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1 Introduction

Immunomodulatory drugs (IMiDs) are a series of compounds that were developed by using the first-generation IMiD thalidomide as the lead compound. Thalidomide, initially introduced as a sedative and used for morning sickness, was withdrawn from the market in the early sixties after it was found to be a teratogen. However, it was later found to be beneficial in the treatment of erythema nodosum leprosum, oral ulcers, graft vs. host disease, and wasting associated with the human immunodeficiency syndrome. Its anti-angiogenic properties were recognized in the early nineties and led to the evaluation of thalidomide as an anti-angiogenic agent in the treatment of several cancers. Following initial trials in relapsed and newly diagnosed multiple myeloma (MM), where it was used alone or in combination with dexamethasone and other anti myeloma agents, it became part of standard therapy for the treatment of MM. The thalidomide structural backbone was used as a template to design and synthesize compounds with increased immunological and anticancer properties but lacking the toxicity associated with the parent compound. In the mid-1990s, a series of amino-phthaloyl-substituted thalidomide analogues were generated, and these were found to be up to 50,000 times more potent at inhibiting TNF- than the parent compound in vitro [1]. Further preclinical testing of these compounds led to the identification of second-generation IMiDs namely lenalidomide (Revlimid, CC-5013) and pomalidomide (Actimid, CC-4047) for study in clinical trials for patients with myeloma. The introduction of these IMiDs and other novel therapeutic agents such as bortezomib has favorably affected the survival of patients with myeloma in the last decade [2].

2 Lenalidomide (Revlimid)

2.1 Preclinical Studies

The chemical name of lenalidomide is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and the empirical formula is C13H13N3O3. The mechanism of action of lenalidomide involves direct cytotoxicity as well as indirect effects by modulating different components of the immune system such as altering cytokine production, inhibiting angiogenesis, regulating T cell co-stimulation, and augmenting the NK cell cytotoxicity.

2.1.1 Alteration of Cytokines

Lenalidomide inhibits the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs [3]. Reduction in IL-6 and TNF-α levels can partially explain the action of lenalidomide in multiple myeloma. IL-6 inhibits the apoptosis of malignant myeloma cells and helps in their proliferation [4]. Lenalidomide downregulates the production of IL-6 directly and also inhibits multiple myeloma—bone marrow stromal cell (BMSC) interaction [5, 6], which augments the apoptosis of myeloma cells [7]. The precise mechanism of TNF-α downregulation by lenalidomide is not known; however, like thalidomide, it possibly increases the degradation of TNF-α mRNA [8]. The downregulation of TNF-α secretion is up to 50,000 times more when compared to thalidomide [1].

2.1.2 T Cell Activation

Besides stimulation of T cell receptor (TCR), a secondary interaction of B7 molecule on APC and CD28 on the T cell surface provides a co-stimulatory signal that augments the T cell response followed by a cascade of cytokine and cellular responses [9]. Lenalidomide and other IMiDs directly induce tyrosine phosphorylation of CD28 on T cells leading to activation of downstream targets such as PI3K, GRB-2-OS, and NF-κb. There is an increase in Th1 type cytokine response resulting in increased genetic expression of IL-2 and IFN-γ which subsequently increases T cell and natural killer (NK) cell-mediated lysis of myeloma cells [3, 10]. IMiDs have been shown to stimulate both cytotoxic CD8+ as well as helper CD4+ cells [11]. Their effects on T helper cells can also potentially mediate Th1 type antitumor immunity in response to tumor cell vaccination in animal models [10].

2.1.3 Augmentation of NK Cell Function

Natural killer (NK) cells are an important component of innate immunity against cancer cells and kill the cell with antibody-dependent cell-mediated cytotoxicity (ADCC) and natural cytotoxicity. Modulation of NK cell function is also believed to contribute to the antitumor activity of lenalidomide in MM. Treatment with thalidomide is accompanied by increased NK cell numbers as well as IL-2 levels, and the mechanism is probably indirect. Hayashi et al. in their study of IMiDs in MM cell lines have demonstrated that culturing PBMC with IMiDs leads to 1.2–1.3-fold increase in the percentage of CD56 cells [12]. IMiDs enhanced ADCC when 51 Cr-labeled MM cells that express CD40 were incubated with rhuCD40 and then subsequently treated with PBMC cells incubated in the presence of IMiDs for 5 days. The increase in NK cell function may be related to the increase in IL-2 production by the T cells as the presence of a monoclonal Ab against IL-2 R blocked the NK cell cytotoxicity. IMiDs also were shown not to directly activate the NK cells, as evidenced by lack of phosphorylation of signaling molecules (ERK/p38MAPK/Akt/PKC) in NK cells [12]. Lenalidomide-enhanced Fc-γ receptor signaling may also play a role in increasing the potency of NK cells.

