Introduction

Multiple myeloma (MM) is a common malignancy accounting for 10% of all blood cancers. It remains incurable, although advances in chemotherapy and autologous stem cell transplantation (ASCT) have improved patients' outcome.¹ There were no further significant advances in the treatment of myeloma until the late 1990s, when thalidomide was found to be effective in patients with relapsed/refractory disease.² However, thalidomide is associated with significant toxicity, especially neurotoxicity, which often necessitates dose reduction or cessation of treatment even in responding patients. A new class of thalidomide derivatives, called immunomodulatory drugs (IMiDs), was subsequently developed and although they are structurally related to thalidomide, they have different anti-inflammatory, immunomodulatory and antiangiogenic potential and toxicity profile.³ Lenalidomide (CC-5013, REVLIMID, CELGENE), the lead compound of the second generation of IMiDs, was first tested in phase I and II trials in refractory/relapsed myeloma with encouraging results.⁴ Lenalidomide has also been studied in other hematologic malignancies, and was first approved by the Food and Drug Administration for use in patients with myelodysplastic syndrome (MDS) associated with a 5q-deletion cytogenetic abnormality.⁵ Subsequently, on the basis of two large phase III trials,^{6, 7} lenalidomide in combination with dexamethasone was approved by the Food and Drug Administration and European Medicines Agency (EMEA) for the treatment of myeloma patients who had received at least one therapy earlier.

Pharmacological and pharmacokinetic properties

Lenalidomide was created by chemical modifications of thalidomide by adding an amino group (NH2-) at position 4 of the phthaloyl ring and removal of the carbonyl group (C=O) of the 4-amino–substituted phthaloyl ring.⁸ It is rapidly absorbed following oral administration and co-administration with foods that does not alter the extend of absorption (area under the concentration ) but reduces the maximal plasma concentration (C_max).⁹ In myeloma patients,⁴ the disposition of lenalidomide is linear with area under the concentration and C_max increasing proportionately with increases in dose. C_max occurs 0.5–4 h post-dose both on days 1 and 28 but area under the concentration is 57% higher than in healthy male volunteers. Multiple dosing does not result in drug accumulation, binding to plasma proteins is approximately 30%, elimination half-life is 3 h and most of the drug is excreted unchanged in the urine within 24 h, thus special care is needed in patients with impaired renal function. Lenalidomide is not extensively metabolized by P450 isoenzymes in vitro⁸ and does not interfere with the metabolism of other drugs in humans, thus co-administration with warfarin is safe.

Mechanism of action

Lenalidomide has immunomodulatory, antiangiogenic, and direct apoptotic properties. IMiDs inhibit myeloma cell growth either through direct interference with key functions of myeloma cells or indirectly through modulation of signaling pathways that regulate their interaction to bone marrow stromal cells. Myeloma cell binding to bone marrow stromal cells triggers myeloma cell proliferation, inhibition of apoptosis and drug resistance as a consequence of adhesion and cytokine-mediated signals. Lenalidomide and thalidomide reduce the secretion of key cytokines such as interleukin 6 (IL-6), insulin-like growth factor 1, vascular endothelial growth factor and tumor necrosis factor- from bone marrow stromal cells and of tumor growth factor- secreted by myeloma cells. IL-6 is a pleiotropic growth factor important for myeloma growth and survival, thus its inhibition is significant in controlling myeloma progression. In addition, other proinflammatory cytokines such as cyclooxygenase-2, ILs-1 and -12 are inhibited.^{10, 11}

Immunomodulatory drugs directly induce apoptosis in myeloma cells by activating Fas-mediated cell death; lenalidomide is a more potent inducer of apoptosis than thalidomide.⁴ Fas-mediated cell death is induced through caspases: caspase-8 is upregulated by IMiDs, but not caspase-9,¹² whereas dexamethasone activates caspase-9, thus their combination enhances apoptotic signaling. IMiDs also downregulate antiapoptotic proteins similar to cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein.¹² Nuclear factor-B a key transcriptional factor regulating the transcription of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein is also inhibited by IMiDs.^{8, 13, 14} Further, IMiDs activate mitochondrial pathways that lead to release of proapoptotic proteins, such as cytochrome c and Smac that help overcome the effects of other antiapoptotic effectors.¹⁵ As dexamethasone triggers release of Smac from the mitochondria but not cytochrome c, its combination with lenalidomide or other IMiDs augments the activity of these agents.

