs 87% [RD]). The OS differences in favor of the Rd arm were seen in patients under 65 years of age (p = 0.022), as well as patients 65 years of age and older (p = 0.002). Lenalidomide plus low-dose dexamethasone was associated with superior OS compared with lenalidomide plus high-dose dexamethasone in newly diagnosed MM; this may be due to the increased mortality in the high-dose arm both due to progression and treatment-related toxicity leading to inability to get therapy [30]. Lenalidomide plus chemotherapy with or without other biologics &/or steroids Lenalidomide bortezomib dexamethasone Recently, a Phase I/II study was conducted to find the MTD of RVD and to assess safety and efficacy in previously untreated MM patients [31]. Maximum planned dose (MPD) has been reached at lenalidomide 25 mg, bortezomib 1.3 mg/m 2 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12, for up to eight 21 day cycles. ORR was 98%, with 71% of patients better than VGPR and 36% CR/nCR. At the MPD, ORR was 100%. The authors concluded that RVD produces high-quality responses and is well tolerated in newly diagnosed MM patients, regardless of their cytogenetic status or International Staging System stage [31]. Lenalidomide cyclophosphamide dexamethasone The Mayo Clinic study on 53 new MM patients receiving courses of lenalidomide cyclophosphamide dexamethasone showed a preliminary CR/VGPR rate of 53%, and 34 patients went on to have a peripheral blood stem cell (PBSC) collection [32]. Bortezomib dexamethasone cyclophosphamide lenalidomide As the combination regimens incorporating bortezomib, lenalidomide, dexamethasone and cyclophosphamide (bortezomib dexamethasone, Revlimid dexamethasone, bortezomib dexamethasone Revlimid [VDR] and

4 Sirohi & Powles bortezomib dexamethasone cyclophosphamide [VDC]), have all shown activity in previously untreated MM, a combination of all four agents (VDCR) may result in even greater activity [33]. The randomized Phase I/II study reported by Kumar et al. (EVOLUTION) is assessing the efficacy and safety of VDR, VDC, and VDCR as initial therapy in newly diagnosed MM patients. The MTD reported by the group for the VDCR regimen is intravenous bortezomib 1.3 mg/m 2 (days 1, 4, 8 and 11), dexamethasone 40 mg orally (days 1, 8 and 15), lenalidomide 15 mg orally (days 1 14) plus cyclophosphamide 500 mg/m 2 orally (days 1 and 8) for up to eight 21-day cycles, followed by bortezomib 1.3 mg/m 2 (days 1, 8, 15 and 22) for four 42-day maintenance cycles. VDCR was well tolerated and hematologic toxicities were manageable [33]. Enrollment to the three arms (VDR, VDC and VDCR) of the Phase II portion of the study is ongoing. Response rates are shown in Table 2. Melphalan prednisone lenalidomide Oral therapy with melphalan or cyclophosphamide, prednisone, and thalidomide are the commonly used regimens for elderly patients with MM [15,34]. The Gruppo Italiano Malattie Ematologiche dell Adulto (GIMEMA) group assessed dosing, efficacy and safety of melphalan prednisone lenalidomide (MPR) in newly diagnosed elderly MM patients [14]. Oral melphalan was dosed from 0.18 to 0.25 mg/kg on days 1 4, prednisone at a 2 mg/kg on days 1 4 and lenalidomide from 5 10 mg on days 1 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as prophylaxis for thrombosis. Of the 54 patients enrolled, the MTD was 0.18 mg/kg of melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a PR, 47.6% VGPR and 24% achieved a CR. At the MTD, grade 3 neutropenia was 38.1%, thrombocytopenia 14.2%, febrile neutropenia 9.5%, vasculitis 9.5% and thromboembolism 5%; grade 4 adverse events (AEs) were neutropenia (14.2%) and thrombocytopenia (9.5%). With oral MPR, hematologic toxicity was frequent but manageable [14]. These results formed the basis for the ongoing European Myeloma Network Phase III study comparing MP with MPR, with or without lenalidomide maintenance. The toxicity and efficacy profile of MPR, a third option in front-line treatment of elderly patients, should be compared with MPT and VMP. The Mayo group reported on the same regimen with melphalan 5 mg/m 2 on days 1 4, prednisolone 60 mg/m 2 days 1 4 and lenalidomide 10 mg days 1 21 of a 28-day cycle. Of the 26 patients enrolled, the ORR was 69% with a CR plus VGPR rate of 31%. Grade 3/4 neutropenia (42%/8%) and thrombocytopenia (20%/8%) were the most common side effects. In total, 42% of patients required granulocyte colony-stimulating factor (G-CSF) [35]. Clarithromycin dexamethasone lenalidomide It has previously been shown that