Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement

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1 REVIEW (2011) 25, & 2011 Macmillan Publishers Limited All rights reserved /11 Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement MA Dimopoulos 1, A Palumbo 2, M Attal 3, M Beksaç 4, FE Davies 5, M Delforge 6, H Einsele 7, R Hajek 8, J-L Harousseau 9, F Leal da Costa 10, H Ludwig 11, U-H Mellqvist 12, GJ Morgan 5, JF San-Miguel 13, S Zweegman 14 and P Sonneveld 15 on behalf of the European Myeloma Network 1 Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece; 2 Divisione di Ematologia dell Università di Torino, Azienda Ospedaliera S Giovanni Battista, Turin, Italy; 3 Division of Hematology, Hôpital Purpan, Toulouse, France; 4 Department of Hematology, Ankara University, Ankara, Turkey; 5 Institute of Cancer Research, Royal Marsden Hospital, London, UK; 6 Department of Hematology, University Hospital Leuven, Leuven, Belgium; 7 Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; 8 Department of Internal Medicine and Hematooncology, Faculty of Hospital Brno and Babak Research Institute, Faculty of Medicine, Masaryk University, Brno-město, Czech Republic; 9 Department of Clinical Haematology, Centre René Gauducheau, Saint-Herblain, France; 10 Bone Marrow Transplantation Unit, Instituto Português de Oncologia, Lisbon, Portugal; 11 First Department of Medicine, Center for Oncology and Hematology, Vienna, Austria; 12 Department of Hematology, University Hospital, Gothenburg, Sweden; 13 Hospital Universitario de Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 14 Department of Hematology, VU University Medical Center, Amsterdam, Netherlands and 15 Department of Hematology, University Hospital Rotterdam, Rotterdam, Netherlands An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. (2011) 25, ; doi: /leu ; published online 4 February 2011 Keywords: lenalidomide; dexamethasone; relapsed; refractory; multiple myeloma Introduction The introduction of thalidomide, lenalidomide and bortezomib into standard therapy has had a positive effect on survival in patients with multiple myeloma (MM). 1,2 Although MM is still considered an incurable disease, long-term disease control is now achievable due in part to the availability of novel therapies. This has led to the emergence of two distinct (but not mutually exclusive) treatment paradigms: achievement of the best possible response with cytoreductive therapy, often given as a multiple-drug regimen, and sustainment of disease control with well-tolerated continuous therapy. 3 Correspondence: Dr MA Dimopoulos, Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, 80 Vas. Sofias, Athens 11528, Greece. mdimop@med.uoa.gr Received 19 October 2010; revised 13 December 2010; accepted 23 December 2010; published online 4 February 2011 Lenalidomide is an immunomodulatory agent that has both direct tumoricidal and immunomodulatory effects in MM The dual mechanism of action of lenalidomide makes it particularly well suited to address both treatment paradigms, and recent evidence indicates that continuous therapy with lenalidomide can improve the quality of response, and prolong the time to relapse and overall survival (OS) When given as monotherapy, lenalidomide is moderately active in patients with relapsed or refractory multiple myeloma (RRMM) However, superior efficacy was noted in combination with dexamethasone; therefore, the combination of lenalidomide and dexamethasone (Len/Dex) was indicated for patients with MM, who have received at least one previous therapy (Table 1). 19,20 Approval of lenalidomide in this setting was based primarily on the results of two multicenter, randomized, placebo-controlled trials comparing Len/Dex with placebo/dex in patients with RRMM Compared with dexamethasone, Len/Dex improved response rates, time to progression (TTP) and OS. Several additional analyses of data from these two trials, known as MM-009 and MM-010, have provided further insight into the effects of Len/Dex in various subpopulations (Table 2). 11,12,24 32 Among these analyses, a pattern has emerged that emphasizes the importance of using Len/Dex early in the course of the disease 24 and continuing Len/Dex therapy in responding patients until disease progression. 11,12 In light of these emerging data, there is a need for refinement of the recommendations regarding the optimal use of Len/Dex in daily practice. In July 2010, an expert panel convened in Munich, Germany, to discuss the available data and provide practical recommendations, focusing on areas where fewer data are available. The following report summarizes the key points on which the expert panel reached a consensus regarding the use of lenalidomide in RRMM. Optimal timing and duration of the therapy What is the optimal time to initiate Len/Dex in relapsing patients? There is evidence to suggest that using Len/Dex at first relapse is more effective than using it after multiple salvage therapies.