Immunomodulatory drugs modulate host immune response mainly through T-cell co-stimulatory activity. Lenalidomide co-stimulates CD28 on T cells, leading to transcriptional activation and increased expression of IL-2 and interferon- genes^{16, 17, 18, 19, 20, 21, 22} stimulating T-cell proliferation and natural killer (NK) cell activity and augmenting T cell and NK cell-mediated lysis of myeloma cells.^{19, 20, 21, 22, 23, 24, 25} It is a more potent stimulator of T-cell proliferation than thalidomide, and is 50–100 times more potent than thalidomide in augmenting IL-2 and interferon- production.

Immunomodulatory drugs do not directly inhibit endothelial cell proliferation but rather block trophic signaling.²⁶ Specifically, IMiDs inhibit the secretion of the angiogenic cytokines vascular endothelial growth factor and bFGF from tumor and stromal cells.^{4, 26, 27} Inhibition of vascular endothelial growth factor secretion is likely to have more diverse effects beyond angiogenesis, as vascular endothelial growth factor has biologic activities that extend beyond endothelial cell proliferation.²⁸ However, antiangiogenic properties are probably not a significant mechanism of antimyeloma activity of lenalidomide; thalidomide is probably a more potent inhibitor of angiogenesis than other IMiDs.

Lenalidomide in relapsed or refractory myeloma

Lenalidomide alone or with dexamethasone

Phase I and II studies showed that lenalidomide was active in heavily pretreated patients.^{4, 35, 36, 30} Responses were seen in patients who had been previously treated with thalidomide or bortezomib or had either single or double ASCT, whereas the addition of dexamethasone increased the response rates. Different dosing levels and dosing schedules of lenalidomide were tested with myelosuppression, mainly neutropenia and thrombocytopenia being the dose limiting toxicities. Neurotoxicity was uncommon and thromboembolism rates were low with lenalidomide monotherapy and increased only after the addition of dexamethasone. Responses (partial response (PR) or better) were seen in 20–40% of patients treated with single-agent lenalidomide, whereas a significant proportion of patients had either a minor response or stabilization of their disease (Table 1).

Table 1 - Lenalidomide-based regimens in relapsed/refractory MM.

Full table

Two phase III, randomized, double-blind, multicenter trials (MM-009 and MM-010) further compared lenalidomide/high-dose dexamethasone to placebo/high-dose dexamethasone pretreated MM patients (Table 2). Patients resistant to dexamethasone or those with a creatinine >2.5 mg per 100 ml were excluded while prophylactic anticoagulation was not administered. Dimopoulos et al.⁶ reported the results of the MM-010 that enrolled 351 patients in Europe, Israel and Australia and Weber et al.⁷ reported the results of the MM-009, which enrolled 354 patients in North America. In both trials, response rates were significantly higher for lenalidomide/dexamethasone than for dexamethasone/placebo (60.2 versus 24%; P<0.001 and 61 versus 19.9%; P<0.001, respectively). The median time to progression for patients treated with lenalidomide/dexamethasone was 11.3 and 11.1 months, respectively compared to 4.7 months in dexamethasone/placebo group (P<0.001 for both studies). Overall survival (OS) was also superior with lenalidomide/dexamethasone (not reached in MM-010 and 29.6 months in MM-009 versus 20.6 and 20.2 months for dexamethasone/placebo; P<0.001 for both studies). Neutropenia was more frequent with lenalidomide/dexamethasone; however, grade 3/4 infection rates were similar. As expected, thromboembolic events (TEs) were more frequent in lenalidomide/dexamethasone (8.5 and 15% for MM-009 and MM-010, respectively) compared to 3.5 and 4.5% in the dexamethasone/placebo group. Lenalidomide was also active in patients who had previously failed thalidomide: 43% of thalidomide-resistant patients responded to lenalidomide/dexamethasone, although this response rate was lower than in thalidomide-sensitive patients (overall response rate (ORR) 63%, P<0.05).⁴² Lenalidomide/dexamethasone was significantly more effective in patients treated at first relapse compared to patients treated in later phases of their disease,⁴³ while it was equally effective in both transplanted and non-transplanted patients⁴⁴ (ORR was 63% compared to 55%, P=0.128 with complete response (CR) rates of 13 versus 16%, P=0.483, respectively). Another interesting finding from the MM-009 and MM-010 is that patients who received lenalidomide with reduced-dose dexamethasone had a significantly higher ORR rate, including a higher CR, a significantly longer median time to progression, median OS and median progression-free survival, compared with those who received lenalidomide and dexamethasone at the assigned dose.⁴⁵ Lenalidomide has also shown activity in bortezomib pretreated patients (ORR 76 versus 82.4% for patients who had not received bortezomib).⁴⁶ Further confirmation is also needed for the proposed ability of lenalidomide to overcome poor prognostic features conferred by adverse cytogenetics, such as t(4;14) and deletions of chromosome 13.⁴⁶