the combination of clarithromycin (Biaxin ), low-dose thalidomide and dexamethasone (BLT D) is effective with an ORR of 93% [36]. Hence, clarithromycin was combined with lenalidomide and dexamethasone (BiRD) as first-line therapy for MM [37]. Dexamethasone (40 mg) was given orally once weekly, clarithromycin (500 mg) was given orally twice daily and lenalidomide (25 mg) was given orally daily on days A total of 90% of patients achieved an objective response (8% CR) to this regimen. Median event-free survival has not been reached in these patients. The actuarial 2 year event-free survival has been reported as 85.2% for those patients who underwent autologous stem cell transplantation compared with 75.2% for those who did not. This regimen did not interfere with hematopoietic stem cell harvest and was effective with manageable side effects (Table 2). Consolidation/maintenance therapy The novel agents are currently being used as consolidation/ maintenance to improve CR rates and hopefully survival. Palumbo et al. recently published on the use of lenalidomide as consolidation/maintenance post-autotransplantation (new patients aged years) [38]. The induction regimen consisted of four 21 day bortezomib, doxorubicin, dexamethasone (PAD) cycles [39]. Patients received a tandem autotransplant with melphalan 100 mg/m 2 followed by consolidation with four 28 day cycles of lenalidomide 25 mg days 1 21 plus prednisone 50 mg alternate days (LP) followed by lenalidomide alone maintenance (10 mg days 1 21 every 28 days). A total of 102 patients have been enrolled. After PAD cycles the PR rate was at least 94% and VGPR was 59%, including 13% CR. After tandem autograft, 88% of patients achieved at least VGPR and 41% CR. After LP consolidation all patients obtained PR, 88% at least VGPR and 53% immunofixation-negative CR. After a median follow-up of 14 months, 1 year PFS was 92%. During LP consolidation, grade 3 4 toxicities included neutropenia (18%), thrombocytopenia (6%), infections (6%) and DVT (6%). The authors have concluded that lenalidomide as consolidation maintenance is a highly effective regimen in elderly patients [38]. The ECOG group, in a Phase III trial (E1A05), is addressing the role of bortezomib and dexamethasone (VD) or VD plus lenalidomide (VRD) as consolidation therapy in those patients who have completed a dexamethasone-based regimen for four to six cycles without progressive disease. The rationale for this trial is that incorporation of active newer agents early in the course of patient pathway could improve long-term results [40]. Trials have shown that prednisone is effective as maintenance therapy [41], hence combinations of lenalidomide and steroids should be tested as maintenance therapy. Also, it has been shown that consolidation therapy with 12 months of thalidomide combined with prednisone prolongs survival when used after a single autologous stem cell transplant, thus providing the basis for evaluation of combination lenalidomide with steroids [42]. A recent subana lysis of the two pivotal registration studies (MM-009 and MM-010) has shown that for patients attaining stable disease (SD) or better, prolonged duration of treatment was associated with significantly longer OS and TTP, and early discontinuation of treatment led to reduced OS and TTP [43] Expert Rev. Anticancer Ther. 9(11), (2009)

5 Lenalidomide in multiple myeloma Drug Profile Table 2. Results of studies using lenalidomide in newly diagnosed myeloma. Treatment Patients (n) CR (%) ORR (%) PFS OS VTE Grade 3/4 neutropenia (%) Grade 3/4 thrombocytopenia (%) RVD * [31] VDCR * 20 4 [32] MPR > year (92%) 2-year (92%) Ref [14] BiRD [37] Lenalidomide + low-dose dexamethasone Lenalidomide + high-dose dexamethasone year (96%) year (87%) 9 19 [30] [30] * Thromboprophylaxis. BiRD: Biaxin, Revlimid, dexamethasone; CR: Complete response; MPR: Melphalan, prednisone, Revlimid; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; RVD: Revlimid, velcade, dexamethasone; VDCR: Velcade, dexamethasone, cyclophosphamide, Revlimid; VTE: Venous thromboembolism. Hence, efforts should be made to manage side effects associated with lenalidomide while maintaining patients on treatment for as long as possible. This also showed that maintaining treatment with lenalidomide and dexamethasone after achieving the optimal response ensures a significant improvement in OS for patients with relapsed/refractory MM [43]. Use of lenalidomide post-allotransplant The majority of patients with MM who survive transplant-related