2 750 Table 1 Indication for lenalidomide plus dexamethasone, and recommended dose and schedule of lenalidomide plus dexamethasone 19,20 Indication For the treatment of MM patients who have received X1 previous therapy Dose and Lenalidomide 25 mg once daily orally on days 1 21 of schedule each 28-day cycle Dexamethasone 40 mg orally on days 1 4, 9 12 and of each 28-day cycle for the first four cycles, then 40 mg once daily on days 1 4 of each 28-day cycle Abbreviation: MM, multiple myeloma. This is consistent with other treatments, because the response to any drug is lower as the disease evolves and progresses. In an analysis of data from MM-009/010, 133 patients received Len/Dex at first relapse, whereas 220 received Len/Dex after two or more previous therapies. 24 The combined rate of complete response (CR) and very good partial response (VGPR) was significantly higher when Len/Dex was given at first relapse (39.8 vs 27.7%; P ¼ 0.025). The median OS was also significantly higher when Len/Dex was used at first relapse compared with when it was used after two or more previous therapies (42.0 vs 35.8 months; P ¼ 0.041). The incidences of adverse events, dose reductions and discontinuations were similar in both groups, despite the longer duration of treatment in patients who received Len/Dex at first relapse. Therefore, in order to maximize response rates and response durability, Len/Dex should be administered at first relapse in patients with RRMM. The type of previous therapy has some impact on the efficacy and safety of Len/Dex. In MM-009/010, Len/Dex was more effective than dexamethasone alone in patients who had received previous thalidomide and in a subset of patients who were resistant to previous thalidomide. 26 Among patients treated with Len/Dex, those who had previous thalidomide had a lower overall response (OR) rate and TTP than thalidomide-naive patients, but OS was comparable, regardless of previous thalidomide use. 26 In a compassionate-use study in heavily pretreated patients (patients had a median of three previous therapies; 91% had previous thalidomide and 68% had previous bortezomib), response and survival were not influenced by previous thalidomide therapy. 33 Avet-Loiseau et al. 34 have also recently reported that previous thalidomide therapy did not influence survival outcomes, but progression during thalidomide was associated with a shorter median OS. Similarly, in a study of 99 patients with RRMM who were treated with Len/Dex with or without bortezomib (based on the presence of neuropathy), resistance to previous thalidomide was a significant predictor of inferior response, progression-free survival (PFS) and OS. 35 However, it should be noted that patients with resistance to previous thalidomide may constitute a group of patients whose disease biology is intrinsically aggressive, irrespective of the treatment administered. Overall, one could expect that patients with true resistance to thalidomide have a 50% chance of response, with an expected TTP of 6 8 months. 26 When such patients have no peripheral neuropathy, a bortezomib-based regimen is indicated. Some groups have reported that previous bortezomib therapy is associated with a higher risk of disease progression after Len/Dex, 34,36 although previous bortezomib therapy did not influence response or survival in the compassionate-use study. 33 Data from the VISTA trial also indicate that use of lenalidomide-based combination therapy at first relapse is equally effective in patients who had or had not received bortezomib as a part of the first-line therapy. 37 Previous treatment with high-dose chemotherapy and autologous stem cell transplantation (ASCT) does not appear to affect the efficacy of Len/Dex. 25,36 The efficacy of Len/Dex was not influenced by the presence of most risk factors, including advanced age, poor performance status, immunoglobulin A (IgA)-type disease and advanced disease stage (Table 2). 29,30 The efficacy of Len/Dex was also comparable in patients with or without renal impairment (RI) 27 and in those with or without neuropathy at baseline. 28 The panel therefore agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM, and should therefore be considered in early lines of MM treatment. The efficacy of Len/Dex appears to be independent of previous therapy, including thalidomide, bortezomib and ASCT, although the efficacy is lower in thalidomide-refractory patients. Len/Dex is therefore an option for patients who have received previous thalidomide, particularly for those with a thalidomide-free interval of 41 year. Other baseline factors, such as age, renal function or existing neuropathy, do not preclude the use of Len/Dex. The choice of regimen at first relapse depends on individual patient characteristics, the safety profile of the regimen and the regimen used as first-line treatment, including the side effects that have occurred with this treatment. For example, Len/Dex may be better suited for patients with preexisting neuropathy, whereas bortezomib-based therapy may be appropriate for patients with renal failure. Some patients may benefit from more intensive lenalidomide-based combinations, such as lenalidomide dexamethasone cyclophosphamide, lenalidomide dexamethasone bortezomib or lenalidomide dexamethasone doxorubicin Other patients may benefit from a second ASCT after lenalidomide re-induction, and this concept will be further explored in future IFM (Intergroup Francophone du Myélome) and European Myeloma Network trials. Len/Dex is most effective when used at first relapse. Len/Dex can be administered regardless of the type of previous therapy. What is the optimal starting dose of lenalidomide when combined with dexamethasone? The starting dose of lenalidomide is 25 mg once daily orally on days 1 21 of each 28-day cycle. When used in combination with dexamethasone in patients with RRMM, the dose of lenalidomide should be based on two key factors: renal function and the presence of cytopenias at baseline (Figure 1). RI is a common complication in patients with MM, 41 and because lenalidomide is excreted primarily via the kidneys, 19,20 lower doses can provide sufficient drug exposure in patients with RI. 42 Lenalidomide is not nephrotoxic, and with appropriate dose modification, it can be given safely and effectively in patients with moderate-to-severe RI. 19,20,43 45 Len/Dex has also been shown to improve renal function in a substantial proportion of these patients. 