Table 2 - Lenalidomide-based regimens in newly diagnosed MM.

Full table

Lenalidomide in combination with conventional chemotherapy

Combinations of lenalidomide/dexamethasone with chemotherapy have been used to increase response rates and quality of responses in pretreated patients; however, these are associated with increased toxicity (Table 1). Nevertheless these combinations induced high response rates as well as VGPR and CR rates. Liposomal doxorubicin and vincristine,³³ doxorubicin³¹ and cyclophosphamide³² have been combined with lenalidomide/dexamethasone (Table 1). Myelosupression is significant and hematopoietic growth factors are frequently needed while thromboembolic events are of concern and routine thromboprophylaxis should be used. Prospective randomized trials are required to prove whether conventional chemotherapeutic agents add to the activity of lenalidomide/dexamethasone.

Lenalidomide in combination with bortezomib

As lenalidomide is less neurotoxic than thalidomide, its combination with bortezomib may have a better toxicity profile compared to combinations of thalidomide with bortezomib. Furthermore, preclinical studies demonstrated that lenalidomide sensitizes myeloma cells to bortezomib.¹² In a phase I/II trial of lenalidomide plus bortezomib in patients with refractory myeloma,⁴⁷ maximum tolerated dose for lenalidomide was 15 mg/day on days 1–14, with bortezomib at 1.0 mg/m² on days 1, 4, 8, 11 administered on a 21-day cycle. In the phase II of the study, dexamethasone was also given. Among 41 patients with relapsed or relapsed and refractory myeloma, 33 were evaluable for response and CR/near CR/PR rate was 55%.³⁴ Toxicities of the combination were manageable, consisting mainly by myelosuppression. Neuropathy rates were 24%, but reached grade 3 in only one patient. Aspirin was given in all patients; however, there were two episodes of deep vein thrombosis and two patients had atrial fibrillation.

Lenalidomide in newly diagnosed myeloma (Table 2)

Initial therapy in patients who are candidates for stem cell transplantation

In newly diagnosed MM, ASCT was superior to conventional dose chemotherapy in two randomized trials.^{48, 49} Until recently, vincristine, doxorubicin, dexamethasone (VAD) was used as standard pretransplant induction. However, mainly in the United States, the combination of thalidomide plus dexamethasone (Thal/Dex) largely replaced VAD as the preferred pretransplant regimen, based on efficacy and ease of administration.^{50, 51, 52, 53} In a recent randomized trial conducted by the Eastern Cooperative Oncology Group Thal/Dex induced significantly higher responses compared to dexamethasone alone (63 versus 41%, P=0.0017).⁵¹ However, Thal/Dex has been associated with a high rate of non-hematologic toxicities and a low rate of CRs. Lenalidomide/dexamethasone was therefore tested as a safer and more effective alternative to Thal/Dex in newly diagnosed myeloma.

In a Mayo Clinic phase II trial, 34 newly diagnosed patients^{54, 37} were treated with lenalidomide plus dexamethasone with aspirin prophylaxis. Thirty-one patients (91%) achieved an objective response, 56% had a CR+VGPR and 3-year OS was 88%; 55% of patients experienced grade 3 or higher non-hematologic toxicity and one patient developed pulmonary embolism, but recovered with therapy. In another phase II trial, clarithromycin plus lenalidomide/dexamethasone (BiRD) was given to newly diagnosed patients for a 90.3% ORR with a combined stringent CR and CR rate of 38.9% while VGPR rate was 73.6%.³⁸ TEs occurred in nine patients (12.5%); most of them had discontinued aspirin.