problems currently relapse post-allotransplant, although this remains the only curative option available to a small group of patients. A group evaluated the efficacy and toxicity of lenalidomide in 24 myeloma patients with relapsed disease after allotransplant [44]. Prior to lenalidomide, salvage treatment included donor lymphocyte infusions in 18 patients, thalidomide in 11 patients and bortezomib in 13 patients. Lenalidomide was given at 15 mg (n = 4) or 25 mg (n = 20) orally once daily on days 1 21 every 28 days and, in 20 patients, in combination with dexamethasone. No prophylactic anticoagulation was used. The most common toxicity was myelosuppression, with 21%/4% grade 3/4 leukopenia. Cerebral infarction was seen in one patient, who received steroids for acute graft-versus-host disease. Objective remission was achieved in 66% of the patients (CR: 8%, VGPR: 8%, PR: 50%) and SD in 13% of the patients, while in 21% progressive disease was noted. Prior treatment with thalidomide or with bortezomib did not influence the rate of CR/PR. Patients with del(13q14) achieved a higher CR/PR rate than those without del(13q14) (p = 0.02) [44]. The median TTP was 9.7 months (95% CI: ) and the median OS was 19.9 months (95% CI: ) suggesting that lenalidomide is effective in relapsed patients with MM post-allograft [44]. The major toxicity is myelosuppression for which dose reduction was required in the majority of patients. The optimal dose of lenalidomide after allogeneic stem cell transplantation needs to be investigated. Early versus late initiation of lenalidomide By targeting the MM earlier in the disease course, more and more studies are looking at whether the use of novel agents earlier rather than later is better for the patient. A subset ana lysis of data from two Phase III studies in patients with relapsed/refractory MM looked at the benefit of initiating lenalidomide dexamethasone at first relapse [45]. Multivariate ana lysis showed that fewer prior therapies, along with b-2 microglobulin (b-2m) 2.5 mg/l or lower, predicted a longer TTP with lenalidomide dexamethasone treatment. Patients with one prior therapy showed a significant improvement in benefit after first relapse compared with those who received two or more therapies. Patients with one prior therapy had significantly prolonged median TTP (17.1 vs 10.6 months; p = 0.026) and PFS (14.1 vs. 9.5 months; p = 0.047) compared with patients treated in later lines. The ORR was higher (66.9 vs 56.8%; p = 0.06), and the CR plus VGPR rate was significantly higher in first relapse (39.8 vs 27.7%; p = 0.025). The OS was significantly prolonged for patients treated with lenalidomide dexamethasone with one prior therapy, compared with patients treated later in salvage (median of 42.0 vs 35.8 months; p = 0.041), with no differences in toxicity, dose reductions or discontinuations despite longer treatment [45]. Therefore, lenalidomide dexamethasone is both effective and tolerable for second-line therapy and the data suggest that the greatest benefit occurs with earlier use. Risk stratification: effect of lenalidomide It is possible that the novel drugs alone or in combination may overcome the poor prognosis as conferred by the molecular/ genomic profile. High-risk disease continues to be defined in various ways. A proposal has been that patients with any of t(4;14), t(14;16), t(14;20), del(17q13), aneuploidy or deletion chromosome 13 by metaphase cytogenetics or plasma cell labeling over 3.0 should be classified as high-risk MM (25% of MM patients for whom current therapies are inadequate) [46]. Studies have shown

6 Sirohi & Powles that MM patients have cytogenetic abnormalities, causing dysregulation of genes at the breakpoints and by point mutations [47]. Lenalidomide overcomes the poor prognosis conferred by chromosome 13 deletion and t(4;14) in MM patients as shown in a recent study except for patients with del(17p13), in which the outcome was significantly worse despite lenalidomide dexamethasone [48]. Bortezomib is also noted to have poor prognosis with this patient population [49]. Patients with 17p- appear to remain a challenge, representing a subgroup with a particularly bad prognosis even with the use of novel agents. Recently, a retrospective ana lysis showed that 17p- retained its poor prognostic significance even after an allograft [50]. Kapoor et al. have defined high-risk as the presence of at least one of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm by metaphase cytogenetics