27,46,47 Renal function, as estimated by creatinine clearance, should be assessed in all patients before starting Len/Dex. The Cockroft Gault formula should be used when estimating creatinine clearance. This formula has the added advantage of accounting for age, which makes additional dose modifications for patient age unnecessary. The panel emphasized that renal function should be monitored closely during treatment with Len/Dex, and the dose should be adjusted accordingly. In a subanalysis of data from MM-009/010, improvement in renal

3 751 Table 2 Results from two randomized trials comparing lenalidomide plus dexamethasone with dexamethasone alone in patients with RRMM Treatment/population n OR (%) CR (%) Median TTP (months) Median OS (months) Comments Total population (n ¼ 704) Len/Dex vs Dex vs vs 21.9 (Po0.001) 15 vs 2 (Po0.001) 13.4 vs 4.6 (Po0.001) 38 vs 31.6 (P ¼ 0.045) Significant improvement in OS despite 47.6% crossover from Dex to Len/Dex Len/Dex patients (n ¼ 353) At first relapse vs X2 previous 133 vs vs 56.8 (P ¼ 0.060) 20.3 vs 11.8 (P ¼ 0.028) 17.1 vs 10.6 (P ¼ 0.026) 42.0 vs 35.8 (P ¼ 0.041) Len/Dex was more effective when used at first relapse therapies 24 ASCT vs no ASCT vs vs 55 (P ¼ 0.12) 13 vs vs 61.4 (P ¼ 0.13) NR Len/Dex was effective, regardless of previous ASCT Thalidomide vs no thalidomide vs vs 64.6 (Po0.05) 7.9 vs 19.0 (Po0.05) 8.4 vs 13.9 (Po0.05) 33.3 vs 36.1 OR and TTP were better in patients with no previous thalidomide, but OS was similar; Len/Dex was more effective than Dex, independent of Mild/no RI vs moderate RI vs 243 vs 82 vs vs 56 vs vs 16 vs vs 11.1 vs vs 29.0 vs 18.4 severe RI 27 (P ¼ 0.006) Previous neuropathy vs no 70 vs vs 64 (P ¼ 0.62) 40 vs 33 a (P ¼ 0.31) a 14.8 vs 12.3 (P ¼ 0.65) Not reached vs 30.6 neuropathy 28 (P ¼ 0.78) previous thalidomide Len/Dex was highly effective and well tolerated in patients with MM who have RI; 72% had improvement in RI during therapy; thrombocytopenia was more common in patients with severe RI Len/Dex was effective regardless of previous neuropathy. Median daily dose intensity of Len was similar in both groups, indicating that it was well tolerated regardless of previous neuropathy Age o65 vs vs 475 years vs 125 vs vs 58.4 vs vs 9.6 vs 25.0 PFS: 10.7 vs 11.1 vs 13.3 NR Len/Dex was more effective than Dex, independent of age; age did not influence adverse events Age o65 vs X65 years vs vs 60 (P ¼ 0.73) NR 11.1 vs 13.2 (P ¼ 0.91) NR Efficacy of Len/Dex was independent of age ECOG 0 vs X vs vs 62 (P ¼ 0.52) NR 10.2 vs 13.1 (P ¼ 0.30) NR Efficacy of Len/Dex was independent of ECOG score Non-IgA vs IgA vs vs 68 (P ¼ 0.10) NR 11.2 vs 10.2 (P ¼ 0.65) NR Efficacy of Len/Dex was independent of IgA status Durie Salmon I II vs III vs vs 60 (P ¼ 0.89) NR 13.6 vs 10.6 (P ¼ 0.21) NR Efficacy of Len/Dex was independent of disease stage b2-microglobulin 103 vs vs 56 (P ¼ 0.002) NR 15.2 vs 9.5 (P ¼ 0.004) NR Patients with high b2-microglobulin had worse outcomes p2.5 vs 42.5 mg/l 30 Patients achieving XPR with Len/Dex CR/VGPR vs PR vs 100 NR NR 27.7 vs 12.0 (Po0.001) Not reached vs 44.2 (P ¼ 0.021) Continued therapy improved depth of response, and CR/VGPR was associated with improved outcomes vs PR: 50% with initial PR later achieved CR/VGPR; CR/VGPR occurred after 6 cycles in 38% Continued therapy vs early 174 vs 38 NR NR NR 50.9 vs 35.0 (P ¼ ) Continued therapy was associated with a lower risk of death discontinuation b,12 (Cox proportional hazard regression P ¼ ) Patients on Len/Dex and progression free at 12 months (n ¼ 116) Len dose reduction at X12 vs 25 vs 39 vs vs 100 vs 94 NR PFS: not reached vs 28 o12 months vs no dose (P ¼ 0.007) vs 37 reduction 31 (P ¼ 0.040) NR To achieve maximum clinical benefit, patients should be treated for 12 months with full-dose Len plus Dex; thereafter, patients may benefit from continued therapy at a lower dose Patients who received full-dose Len (n ¼ 233) Dex dose reduction vs no Dex 46 vs vs 50.8 (Po0.05) 23.9 vs 13.0 (Po0.01) vs 45.6 (P ¼ 0.002) vs dose reduction 32 (P ¼ 0.19) Dex dose reduction improved efficacy; adverse event rates were similar in both groups Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; Dex, dexamethasone; ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; Len, lenalidomide; NR, not reported; OR, overall response; OS, overall survival; PFS, progression-free survival; PR, partial response; RI, renal impairment; RRMM, relapsed or refractory multiple myeloma; TTP, time to progression; VGPR, very good partial response. a Includes VGPR. b Continued therapy defined as ongoing treatment after achieving PR or better, or discontinuing treatment due to disease progression; early discontinuation defined as patients who achieved PR or better and stopped treatment for adverse events, withdrawal of consent or other reasons.