The Eastern Cooperative Oncology Group recently reported a randomized trial testing lenalidomide/high-dose dexamethasone (dexamethasone 40 mg on days 1–4, 9–12, 17–20) versus lenalidomide/low-dose dexamethasone (dexamethasone 40 mg once weekly) in newly diagnosed myeloma;³⁹ 445 patients were accrued: 223 were randomized to lenalidomide/high-dose dexamethasone and 222 to lenalidomide/low-dose dexamethasone. The interim analysis showed that 1-year (96 versus 88%, P=0.003) and 2-year (87 versus 75%, P=0.009) survival was significantly superior with lenalidomide/low-dose dexamethasone. Grade 3 or higher non-hematologic toxicities occurred in 55 versus 66%. The incidence of TEs was also significantly lower with lenalidomide/low-dose dexamethasone (Table 2).

These results along with other data from the MM-009 and MM-010⁴⁵ show that lenalidomide/low-dose dexamethasone is the preferred dosing schema for the combination. On the basis of this data, lenalidomide/low-dose dexamethasone is the preferred initial therapy in the Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) protocol in patients who are transplant candidates.

The results of a randomized trial comparing lenalidomide plus dexamethasone to placebo/dexamethasone conducted by the Southwest Oncology Group (SWOG) in patients ineligible for ASCT were also presented.⁵⁵ The trial was closed early, after 198 patients were enrolled, due to external data showing that high-dose dexamethasone is not an acceptable control arm. Response rates and estimated 1-year progression-free survival rates (77 versus 55%, P=0.002) were significantly higher in the lenalidomide/dexamethasone arm although 1-year OS was not different, probably due to crossover (40 patients crossed over). TEs rates were high even after aspirin prophylaxis was introduced.⁴⁰ The combination of lenalidomide with bortezomib and dexamethasone has also been shown to be very active in newly diagnosed patients with high response rates and manageable toxicity. This combination was used in patients who are either eligible or ineligible for ASCT^{41, 56}. A randomized trial comparing lenalidomide/low-dose dexamethasone versus bortezomib, lenalidomide, low-dose dexamethasone is expected to open in the United States next year.

Elderly patients with newly diagnosed myeloma

In newly diagnosed myeloma, melphalan, prednisone, thalidomide (MPT) has emerged as the new standard of care for patients >65 years, but has limitations due to the non-hematologic toxicity of thalidomide.^{57, 58, 59} Data from MM-009 and MM-010 studies showed that both elderly (aged 65 years) and younger patients can benefit from lenalidomide.⁶⁰ Palumbo et al.⁶¹ reported promising results from a phase I/II trial using the combination of melphalan, prednisone and lenalidomide in 54 patients older than 65 years with newly diagnosed myeloma. At the maximum tolerated dose, 81% of patients responded, including 48% VGPR and 24% CRs with 1-year event-free and OS rates of 92 and 100%, respectively (Table 2). The main grade 3 or higher adverse events were neutropenia (38%) and thrombocytopenia (14%). Aspirin was given as thromboprophylaxis and the incidence of thromboembolic events in this trial was low (5%). In another phase II trial, lenalidomide with melphalan were given in elderly, non-ASCT eligible patients, without steroids. However, this combination was associated with significant myelotoxicity.⁶² An ongoing randomized trial is comparing melphalan, prednisone with or without lenalidomide in previously untreated, elderly MM patients while another randomized trial will compare lenalidomide/low-dose dexamethasone with melphalan, prednisone and thalidomide.