only, deletion of p53 (locus 17p13), immunoglobulin heavy chain translocations [t(4;14) or t(14;16)] by FISH or cytogenetics, or plasma cell labeling in dexamethasone of at least 3%. Patients without any of these features were considered standard risk. They have shown that high-risk patients attain less durable responses with the lenalidomide dexamethasone combination compared with standard-risk patients, with no significant differences in OS [51]. The International Myeloma Working Group stratifies patients in risk categories based on serum b-2m and serum albumin. Stage I was defined as b-2m under 3.5 mg/l plus serum albumin 3.5 g/dl or higher; stage II as neither stage I nor III, and stage III as b-2m of at least 5.5 mg/l (highest risk group) [52]. A Greek group has shown the validity of the system with the use of novel agents. These novel agents, including lenalidomide, were not able to overcome the high risk [53]. Safety Side effects associated with the use of lenalidomide may include, the following: thrombocytopenia, neutropenia, neutropenic fever, diarrhea, pruritus, skin rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, back pain, pyrexia, cardiac arrhythmias and peripheral edema [54]. Myelosuppression (grade 3 or 4 thrombocytopenia/neutropenia) was the most common side effect and can be managed with dose reductions or interruptions. The incidence of grade 3 4 neutropenia was 41% (grade 3 4 infections 21.5%) in the MM-009 and 29% in the MM-010 study, and the incidence of thrombocytopenia was 15% in MM-009 and 11% in MM-010 study [18,19]. In view of neutropenia, there remains a risk of infection, especially during the first few months of treatment while the dose for the particular patient is being optimized. The depth of myelosuppression is higher if patients have previously received an autotransplant and also in patients with renal dysfunction [10,55]. Close monitoring of neutrophil and platelet counts, both prior to and during treatment, is recommended. In addition, as an analog of thalidomide, lenalidomide is presumed to carry a serious teratogenic risk. The drug is only available through a closely monitored distribution and education program, designed to minimize the chance that lenalidomide is administered to a pregnant patient. Venous thromboembolism Lenalidomide has been associated with an increased risk of DVT and PE in approximately 20% of patients, and the risk can be decreased with effective use of prophylaxis, avoiding the use of erythropoietin and the use of lower doses of dexamethasone. The ECOG group recently looked at the impact of venous thromboembolism (VTE) on OS of patients with newly diagnosed MM in the E4A03 Phase III trial of RD versus Rd [56]. After the first 264 patients were enrolled the trial, mandatory thromboprophylaxis of aspirin for all patients was advised, with a recommendation to use either warfarin (target INR 2 3) or low-molecular-weight heparin (LMWH) among patients in the RD arm. Of the 445 patients enrolled, overall VTE occurred in 18.5% of patients; 25.6% in the RD arm and 11.4% in the Rd arm. The rate of VTE did not change substantially before and after the prophylaxis amendment. In a Cox model, VTE status as a time-varying covariate was marginally significant (HR: 1.54; 95% CI: ; p = 0.074), suggesting that patients who develop VTE have a higher risk of death. The occurrence of VTE may adversely affect the survival of patients with newly diagnosed MM receiving Revlimid dexamethasone [56]. Besides lowering the dose of dexamethasone, studies investigating optimum thromboprophylaxis are needed. It is recommended that patients should receive education on the symptoms associated with these conditions, and seek medical help immediately if symptoms appear. In the MM-009 trial, 15% of patients in the lenalidomide group developed VTE, compared with 3.5% in the dexamethasone/placebo group [18]. Various VTE prophylaxis strategies, such as LMWH, warfarin or aspirin, have been investigated. Based on the available evidence, a prophylaxis strategy has been recommended according to a risk-assessment model, including age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia [57]. Myeloma-related risk factors include diagnosis and hyperviscosity. The incidence of VTE was very high in patients who receive highdose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommended aspirin for patients with one or no risk factors for VTE and LMWH (equivalent to enoxaparin 40 mg/day) for those with two or more individual/myelomarelated