4 752 Creatinine clearance Renal function Normal CLCr 50ml/min Moderate RI 30ml/min CLCr <50 ml/min Severe RI CLCr <30 ml/min End-stage renal disease CLCr <30 ml/min (requiring dialysis) Lenalidomide starting dose Baseline ANC >1000/µl and platelets >50 000/μl 25 mg once daily 10 mg once daily a 15 mg every other day b 5 mg once daily c Baseline ANC <1000/µl or platelets <50 000/μl 15 mg once daily (GF support/platelet transfusion as needed; monitor frequently) 15 mg every other day b (GF support/platelet transfusion as needed; monitor frequently) 5 mg once daily 5 mg every other (GF support/platelet day transfusion as (GF support/platelet needed; monitor transfusion as frequently) needed; monitor frequently) Adjust the dose at each cycle if changes in CLCr or blood cell counts occur Figure 1 Recommendations for identifying the optimal starting dose of lenalidomide when used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma. a Dose may be escalated to 15 mg once daily after two cycles if patient does not respond to and is tolerating treatment. b Dose may be escalated to 10 mg once daily if the patient is tolerating treatment. c On dialysis days, the dose should be administered following dialysis. ANC, absolute neutrophil count; CLCr, creatinine clearance; GF, growth factor; RI, renal impairment. function was observed during Len/Dex therapy in 72% of patients with moderate-to-severe RI at baseline. 27 Therefore, with appropriate dose adjustment and monitoring, patients with RI can safely receive Len/Dex with good outcomes. According to its prescribing information, lenalidomide should not be started in patients with absolute neutrophil count (ANC) o1000 per ml and/or platelet count o per ml. 19 However, the panel consented that Len/Dex can be initiated in these patients, provided that careful monitoring and prophylactic strategies, including growth factor support and platelet transfusions, are used and the starting dose of lenalidomide (as determined by creatinine clearance) is reduced by one step (Figure 1). In addition, the panel agreed that the threshold for thrombocytopenia requiring those measures can be reduced to per ml. Some panel members noted that, in practice, granulocyte colony-stimulating factor (G-CSF) is often given concomitantly at the start of Len/Dex therapy or very soon after treatment initiation, and felt that a short course of G-CSF (3 days) should be considered in certain cases, such as for patients with increased bone marrow infiltration. 48 This may be particularly valuable in patients who have failed other treatments and for whom lenalidomide is the only option. However, given the lack of prospective data on G-CSF use in this setting, the panel could not provide definitive recommendations. The starting dose of lenalidomide, when used in combination with dexamethasone, should be adjusted for patients with RI and/or cytopenias. Creatinine clearance (calculated using the Cockcroft Gault formula) and complete blood count should be assessed in all patients before initiating Len/Dex. For patients with RI, the starting dose of lenalidomide should be reduced, depending on the degree of impairment. For patients with RI and neutropenia or thrombocytopenia at baseline, the starting dose of lenalidomide should be reduced further. What is the optimal starting dose of dexamethasone? Compared with the standard (high-dose) Len/Dex regimen, use of a lower total dose of dexamethasone has been associated with a reduction in serious adverse events (including thromboembolic complications) and early deaths, particularly within the first 4 months of therapy, when given to patients with newly diagnosed MM. 49 The reduced toxicity observed with the lower doses of dexamethasone translated in significantly longer median OS. It has been suggested that dexamethasone enhances the tumoricidal effects of lenalidomide but partly antagonizes its immunomodulatory effects, 4 which may add to the improved efficacy observed with low-dose dexamethasone. Few studies have analyzed the effects of dexamethasone dose when used in combination with lenalidomide in the relapsed/ refractory setting. In MM-009/010, adjustments to the dose of dexamethasone were associated with improved tolerability and efficacy, 32 and some studies have begun to incorporate lower doses of dexamethasone, reflective of clinical practice. 33,46,50,51 Given the available data, which suggest that lower doses of dexamethasone result in better tolerability with no loss of efficacy, the panel made recommendations regarding dexamethasone dose when used in combination with lenalidomide according to age (Table 3). Standard, high-dose dexamethasone 19,20 should be considered for certain cases, such as patients with cord compression, hypercalcemia or renal failure. The panel also recommended considering prednisone as an alternative to dexamethasone for patients who tolerate dexamethasone poorly. Although there are less published data, a recent report on lenalidomide and prednisone combined with cyclophosphamide indicates that the combination is well tolerated. 52 In this study, prednisone was started at 20 mg daily and tapered to 10 mg within 8 weeks after starting therapy. The good tolerability of an immunomodulatory agent in combination with prednisone is further supported by studies of thalidomide and prednisone as maintenance therapy following high-dose chemotherapy and ASCT. 53,54

5 Table 3 Panel recommendations on dexamethasone dosing according to age Age (years) Dexamethasone dose o65 40 mg per day on days 1 4 and of each 28-day cycle for the first four cycles, followed by 40 mg weekly (days 1, 8, 15, 22 of each 28-day cycle) mg per day weekly mg per day weekly The use of low-dose dexamethasone in combination with lenalidomide can result in better tolerability with no loss of efficacy compared with the standard regimen. The recommended dose of dexamethasone in combination with lenalidomide according to age in patients with RRMM is shown in Table 3. What is the optimal duration of Len/Dex therapy? In MM-009/010, study treatment continued until progression or unacceptable toxicity. 21,22 Importantly, 50% of patients who initially achieved a PR later achieved a CR or VGPR with continued treatment. 11 In 38% of cases, this improvement in the depth of response occurred after six cycles of Len/Dex, and 7% of patients experienced an upgrade in the quality of response after 12 cycles. Compared with patients who achieved a PR only, those who had a best response of CR or VGPR had significantly longer median TTP (27.7 vs 12.0 months; Po0.001) and OS (not yet reached vs 44.2 months; P ¼ 0.021), highlighting the importance of continuing therapy. 11 Similar findings were seen when patients who discontinued treatment early were assessed. 12 Among patients who responded to Len/Dex, those who continued therapy had a lower risk of death than those who discontinued early for reasons other than disease progression, such as adverse events or withdrawal of consent (Cox proportional hazard regression analysis: Po0.001). 12 The value of continuous therapy with lenalidomide is supported by several trials reported at recent congresses These trials evaluated lenalidomide maintenance therapy after ASCT or as a continuous therapy (for example, after induction with melphalan prednisone lenalidomide (MPR) in transplant-ineligible patients with newly diagnosed MM, 13 15,55 and indicated that continuous therapy with lenalidomide is well tolerated and prolongs the time to relapse The panel agreed that long-term treatment should be given at the best-tolerated dose of both lenalidomide and dexamethasone. Lenalidomide is generally well tolerated, which allows for patients to be treated continuously. In a post-approval safety study of 518 patients with RRMM, Len/Dex was associated with lower discontinuation rates owing to adverse events compared with bortezomib or thalidomide (6.2 vs 13.3 and 11.1%, respectively). 