Lenalidomide in systemic light chain amyloidosis

Systemic light chain (AL) amyloidosis is a plasma cell disorder with limited treatment options. Standard therapy consists of melphalan plus dexamethasone; selected patients with limited organ involvement are considered for high-dose melphalan with ASCT.^{63, 64} Thalidomide has shown limited activity and increased toxicity in amyloidosis patients compared to MM.^{65, 66, 67} The more favorable toxicity profile of lenalidomide has led to the investigation of the drug in AL amyloidosis. Two phase II studies explored the feasibility and toxicity of lenalidomide in the treatment of patients with AL amyloidosis.^{68, 69} In both studies, lenalidomide was started at 25 mg for 21 days of a 28-day cycle; dexamethasone was added if no hematologic response was seen after three cycles. However, due to toxicity, the dose of lenalidomide was reduced to 15 mg or less in most patients. In the first trial,⁶⁹ 34 patients were enrolled and 24 patients completed at least three cycles of treatment (median of six cycles) for a hematologic response rate of 67%, with seven patients (two with lenalidomide monotherapy and five after the addition of dexamethasone) achieving complete hematologic and 38% (nine patients) achieving a partial hematologic response, all in patients with previously treated disease. Organ response rates were lower with 6 of 17 patients having renal response and one patient with heart failure showing clinical improvement. In the second trial from the Boston group,⁶⁸ 22 patients were enrolled, 13 were pretreated including 6 patients with previous ASCT. Only one patient achieved a hematologic response to single-agent lenalidomide; however, when dexamethasone was added, 45% achieved a hematologic or organ response. In a recently presented update,⁷⁰ hematologic ORR was 60% (24% CR, 36% PR). Most CRs occurred at 3–6 months of treatment, but some patients achieved CR after 18 months or more of therapy. Organ responses were seen in most patients with hematologic CR (renal responses) and five of eight patients in CR maintain remission for 6–30 months. Myelosuppression, skin rash, respiratory infections and thromboembolic events were the most frequent toxicities. Aspirin prophylaxis was not given initially but was added later to all patients. Both studies showed a higher rate of hematological responses for lenalidomide/dexamethasone compared to single-agent lenalidomide. As with thalidomide, lenalidomide appears less well tolerated in AL amyloidosis compared to myeloma, and most patients required dose reduction due to side effects. Lenalidomide plus dexamethasone is a reasonable option as salvage therapy for patients with AL amyloidosis in whom alkylator-based therapy or transplantation did not show positive results.

Lenalidomide in Waldenströms macroglobulinemia

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma involving the bone marrow and secreting monoclonal IgM. Treatment options include alkylating agents, nucleoside analogs and monoclonal antibodies, either alone or in combination. Rituximab, a monoclonal anti-CD20 antibody, has shown activity in WM, is not myelosupressive and lacks long-term toxicities seen with nucleoside analogs and alkylating agents.⁷¹ Preclinical data have shown that thalidomide, and probably other IMiDs, can enhance rituximab-induced antibody-dependent cytotoxicity. Thalidomide combined with rituximab was active in WM patients, inducing high response rates and durable remissions.⁷² However, almost half of WM patients developed neuropathy necessitating dose reduction or discontinuation of thalidomide. Lenalidomide is less neurotoxic and thus it was subsequently combined with rituximab in 16 symptomatic WM patients, 75% of whom were untreated.⁷³ Twelve patients were evaluable for response: four (33%) achieved a PR and four (33%) minor response; four of eight responding patients progressed within a median of 17 (2–34) months. The combination was associated with anemia, which was observed in 13 of 16 patients within 2 weeks of treatment initiation. No hemolysis or generalized myelosuppression was observed and the anemia was refractory to erythropoietin in many patients. A quick rise in hematocrit values was observed after discontinuation of lenalidomide. Anemia also occurred at lower starting doses or even with dose reductions to 5 mg daily. Thus, lenalidomide in combination with rituximab is poorly tolerated, while response rates and duration of response are probably inferior to those observed with thalidomide/rituximab.

Lenalidomide in patients with renal impairment

Renal impairment is a major complication of myeloma; approximately 30% of myeloma patients have underlying renal dysfunction at presentation⁷⁴ and this complication may increase further in patients with relapsed/refractory disease. Lenalidomide is renaly excreted; thus, it is important to evaluate whether it can be safely administered to patients with renal dysfunction. Serum creatinine >2.5 mg/dL was an exclusion criterion during enrollment in phase III studies. Patients with mild renal impairment who received lenalidomide developed thrombocytopenia more frequently than patients with creatinine clearance >50 ml/min.⁷⁵ In another series of relapsed myeloma patients who received lenalidomide with or without corticosteroids, those who had renal impairment (defined as serum creatinine 1.0–2.5 mg/dL for females and 1.2–2.5 mg/dL for males), had similar response rates to patients with normal renal function, again at the expense of thrombocytopenia.⁷⁶ However, in this report only five patients had serum creatinine >2 mg/dL. Currently, lenalidomide is not recommended for patients with serum creatinine >2.5 mg/dL and dose reduction should be considered if the use of the drug becomes clinically necessary. In a pharmacokinetic study in 30 patients with various degrees of renal insufficiency,⁷⁷ total and renal clearance of lenalidomide were strongly correlated with creatinine clearance (R>0.9, P<0.01) and area under the concentration increased with decreasing creatinine clearance. On the basis of these data, dose modifications have been suggested according to the renal function: no dose reduction for creatinine clearance 50 ml/min; 10 mg/day for creatinine clearance 30–50 ml/min; 15 mg every other day for patients with creatinine clearance <30 ml/min but not on dialysis; and 15 mg thrice per week after each dialysis in patients requiring dialysis. However, more safety data are needed for patients with moderate or severe renal failure before definite recommendations can be made.