risk factors. In addition, LMWH was recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic international normalized ratio of 2 3 is an alternative to LMWH, although there are limited data on this. These recommendations were based on results of common sense or are derived from the extrapolation of data from many studies not specifically designed to answer these questions [57]. Further investigation is needed to define the best VTE prophylaxis. This increased risk of VTE is probably not only related to the amount of steroids but also to the amount of lenalidomide, so that combination therapies may have a lower risk of VTE, particularly when the dose of steroids and lenalidomide is lower and bortezomib is included. The latter drug in some studies has been suggested to reduce the risk of VTE when added to immunomodulatory drugs (IMiDs) with steroids [58] Expert Rev. Anticancer Ther. 9(11), (2009)

7 Lenalidomide in multiple myeloma Drug Profile Renal failure Up to 25 30% patients with MM may present with renal failure and usually have high-risk disease, hence it is quite important for these patients to have access to effective novel agents [1,59]. Most Phase III trials exclude patients with creatinine over 221 µm/l [18]. Recently, Niesvizky et al. reported on lenalidomide-induced myelosuppression as linked to renal function [55]. They observed that a creatinine clearance (CrCl) of less than 40 ml/min was associated with significant myelosuppression and required a dose reduction of lenalidomide in 80% of patients. The dose reduction occurred at a median of over 150 days. The ORR did not correlate with renal insufficiency in this study. Pharmacokinetic data were not collected. A study presented at the American Society of Hematology 2008 annual meeting, looked at using lenalidomide dexamethasone in 40 patients with light-chain amyloidosis and severely impaired renal and cardiac function. Patients received lenalidomide 15 mg every 48 hours for CrCl less than 40 ml/min and 15 mg three-times a week for dialysis patients [60]. VTE prophylaxis consisted of aspirin 100 mg (n = 35) or LMWH (n = 4). The median number of administered lenalidomide dexamethasone cycles was three out of a planned six (range one to 12). Hematological toxicity greater than National Cancer Institute (NCI) grade 2 required dose reduction of lenalidomide in ten patients. Seven patients died early during lenalidomide dexamethasone therapy (four with Mayo stage II, three with end-stage renal disease). Three patients stopped treatment due to side effects after receiving fewer than three cycles. In total, 24 patients were still on therapy with lenalidomide dexamethasone. The hematological remission rate was 50%. The recommendation for patients with MM with CrCl less than 30 ml/min on dialysis is lenalidomide 5 mg once daily (on dialysis days, dose should be administered after dialysis); for those with CrCl less than 30 ml/min not requiring dialysis, the dose is 15 mg every 48 h. For patients with moderate renal impairment (CrCl between ml/min), the recommended dose is 10 mg every 24 h. Elderly patients The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MY.11 trial has looked at the use of melphalan lenalidomide in elderly patients with MM who were ineligible for HSCT. Planned treatment consisted of melphalan 5 mg/m 2 on days 1 4 and lenalidomide 10 mg on days 1 21, given every 28 days for 12 cycles. A total of 35 patients (median age 71.4 years; planned accrual was 41 patients) were enrolled before the study was closed due to the frequency of dose-limiting toxicities that surpassed predefined boundaries [61]. Although this was an active combination, the regimen was associated with considerable myelosuppression and without the routine use of G-CSF, the doses used in the MY.11 study were not tolerable. An Italian group has analyzed the kinetics of neutropenia and thrombocytopenia in elderly newly diagnosed patients with MM who received melphalan, prednisone and lenalidomide (MPR), and have shown that the incidence and depth of neutropenia did not increase with the number of cycles. Grade 3 4 hematologic toxicity was more frequent in patients with low baseline neutrophil count and in those with Bence-Jones MM. Grade 3 neutropenia occurred in 38.1% of patients, grade-4 neutropenia in 14.2% of patients and febrile neutropenia in 9.5%. G-CSF was administered in 42.3% of patients [62]. Stem cell mobilization With the early and effective use of novel treatments, patients are opting to have delayed