56 Caution is required with long-term dexamethasone treatment because of its adverse systemic effects. However, there are no data regarding the efficacy of continuous lenalidomide monotherapy in relapsed patients. A retrospective analysis of data from MM-009/010 showed that patients whose dexamethasone dose was reduced (p20 mg for X1 cycle during the first four cycles, given for 4 days, or p20 mg for X1 cycle for the remaining cycles) had significantly improved efficacy, in terms of improved response rate (Po0.001), TTP (Po0.005) and OS (Po0.019). 32 The dexamethasone dose was reduced owing to adverse events in 89% of these patients and there were no differences in age, burden of disease or performance status compared with patients who did not have dexamethasone dose reductions. Another set of analyses that investigated lenalidomide dose modifications for adverse events showed that among patients who responded to and remained on treatment for X12 months, those who had a subsequent reduction in lenalidomide dose fared better than those with earlier lenalidomide dose reductions (that is, within 12 months) and those who never had a dose reduction. 31 These data suggest that a full lenalidomide dose during the first 12 months of treatment is important for optimal efficacy; thereafter, the lenalidomide dose can be reduced to manage adverse events without compromising the efficacy of the regimen. Altogether, these findings underscore the importance of managing early adverse events effectively and considering modifications to the doses of dexamethasone and lenalidomide in order to continue therapy until progression. Although treatment until progression is the current practice, the optimal duration of treatment has not been formally studied. A trial comparing Len/Dex treatment until progression vs treatment for a limited number of cycles, allowing for re-treatment, may be needed. On the basis of the available data, treatment with Len/Dex may continue in responding patients until evidence of disease progression. The same approach may apply for patients with stable disease when other treatment options are not available. Treatment should continue at the best-tolerated dose of each agent. Caution with long-term dexamethasone use is required. How often should patients be monitored during therapy? The panel felt that patients with no cytopenias at baseline should be monitored every 2 weeks for the first 2 3 cycles. Patients with low ANC or platelet count at baseline may require more intensive monitoring, as clinically indicated. For responding patients, assessment before each new treatment cycle (that is, every 4 weeks) is sufficient. Patients without cytopenias at baseline may be monitored every 2 weeks for the first 2 3 treatment cycles. Patients with neutropenia or thrombocytopenia at baseline may require more intensive monitoring, as clinically indicated. For responding patients receiving continuous Len/Dex therapy, monitoring at the start of each new treatment cycle (that is, every 4 weeks) is sufficient. Patients with RI may require more intensive monitoring. Use in special populations Advanced age Two subanalyses of MM-009/010 have specifically addressed the impact of patient age on the efficacy and safety of Len/Dex (Table 2). 29,30 In the first analysis, patients were classified into three groups (o65, and 475 years). 29 Response rates to 753

6 754 Len/Dex were similar in all three groups and consistently higher than that achieved with Dex alone. In each age group, median TTP was consistently higher with Len/Dex than with Dex alone, indicating that the benefit of Len/Dex over Dex alone is independent of patient age. Importantly, age did not influence the rates of adverse events with Len/Dex. Similar results were seen when patients treated with Len/Dex in MM-009/010 were classified into two groups (o65 and X65 years); response rates and median TTP were similar in both groups. 30 On the basis of the available evidence, the panel agreed that Len/Dex was an appropriate treatment option for RRMM, regardless of patient age. They noted that, for elderly patients with RRMM, Len/Dex appears to be one of the most effective and best-tolerated regimens currently available. The panel concluded that Len/Dex appears to be effective and well tolerated in patients with moderate or severe RI, provided that appropriate dose adjustments are made. Clinicians should be aware that a substantial proportion of patients with RI at baseline experience improvement in renal function during treatment with Len/Dex. To ensure optimal efficacy, the lenalidomide dose should be adjusted according to the creatinine clearance at each cycle. Len/Dex is safe and effective in patients with RI, provided that the dose of lenalidomide is adjusted appropriately according to the creatinine clearance at each cycle. Len/Dex is an appropriate treatment option for patients with RRMM, regardless of age. Renal impairment Experience with Len/Dex in patients with RI is limited, as most trials have excluded such patients. In MM-009/010, patients with serum creatinine levels 42.5 mg/dl were excluded. When assessed by creatinine clearance, however, 82 patients (24%) treated with Len/Dex were deemed to have moderate RI (creatinine clearance ml/min) and 16 patients (5%) had severe RI (creatinine clearance o30 ml/min) at baseline. 27 Response rates and TTP were similar in patients with mild or no RI, moderate RI and severe RI. As expected, median OS was significantly shorter in patients with severe RI (18.4 months) than in those with mild or no RI (38.9 months; P ¼ 0.006) or moderate RI (29.0 months; P ¼ 0.006). Improvement in renal function was observed in 72% of patients treated with Len/Dex with moderate or severe RI at study entry. Patients with severe RI were more likely to experience thrombocytopenia and require lenalidomide dose reductions or delays than those with mild or no RI. Similar data were reported from an analysis of patients with newly diagnosed MM treated with Len/Dex: baseline creatinine clearance was inversely related to the risk of grade 3 or higher myelosuppression and the need for subsequent reductions in lenalidomide dose. 57 As previously discussed, lenalidomide is renally excreted (this should not be confused with renal toxicity), and therefore lower doses may provide sufficient drug exposure in patients with RI that results in delayed clearance of the drug. 42 Chen et al. 43 assessed the pharmacokinetics of lenalidomide in patients with varying degrees of renal function and proposed a dosing modification scheme based on renal function. Application of this type of dosing approach has been tested in 50 consecutive patients with RRMM treated with Len/Dex. 46 Among the 12 patients with RI at baseline, the response rate was 61%, which was similar to that achieved in patients without RI (58%). Both groups had similar PFS and OS, and the incidence of adverse events was not increased in those with RI. Improvement in renal function was observed in 40% of patients with RI at baseline. A separate study showed that lenalidomide can also be used in patients with severe RI requiring dialysis, provided close monitoring for neutropenia and infectious complications is performed, because these patients have a high risk of infection. 44 These findings, albeit from two studies, indicate that Len/Dex is equally safe and effective in patients with and without RI, provided that appropriate dose modifications are made. Cytogenetic abnormalities Certain cytogenetic abnormalities have been linked to poor outcomes in MM. For example, del(13q), t(4;14) and del(17p) have been identified as important prognostic factors in MM However, there is some heterogeneity even within these subpopulations in terms of outcomes, 62 which may be related to differences in methodology, genetic composition and the use of salvage regimens. 