Toxicity and practical management

Lenalidomide has a different toxicity profile compared to thalidomide (Table 3). Differences include lower rates of neuropathy, sedation and constipation. In patients with pre-existing neuropathy, some worsening of neuropathy may occur, although in phase III trials the incidence of grade 3 or 4 neuropathy was <2%.

Table 3 - Common toxicities of lenalidomide.

Full table

Myelosuppression

In contrast to thalidomide, myelosuppression is the most frequent toxicity of lenalidomide. Thrombocytopenia and neutropenia are the most common reasons for dose reduction or delay.^{6, 7} Whereas grade 3–4 anemia occurred only in 8.4% of patients treated with lenalidomide/dexamethasone, grade 3–4 thrombocytopenia and neutropenia have been reported in up to 13% and 38.4% of MM patients, respectively.^{37, 78} Grade 3–4 thrombocytopenia is significantly more common in patients with renal impairment (creatinine clearance <50 ml/min) than those with normal renal function.⁷⁵ Monitoring blood counts, temporary interruption of treatment or dose reductions are recommended, while granulocyte-colony-stimulating factor may be used concomitantly with lenalidomide. In the experience of the authors, granulocyte-colony-stimulating factor use is frequently needed in older patients and in those receiving lenalidomide–chemotherapy combinations. Erythropoiesis-stimulating agents may be used in patients with anemia, based on published recommendations. In patients with renal impairment, closer monitoring may be needed and dose reductions should be based on recent recommendations.⁷⁷

Dexamethasone, especially at high doses, increases the risk of infections.³⁹ Neutropenic infections are not significantly increased in patients treated with lenalidomide/dexamethasone compared to dexamethasone alone.^{6, 7} However, combinations with chemotherapy resulted in high rates of neutropenia and infections.^{33, 31} Prophylactic antibiotics may reduce this risk and patients who are at increased risk such as those on high-dose dexamethasone or those receiving lenalidomide with chemotherapy, elderly patients, those with a history of increased infection rate or other concomitant medical problems (congestive heart failure, COPD, renal insufficiency, diabetes) should probably receive prophylaxis. Trimethoprim/sulfamethoxazole, which is also active against pneumocystis carinii, or ciprofloxacin are usually given. Neutropenic fever, is not very common, although the rate of neutropenia is high, which is different from observations in myelodysplastic syndromes. Nevertheless, neutropenic fever may occur, and requires prompt medical management. A hypersensitivity pneumonitis has also been described with the use of lenalidomide, which does not respond to antibiotic treatment.⁷⁹

In most patients, frontline therapy with lenalidomide does not preclude adequate collection of stem cells.^{54, 37} However, there is probably a reduction in the yield of stem cells with lenalidomide therapy in newly diagnosed myeloma.⁸⁰ With growth factor mobilization, a significant decrease in total CD34+ cells collected (P<0.001), average daily collection (P<0.001) and day 1 collection yield (P<0.001) was seen with lenalidomide therapy compared to other induction regimens (single-agent dexamethasone, thalidomide–dexamethasone and VAD), while 3 of 48 patients treated with lenalidomide/dexamethasone failed to mobilize adequate stem cells. Thus, we recommend that patients who are candidates for ASCT receive no more than six cycles of lenalidomide before stem cell mobilization, and that lenalidomide be held for approximately 4 weeks before mobilization.

Thromboembolism

Lenalidomide is associated with TEs. When used as a single agent the risk of TEs is small (5%);^{30, 29} however, the addition of dexamethasone sharply increases this risk. In relapsed/refractory myeloma patients, pulmonary embolism and deep vein thrombosis were increased in lenalidomide/dexamethasone arm compared to dexamethasone alone (12 versus 4%).^{6, 7} TEs were also noted in amyloidosis trials^{68, 69} when dexamethasone was added. In newly diagnosed patients, lenalidomide/high-dose dexamethasone was associated with significantly higher risk of TEs than lenalidomide/low-dose dexamethasone (23.8 versus 9.1%, P<0.001).⁸¹ The concomitant administration of erythropoietin may also increase the risk of TEs.⁸² Before thalidomide treatment and combinations with chemotherapy are also predisposing factors.