HSCT. It is crucial that in young, fit patients, autologous PBSCs are collected during the first remission for possible transplant in the future. The impact of lenalidomide on collection of PBSCs in newly diagnosed patients has been assessed by the Mayo group [63]. They compared various initial treatment strategies and their impact on stem cell collection and showed that for those patients mobilized with G-CSF alone, there was a significant decrease in total CD34 + cells collected (p < 0.001), average daily collection (p < 0.001), day 1 collection (p < 0.001) and increased number of aphereses (p = 0.004) in patients treated with lenalidomide compared with those receiving dexamethasone, thalidomide dexamethasone or VAD. A similar trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration of lenalidomide therapy as well as increasing age (p = 0.002). There was no effect on quality of PBSC collected based on similar engraftment across all groups. Recent ana lysis from the same group has shown that the inability to collect adequate stem cells with lenalidomide appears to be related to patient age and the duration of lenalidomide therapy, hence they recommend early stem cell collection and storage if a delayed transplantation approach is taken [64]. Patients receiving more than four cycles of therapy and those over 65 years of age should undergo mobilization with cyclophosphamide plus G-CSF, rather than G-CSF alone. Majority of the patients who fail G-CSFbased collection can be mobilized using cyclophosphamide and G-CSF. Early identification of failures after G-CSF administration using the peripheral CD34 counts can potentially allow salvage using strategies such as AMD3100 (plerixafor). The International Myeloma Working Group also recommends collection of PBSC within four cycles on initial therapy with lenalidomide. If patients receive more than four cycles of lenalidomide, mobilization with cyclophosphamide plus G-CSF priming is recommended [65]. There is evidence from another study to suggest that stem cell mobilization is compromised after lenalidomide therapy [66]. It appears that plerixafor may overcome these problems [67,68]. Health economics Introduction of these new and mostly expensive treatments poses major problems worldwide for healthcare systems with finite resources [69]. Reliable assessment of efficacy and cost effectiveness of new treatments is a priority, especially in comparison with standard treatments. An economic evaluation of using lenalidomide dexamethasone was undertaken recently and showed that its use is associated with a substantial improvement in survival and quality adjusted life years [70]. The study concluded that although estimated incremental costs

8 Sirohi & Powles are large, the improvements in health outcomes yield incremental cost effectiveness ratios below 30,000 per quality-adjusted life year. Lenalidomide dexamethasone continued to be cost effective when used to treat treated patients previously with thalidomide. Undiscounted incremental cost effectiveness ratios are lower because survival benefits are not fully realized until end-of-life and so are subject to a higher degree of compound discounting than the costs that are incurred relatively early. Univariate and probabilistic sensitivity analyses showed that results remain consistent through broad changes in model parameters [70]. Lenalidomide has recently been approved by the NICE (launched in April 1999 and covers England and Wales to provide guidance to NHS on clinical effectiveness and also develop guidelines outlining best practice) Appraisal Committee and the recommendations are as follows [102]: lenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of MM in people who have received two or more prior therapies, under the following circumstances: NHS will cover the cost of the drug for the first 2 years (26 cycles of 28 days) of treatment. The drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for longer than 2 years will be met by the manufacturer. People currently receiving lenalidomide for the treatment of MM, but who have not received two or more prior therapies, should have the option to continue therapy until they or their clinicians consider it appropriate to stop. Newer IMiDs The IMiD thalidomide analog CC-5013/lenalidomide was the first to be clinically available and licensed. CC-4047/pomalidomide underwent initial clinical trials in the UK and Phase I data were reported in 2004, although further development of this agent was abandoned until