34,56,63 The impact of treatment with novel therapies in patients with high-risk cytogenetics is a matter of ongoing research. Recent studies have evaluated the impact of cytogenetic abnormalities on outcomes following Len/Dex treatment in patients with RRMM and have produced mixed results. In an analysis of 130 patients treated as part of the expanded-access program for lenalidomide (MM-016), Reece et al. 36 showed that Len/Dex can overcome the poor prognosis associated with del(13) and t(4;14): response rates and OS in these patients were similar to those in patients without these abnormalities. The 12 patients with del(17p), however, fared worse than those without del(17p). In contrast, Avet-Loiseau et al. 34 found that patients with del(13q) and t(4;14) had significantly lower response rates, PFS and OS compared with patients without these abnormalities, among 207 patients treated with Len/Dex. Results according to del(17p) status could not be evaluated because of the low number of patients with del(17p) (n ¼ 8). The contrasting results in terms of the influence of del(13) and t(4;14) may be because of differences in study populations: patients in the second study were older (median age 65 vs 61 years) and more heavily pretreated (median number of previous therapies 3 vs 2), including previous thalidomide (86 vs 54%) and bortezomib (81 vs 45%). 34,36 Dimopoulos et al. 35 analyzed the influence of cytogenetic abnormalities on outcomes following treatment with Len/Dex with or without bortezomib in patients with RRMM. Patients were considered to have poor-risk cytogenetics if they had any of the following: non-hyperdiploid metaphase karyotype, del(13q), del(17p), t(4;14), t(14;16) or amp(1q21). OR and survival outcomes were inferior in patients with poor-risk cytogenetics, including those with del(13q), del(17p), t(4;14) and amp(1q21), although the number of patients in each subgroup was small. In patients with newly diagnosed MM treated with Len/Dex, abnormal karyotype has been associated with shorter survival times. 64,65 In an analysis of 100 patients treated with Len/Dex, 16% were deemed high risk on the basis of a combination of cytogenetic abnormalities and increased plasma cell labeling index. 62 In this study, response rates were similarly high in highrisk and standard-risk patients (81 and 89%; P ¼ 0.56), but median PFS was lower in high-risk patients (18.5 vs 36.5 months;

7 Po0.001). Preliminary results of studies evaluating novel combinations of lenalidomide and bortezomib in patients with RRMM indicate that this approach may also overcome the negative effects of certain cytogenetic abnormalities, although the prognosis of those with del(17p) remains poor. 35,66 The panel felt that it was not yet possible to provide definitive recommendations regarding the use of novel agents in specific subpopulations on the basis of cytogenetic characteristics at this time. Most of the available data are based on small subpopulations with limited follow-up, and patient characteristics and methodology vary widely among these studies, including definitions of high-risk cytogenetics. Given the inability of lenalidomide and other novel therapies, such as thalidomide 67 and bortezomib, 68 to overcome the poor prognosis conferred by del(17p), these patients should be included in clinical trials that evaluate experimental agents and combinations. More data are needed before definitive recommendations can be made regarding the influence of cytogenetic abnormalities on the efficacy of Len/Dex. Enrollment in a clinical trial is recommended for patients with del(17p). ANC >1000/µl Resume Len at same dose level If ANC <500/µl: Suspend Len and add G-CSF At the start of next cycle: ANC <1000/µl Aggressive disease? Yes Resume Len at same dose level with G-CSF No Resume Len at 1 dose level lower Figure 2 Recommended approach to the management of neutropenia during treatment with lenalidomide and dexamethasone. ANC, absolute neutrophil count; G-CSF, granulocyte colony-stimulating factor; Len, lenalidomide. 755 Prevention and management of adverse events The most common grade 3 or higher adverse events reported in MM-009/010 patients treated with Len/Dex were neutropenia (35%), thromboembolic events (16%), thrombocytopenia (13%), anemia (11%) and pneumonia (9%). 23 Other grade 3 or higher events included hyperglycemia, fatigue, muscle weakness, hypokalemia and asthenia. Similar results were found in patients treated with Len/Dex in the community as part of an expandedaccess program (MM-016), in whom the most common grade 3 or higher adverse events were myelosuppression (45%), fatigue (10%) and pneumonia (7%). 69 Importantly, the risk of adverse events, including neutropenia, thrombocytopenia and venous thromboembolism (VTE), appears to be highest during the initial cycles of Len/Dex therapy and decreases dramatically thereafter. 70 Clinicians should therefore be particularly vigilant during the initial cycles of Len/Dex in order to prevent or manage any potential adverse events that may arise, so that treatment can continue. It should also be noted that dose adjustments rather than dose discontinuation can often be used to manage adverse events, and thereby ensure that patients are able to receive the benefits of continuous therapy as discussed earlier. Myelosuppression Myelosuppression, particularly neutropenia and thrombocytopenia, is common in patients treated with Len/Dex, but is generally predictable and manageable. 71 In MM-009/010, neutropenia occurred early in the course of treatment: the most severe event occurred within 6 months in 52% of patients and within 12 months in 76% of patients. 71 The rate of febrile neutropenia was low (3%), and few patients discontinued treatment (3%) or required lenalidomide dose reductions (14%) due to neutropenia. Grade 3 or higher thrombocytopenia was observed in 13% of patients, 23 but the risk of thrombocytopenia decreased as treatment continued. 12,70 General guidelines are available on the management of neutropenia and thrombocytopenia during treatment with Table 4 Recommended dose reduction levels for lenalidomide a and dexamethasone b Dose level Lenalidomide dose (mg) Dexamethasone dose (mg) Starting dose c a For grade 3/4 neutropenia, thrombocytopenia or other adverse events. b For dexamethasone-related adverse events (for example, myopathy, chronic non-neutropenic infection, psychological changes and hyperglycemia). c Discontinuation of dexamethasone. Len/Dex. 19,20 For severe neutropenia (ANC o500 per ml), the panel recommended the suspending lenalidomide therapy and adding G-CSF support to help boost the neutrophil count (Figure 2). At the next cycle, treatment may resume using the same dose, provided that ANC is per ml. If the ANC is o1000 per ml, the lenalidomide dose should be reduced by one level (Table 4), unless the patient has a high tumor burden or aggressive disease, in which case clinicians may consider maintaining the previous dose of lenalidomide and provide G-CSF support. Some panel members advocated more aggressive use of G-CSF in order to avoid treatment delays or dose reductions, and there is some evidence that prophylactic use of G-CSF can help to prevent further neutropenia, treatment delays, dose reductions and infections when used during the initial cycles of treatment with Len/Dex. 45 For low platelet counts, the panel recommends following the general guidelines provided in the prescribing information for lenalidomide. 19,20 Neutropenia and thrombocytopenia often occur in patients treated with Len/Dex, but are predictable and manageable.