Antithrombotic prophylaxis is mandatory when patients are treated with lenalidomide combinations. In patients treated upfront with lenalidomide/high-dose dexamethasone, addition of aspirin (80 mg or 325 mg/day) resulted in a 3% incidence of TEs.⁵⁴ In a similar trial conducted by SWOG the incidence of TEs was 75% for patients without prophylaxis and 15% for those receiving aspirin at 325 mg.⁴⁰ In patients aged >65 years who received upfront lenalidomide with MP and aspirin (100 mg/day), TE rates were 3.8%.⁶¹ Currently, the optimal regimen has not been defined, but high-risk patients that is, those with newly diagnosed disease, who receive high-dose dexamethasone regimens, who have a history of thrombosis, immobilized patients or relapsed patients with high tumor burden, should probably receive anticoagulation with low molecular weight heparins or full-dose coumadinl while patients at lower risk may be considered for aspirin. In case of a TE, appropriate treatment should be provided. Low molecular weight heparins may reduce the risk of recurrence more than coumadin does;⁸³ however, in patients with severe renal impairment (creatinine clearance 30 mg/ml), low molecular weight heparins has been associated with an increased risk of bleeding.⁸⁴

The previous occurrence of a TE, including pulmonary embolism, is not an exclusion criterion for treatment with lenalidomide combinations; however, full adherence to antithrombotic prophylaxis is mandatory.

Other non-hematologic side effects

Fatigue is frequently reported. Hypogonadism and hypothyroidism are unusual but should be considered in patients who report excessive fatigue or constipation. Cardiac arrhythmias, mainly atrial fibrillation, have been reported mainly in patients treated with lenalidomide and high-dose dexamethasone,^{7, 81} regular monitoring is recommended. Muscle cramps have also been reported. Skin rashes are common in patients who were treated with lenalidomide⁷ but only rarely are severe enough to necessitate dose interruption. Addition of dexamethasone may delay the onset of the rash. Interestingly, in patients with amyloidosis treated with lenalidomide or lenalidomide/dexamethasone, rash is an early and common side effect.^{68, 69, 85} Antihistamines and, in persistent cases, continuous low-dose prednisone can be used for the management of the rash. It is mostly self-limiting but in some cases dose reduction or discontinuation of lenalidomide may be necessary.

Precautions to prevent teratogenicity

In view of its teratogenic effect thalidomide is marketed under the STEPS program to prevent this complication.⁸⁶ Lenalidomide is not associated with teratogenicity in the New Zealand rabbit model—the only model in which thalidomide-related teratogenicity has been detected.²⁴ However, the experience with thalidomide has led to the marketing of lenalidomide under a special restricted distribution program (RevAssistSM). All women of childbearing age should have effective contraception (with two reliable forms of contraception) and should have two negative pregnancy tests with the first test performed within 10–14 days, and the second test within 24 h before prescribing lenalidomide. Pregnancy testing one should also continue during the treatment. Males receiving lenalidomide should use a latex condom.

Future directions

Lenalidomide is now an established treatment for patients with relapsed or refractory myeloma, and is increasingly used as initial therapy in newly diagnosed patients. It induces high rates of CR and near CR in both untreated and pretreated patients. Low-dose dexamethasone should probably be preferred in combination with lenalidomide with reduced toxicity and high response rates, while melphalan, prednisone and lenalidomide appears promising for patients with newly diagnosed myeloma. Patients who are resistant to thalidomide may benefit from lenalidomide, while ongoing studies will assess whether patients who acquire resistance to lenalidomide may subsequently respond to thalidomide. Oral administration and a predictable toxicity profile make lenalidomide a good candidate for maintenance therapy. Combinations of lenalidomide with bortezomib, as well as with conventional chemotherapy are likely to become the backbone of future myeloma therapies. Future and ongoing studies will answer several important questions concerning the optimal duration of treatment with lenalidomide, its role in patients with high-risk disease and mechanisms of lenalidomide resistance.

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Acknowledgements

This study was supported in part by Grants CA93842, CA10080, CA107476, CA62242 from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services.