recently [71]. The original study showed in 24 patients where CC-4047 was well tolerated, that the treatment-related incidence of thrombosis was 12.5%, dose-limiting hematologic neutropenia was observed in six patients, no grade 4 dose-limiting thrombocytopenia was observed and the MTD of CC-4047 was 2 mg/day [71]. Interest in this agent has been rekindled and Phase II data were reported at ASH 2008 in combination with low-dose dexamethasone in patients with relapsed/refractory MM [72]. In 37 patients, pomalidomide 2 mg/day was given orally on days 1 28 of a 28 day cycle. Dexamethasone was given orally at a dose of 40 mg/day on days 1, 8, 15 and 22 of each cycle. All patients received aspirin 325 mg as thromboprophylaxis. Grade 3 neutropenia occurred in 31% of patients; grade 3 thrombocytopenia in 3%; and 16% had grade 1/2 neuropathy. A total of 62% achieved an objective response to therapy; including 24% with VGPR; 38% with PR; and 16% with SD [72]. Objective responses were seen in 29% patients who were refractory to lenalidomide, which is encouraging. Preclinical/Phase I/II combinations with new biologicals Recent data on the combination of a novel proteasome inhibitor salinosporamide (NPI-0052) and lenalidomide shows that combining NPI-0052 and lenalidomide induces synergistic/ additive antimyeloma activity in vitro using myeloma cell lines or patient CD138 + MM cells, providing the preclinical rationale for combining these two drugs [73]. Vorinostat is an inhibitor of class I and II histone deacetylases, which play key roles in the regulation of both transcriptional and post-transcriptional activity in MM. Preclinical data suggest that the addition of vorinostat to lenalidomide and dexamethasone has at least additive, and possibly synergistic, therapeutic potential. A Phase I study assessed this combination in patients with relapsed/refractory MM [74]. Patients received vorinostat daily, orally for 14 days with 7 days on (days 1 7 and 15 21), with lenalidomide daily for 21 days and oral dexamethasone 40 mg/ day (days 1, 8, 15 and 22; cycles were repeated every 28 days); use of concomitant prophylactic aspirin was recommended. Of seven patients, six have reported at least one AE, the most frequently reported AE being anemia (n = 4; 57%). Serious AEs were reported by two patients (29%), none of which were considered drug related. No patients have discontinued due to AEs or serious AEs, and no dose-limiting toxicity has been observed to date. Perifosine, an oral signal transduction modulator with multiple effects, including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone in patients with relapsed/refractory MM. [75]. A Phase I trial reports on the combination of perifosine lenalidomide dexamethasone, as an oral combination in patients with relapsed/refractory MM [76]. Of the 30 patients evaluable for safety, the grade 3/4 AEs reported by 5% or more included neutropenia (20%), hypophosphatemia (17%), thrombocytopenia (13%), anemia (10%) and fatigue (7%). Patients tolerated perifosine lenalidomide dexamethasone well with manageable toxicity, and with encouraging clinical activity as seen by an ORR ( PR) of 50% [76]. Expert commentary Lenalidomide, in combination with dexamethasone, is currently indicated for the treatment of patients with MM who have received at least one prior therapy and their use as induction therapy should be restricted to clinical trials until additional mature data and long-term follow-up are available. Among the currently licensed indications for drugs for patients, it is not possible to recommend whether and in what order it is best to give thalidomide, lenalidomide or bortezomib to patients with advanced MM. We should be guided by patient choice and convenience, as well as efficacy. Five-year view Lenalidomide will have an established role in the treatment of newly diagnosed patients with MM in combination therapy. Whether lenalidomide is best administered as a two-, three- or four-drug combination therapy or as sequential therapy remains to be seen. A better definition of dosing of lenalidomide should also be established. Is 25 mg really better than 10 mg or even 5 mg when combined with steroids? Safety issues, especially relating to anticoagulation, renal failure and cytopenias, will be important to clear up. It is hoped that risk stratification will have optimized which groups of patients may specifically benefit from 1566 Expert Rev. Anticancer Ther. 9(11), (2009)