8 756 Neutropenia can be managed with a combination of growth factor support, lenalidomide dose modifications or discontinuation. Thrombocytopenia can be managed with a combination of platelet transfusions, lenalidomide dose modifications or discontinuation. Venous thromboembolism The risk of VTE is low when lenalidomide is given as monotherapy, but increases when it is used in combination with high-dose dexamethasone, particularly in elderly patients. 49,72 Concomitant use of erythropoietin may also increase the risk of VTE. 73,74 The incidence of VTE in patients treated with Len/Dex in MM-009/010 was 16%; however, in these trials, thromboprophylaxis was not a requirement. 21,22 Other studies have since shown that prophylaxis with low-molecular-weight heparin (LMWH) or low-dose aspirin effectively reduces the risk of VTE to 2 5%, which is comparable to the background risk in patients with MM. 33,50,75 In previously untreated patients, aspirin prophylaxis has been shown to reduce the risk of VTE from 75% (9 of 12 patients) to 15% (4 of 26 patients). 76 As highdose dexamethasone is a risk factor for VTE, the use of lower doses of dexamethasone may also contribute to a reduction in VTE risk. 49,75 For patients with a standard risk of VTE, low-dose aspirin ( mg) during Len/Dex therapy provides sufficient thromboprophylaxis (Figure 3). 75 For patients with a higher risk of VTE, especially immobilized patients and those with a history of VTE, prophylactic doses of LMWH should be considered. 50,75 The panel felt that treatment with LMWH should continue for at least the first four cycles of Len/Dex, corresponding to the period in which high-dose dexamethasone is given and the risk of VTE is highest. Patients should then be switched to aspirin prophylaxis for the rest of their treatment. The panel emphasized the importance of continuing prophylaxis for the duration of treatment, as late VTE events have been recorded, particularly after thromboprophylaxis is discontinued. For patients with RI, the dose of LMWH should be adjusted accordingly. Patients on Len/Dex treatment who develop VTE should suspend the treatment and receive LMWH at therapeutic doses. When patients are stable on anticoagulation therapy, Len/Dex treatment could be safely reinstated in those patients who benefit from Len/Dex therapy. 77 Thromboprophylaxis should be considered for patients treated with Len/Dex. Aspirin prophylaxis is appropriate for patients with a standard risk of VTE. LMWH is recommended for patients with a higher risk of VTE. LMWH prophylaxis should continue for at least the first four cycles of therapy; thereafter, patients may be switched to aspirin prophylaxis. Thromboprophylaxis should continue for the entire duration of treatment with Len/Dex. Len/Dex should be resumed in patients considered stable on anticoagulation therapy. Rash Rash has been reported in 16% of patients receiving Len/Dex. 21,22 Rash is more likely to occur during the first cycle of therapy, although late reactions have been noted. In general, Len/Dex-associated rash is self-limiting and typically resolves within a few weeks. 78 A short course of low-dose prednisone may be considered for patients with mild, but relatively extensive, maculopapular rash. Rash rarely necessitates treatment modification, although some severe cases may require a delay or reduction in lenalidomide dose. 75 Rare cases of Stevens Johnson syndrome have been reported. 19,20 Patients with a previous history of grade 4 rash associated with thalidomide should not receive lenalidomide. 20 If the rash is not severe, the patient may be given lenalidomide with caution. The panel recommended that limited, localized rash should be treated with antihistamines and topical steroids as needed while treatment with Len/Dex continues. If a diffuse, desquamating, exfoliative or bullous rash develops, lenalidomide treatment should be discontinued permanently. Standard risk Assess VTE risk High risk a Antihistamines and topical steroids can be considered for patients who develop limited, localized rash during treatment with Len/Dex. Treatment with lenalidomide should be discontinued permanently in patients who develop diffuse, desquamating, exfoliative or bullous rash. Aspirin prophylaxis, continuous for the duration of Len/Dex therapy LMWH prophylaxis during the first 4 cycles of Len/Dex After 4 cycles, switch to aspirin prophylaxis, for the remainder of Len/Dex therapy Fatigue Fatigue is a frequently encountered problem in elderly patients with MM, and a common reason for treatment discontinuation. In MM-009/010, fatigue was reported in 27% of patients. 21,22 The panel emphasized the importance of considering other possible causes of fatigue, including dexamethasone-related myopathy, anemia, infection, hypothyroidism and depression. 79 For severe fatigue, a reduction in the dose of lenalidomide may be considered. Figure 3 Recommendations for determining appropriate thromboprophylaxis in patients with relapsed or refractory multiple myeloma treated with Len/Dex. a High risk includes immobilization and previous history. Dex, dexamethasone; Len, lenalidomide; LMWH, low molecular-weight heparin; VTE, venous thromboembolism. Other common causes of fatigue, such as anemia, hypothyroidism, infection and depression should be considered.