9 Lenalidomide in multiple myeloma Drug Profile lenalidomide therapy. This is necessary to reduce costs and allow cost-effective treatments that are realistic for approval by funding bodies around the world. Use of lenalidomide in a post-transplant setting (allogeneic and autologous) will be better defined over the next 5 years and the place, dose and duration of lenalidomide as maintenance therapy for patients with MM needs to be established. Future studies defining gene and protein targets of lenalidomide will allow a scientific rationale for combination with other known and new drugs. Long-term follow-up data on lenalidomide will lead to an increase in the plateau of year survivors (i.e., operational cures ). Financial & competing interests disclosure Ray Powles is on the advisory board for Kyowa Hakko Kirin. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Key issues Two pivotal Phase III studies in America and Europe (MM-009, and MM-010) have shown increased activity of lenalidomide in combination with dexamethasone with combined response rates of 59 versus 21 24% for dexamethasone, and complete response rates of versus 1 4% in patients with relapsed/refractory multiple myeloma. Lenalidomide works after thalidomide (subgroup analysis of MM-009 and MM-010), but it is unknown if thalidomide works after the use of lenalidomide. Lenalidomide is now being increasingly used for newly diagnosed patients with or without chemotherapy and is also being combined with other biological agents to establish the optimum synergic combinations. The optimum duration of treatment with lenalidomide is unknown. Should lenalidomide be given indefinitely, stopped at the time of maximum response or at the time of disease progression if well tolerated? Lenalidomide is usually well tolerated, although myelosuppression can occur in up to 30% of patients in some studies and needs close monitoring. Long-term safety data are awaited. Risk stratification is being devised to define which patients are more likely to benefit from lenalidomide therapy. There are currently no biomarkers to predict this. Studies are ongoing and these are crucial to maximize cost effectiveness. Healthcare systems cannot afford long-term treatment for all patients. The optimal dose of lenalidomide in patients with renal dysfunction and post-allotransplant is not well defined, results of clinical trials are awaited. References 1 Sirohi B, Powles R. Multiple myeloma. Lancet 363(9412), (2004). 2 Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341(21), (1999). 3 Richardson PG, Schlossman RL, Weller E et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100(9), (2002). 4 Richardson PG, Xie W, Mitsiades C et al. Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J. Clin. Oncol. 27(21), (2009). 5 Sirohi B, Powles R, Mehta J et al. An elective single autograft with high-dose melphalan: single-center study of 451 patients. Bone Marrow Transplant. 36(1), (2005). 6 Sirohi B, Powles R, Harousseau JL, Anderson KC. The evolving background for high-dose treatment for myeloma. Bone Marrow Transplant. 40(12), (2007). 7 Hideshima T, Chauhan D, Shima Y et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96(9), (2000). 8 Dimopoulos MA, Kastritis E, Rajkumar SV. Treatment of plasma cell dyscrasias with lenalidomide. Leukemia 22(7), (2008). 9 Galustian C, Dalgleish A. Lenalidomide: a novel anticancer drug with multiple modalities. Expert Opin. Pharmacother. 10(1), (2009). 10 Richardson PG, Blood E, Mitsiades CS et al. A randomized Phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 108(10), (2006). 11 Anderson KC. Lenalidomide and thalidomide: mechanisms of action similarities and differences. Semin. Hematol. 42(4 Suppl. 4), S3 S8 (2005). 12 Galustian C, Meyer B, Labarthe MC et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol. Immunother. 58(7), (2009). 13 Richardson PG, Schlossman RL, Weller E et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100(9), (2002). 14 Palumbo A, Falco P, Corradini P et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA Italian Multiple Myeloma Network. J. Clin. Oncol. 25(28), (2007). 15 Palumbo A, Bringhen S, Caravita T et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367(9513), (2006). 16 Cavo M, Patriarca F, Tacchetti P et al. Bortezomib (Velcade ) thalidomide dexamethasone (VTD) vs thalidomide dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). ASH Annual Meeting Abstracts 110(11), 73 (2007). 17 Richardson P, Lonial S, Jakubowiak A et al. Lenalidomide, bortezomib, and dexamethasone in patients with newly