9 Other adverse events Infection was reported in 14% of patients treated with Len/Dex in MM-009/ ,22 Because dexamethasone therapy increases the risk of infection, routine antibiotic prophylaxis should be considered for the first 3 months of therapy and is particularly recommended for patients with aggressive disease, history of infectious complications or neutropenia. No consensus was reached regarding the type of antibiotic regimen to use, and practice varied widely among panel members (trimethoprim sulfamethoxazole, quinolones, penicillin and so on). It was therefore decided that, at this time, clinicians should follow the standard protocols for antibiotic prophylaxis as established by their institution. It should be noted that, in some cases, lenalidomide may cause fever, but this typically resolves with treatment with low-dose steroids. For patients who develop fever, a standard diagnostic work-up for infection is recommended. Muscle cramps, which have been reported in 30% of patients treated with Len/Dex, 19,20 can usually be managed with magnesium supplementation and rarely require treatment modifications. Neuropathy, particularly peripheral neuropathy, is a relatively common and cumulative side effect of bortezomib and thalidomide, but is rarely seen with lenalidomide. 28 Inasubanalysisofdatafrom MM-009/010, patients with existing peripheral neuropathy received a similar mean daily dose of lenalidomide as those who did not have neuropathy. The mean treatment duration, response rate, TTP and OS were also similar in patients with and without existing neuropathy. 28 In general, lenalidomide can be given safely to patients with existing neuropathy or a history of neuropathy. However, clinicians should be aware that lenalidomide may occasionally exacerbate existing neuropathy during early cycles. 28 For dexamethasone-related symptoms, such as myopathy, chronic non-neutropenic infections, fatigue, psychological changes or hyperglycemia, a reduction in the dose of dexamethasone should be considered (Table 4). Contraception must be used by female patients of childbearing potential. Male patients must use condoms throughout the treatment duration, including dose interruptions, and for 1 week following discontinuation of treatment if their partner is pregnant or of childbearing potential and does not use contraception (further information is provided in the Revlimid SMPC and PI). 19,20 To prevent infection, routine antibiotic prophylaxis should be considered for the first three cycles of therapy, particularly for patients with a history of infectious complications or neutropenia. Muscle cramps rarely require dose modifications; magnesium supplementation may be considered. Lenalidomide rarely exacerbates preexisting neuropathy. Reduction in the dose of dexamethasone should be considered for patients who develop dexamethasone-related symptoms, such as myopathy, non-neutropenic infection, psychological changes and hyperglycemia. Caution should be taken in women with childbearing potential and in sexually active male patients. Consensus summary The combination of lenalidomide and dexamethasone is an effective and well-tolerated treatment option for patients with RRMM. Ideally, treatment with Len/Dex should be given as early lines of MM therapy and may continue until disease progression to optimize patient outcomes. In responding patients, including those with stable disease, continuing Len/Dex therapy is associated with further improvement in the quality of response and improved outcomes. Len/Dex is effective and can be given safely in patients with RI, provided that the dose is adjusted appropriately. The efficacy and tolerability of Len/Dex are independent of patient age and other risk factors, such as performance status and disease stage. Resistance to previous MM therapies reduces response to Len/Dex, which could be owing to the intrinsic aggressive nature of the disease. More data are needed to determine the efficacy of Len/Dex in patients with cytogenetic abnormalities; however, the available evidence indicates that patients with del(17p) clearly do not benefit from currently available therapies, and should be considered candidates for clinical trials. Successful prevention and management of adverse events provides the patient with the opportunity to continue Len/Dex therapy and achieve improved outcomes. Most adverse events occur during the first few cycles of therapy. The risk of VTE can be minimized with proper prophylaxis, particularly in high-risk patients, such as immobilized patients and those with a history of VTE. Neutropenia and thrombocytopenia can be managed with a combination of supportive-care measures (that is, G-CSF support, platelet transfusions), treatment delays and lenalidomide dose reductions. Other adverse events can be managed with standard clinical interventions and dose modifications. In conclusion, the available evidence indicates that Len/Dex is an effective and well-tolerated treatment, regardless of patient age, disease stage and renal function. Further, in patients with RRMM, Len/Dex is most effective when administered at first relapse as a continuous long-term treatment. Conflict of interest MAD had a consultant role for, and has received honoraria from, Celgene. AP is a speaker for, advisory board member of, and has received a research grant from, Celgene. HL has received honoraria from, and is a speakers bureau member of Celgene, Mundipharma and Ortho Biotech. MA is an advisory board member of Celgene. MB is a speakers bureau member of Celgene and Janssen-Cilag, and has received honorarium from Celgene. HE has received honoraria from Celgene. FLC had a consultant role for, and received honoraria from, Celgene, Amgen, MSD and Janssen-Cilag. U-HM is an advisory board member of Celgene and has received a research grant from Janssen-Cilag. FED has served as a speakers bureau member of Celgene and Ortho Biotech, and has participated in advisory boards of Celgene, Ortho Biotech and Novartis. J-LH has received consulting and lecture fees from Celgene. MD is an advisory board member of, and has received honoraria as a speaker from, Celgene. PS is an advisory board member of Celgene, Janssen- Cilag and Onyx, and has received research funding from Celgene and Janssen-Cilag. RH has received reimbursement of expenses and honoraria for attending symposia from Celgene. JFS-M has received compensation as a scientific advisory board member from Millennium, Celgene and Janssen-Cilag. SZ has received compensation as a scientific advisory board member of Celgene. GJM received payment for lectures including service on speakers bureaus from Novartis, Celgene and Ortho Biotech. Acknowledgements We received support regarding linguistic improvement, artwork and formatting of the manuscript from Excerpta Medica, funded 757