2.1.4 Anti-angiogenic Activity

Thalidomide and IMiDs has been shown to have antiangiogenic properties that are independent of their immunomodulatory effects [13, 14]. Tumor associated endothelial cells are more dependent on the VEGF receptor signaling for growth and survival compared to normal endothelial cells [15]. Early studies showed that thalidomide had anti angiogenic activity in a rabbit model of corneal neovascularization that was induced as a response to bFGF [13]. Thalidomide and the newer IMiDs have also been shown to significantly decrease the expression of angiogenic factors VEGF and IL-6 in multiple myeloma [16]. The overall superiority of newer IMiDs over thalidomide regarding antiangiogenic effect is controversial [14, 17], but the data suggests that thalidomide is a potent inhibitor of endothelial cell migration whereas lenalidomide and pomalidomide are more potent inhibitors of other aspects of the angiogenic process, such as inhibition of endothelial cell attachment, migration, and differentiation [14]. Apart from alteration in the levels of VEGF, lenalidomide partially inhibits Akt phosphorylation after VEGF stimulation in endothelial cells and also has inhibitory effects on phosphorylation of Gab1, a protein upstream of Akt 1 [18, 19]. These observations demonstrate that IMiDs may affect angiogenesis by multiple mechanisms.

2.1.5 Direct Antitumor Activity

Lenalidomide treatment has also shown anti proliferative activity against MM cells in the absence of immune effector cells [20]. Malignant plasma cells derived from refractory cases of myeloma were shown to be susceptible to IMiD-induced growth arrest. Lenalidomide upregulates cyclin-dependent kinase (CDK) inhibitor, p21 waf-1, a key cell cycle regulator that modulates the activity of CDKs. Similarly reductions in CDK2 activity have been demonstrated in myeloma-derived cell lines, U266 and LP-1 [21]. In contrast, the normal B cells obtained from healthy donors were immune from growth inhibition and did not show any upregulation of p21 expression after 3 days of lenalidomide treatment. In other studies, thalidomide and its analogues have also been shown to induce apoptosis in MM cell lines [22]. Effects on apoptosis in MM cells is secondary to increased potentiation of TNF-related apoptosis inducing ligand (TRAIL), inhibition of apoptosis protein-2, increased sensitivity to Fas-mediated cell death, upregulation of caspase-8 activation, downregulation of caspase-8 inhibitors (FLIP, cIAP2), downregulation of NF-κb activity, and inhibition of prosurvival effects of IGF-1 [23].

2.1.6 Effects on Multiple Myeloma Microenvironment

In multiple myeloma, osteoclasts lead to bone resorption and secrete survival factors for MM cells. The interaction between MM cells and BMSC in turn leads to increased production of IL-6 and other growth factors for MM cells and osteoclasts [24]. Lenalidomide alters the myeloma microenvironment by directly decreasing the formation of tartrate-resistant acid phosphatase (TRAP) positive cells which form osteoclasts [5]. Additionally, it decreases αVβ3-integrin levels, an adhesion molecule needed for osteoclast activation, and downregulates cathepsin K, a major cysteine protease expressed in osteoclasts, pertinent for matrix degradation in the resorption process [5]. It downregulates the important mediators of osteoclastogenesis such as transcription factor PU.1 and MAP kinase pERK and reduces the levels of bone remodeling factor-receptor activator of NF-κb ligand. IMiDs are also known to decrease the cell surface adhesion molecules such as ICAM-1, VCAM-1, and E-selectin and inhibit the adhesion of MM cells to BMSC [6]. Thus, lenalidomide interferes with the synergism among the osteoclasts, MM cells, and BMSC and decreases osteoclastogenesis by acting at various levels.

2.2 Safety

Though teratogenicity of lenalidomide in humans is not proven, its structural similarity to thalidomide and induction of malformations in the offspring of female monkeys has raised concerns [25]. Caution should be taken in women with childbearing potential and in sexually active male patients.

The most common grade 3 or higher adverse events reported in MM-009/010 patients treated with Len/Dex was neutropenia found in more than one-third followed by thromboembolic events (16%), thrombocytopenia (13%), anemia (11%), and pneumonia (9%) [26]. An expanded access program (MM-016) over 1,400 similar patients showed that at least one grade 3 or 4 adverse event was reported in 70% of patients, most common being myelosuppression (45%), fatigue (10%), and pneumonia (7%) [27]. Toxicity effects noted in various studies involving lenalidomide in MM are listed in Table 8.1.

Table 8.1 Toxicity profile of lenalidomide
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Previously untreated patients are at a lower risk for myelosuppression (12–21%) than patients with refractory or relapsing myeloma (38–69%). Neutropenia is much more common than thrombocytopenia and anemia but is generally predictable and associated with low rate of febrile neutropenia (3%) [39]. Particular vigilance needs to be kept especially during the initial cycles as the risk of myelosuppression appears to be highest during this phase [40]. Myelosuppression can usually be managed with growth factor support and/or lenalidomide dose reductions but may require discontinuation of treatment in a few (less than 4%) [27].

The risk of venous thromboembolism (VTE) is low when lenalidomide is given as monotherapy but increases significantly when it is used in combination with dexamethasone, particularly at high dose as well as with concomitant administration of erythropoietic agents [36, 41, 42]. The risk also appears to increase in combinations with cytotoxic chemotherapy, particularly anthracyclines [42]. The incidence of VTE in patients treated with Len-Dex without thromboprophylaxis in MM-009/010 was 16% [26]. However most recent studies have shown that prophylaxis with low-molecular-weight heparin (LMWH) or low-dose aspirin effectively reduces the risk of VTE to less than 5%, which is comparable to the background risk in patients with MM [42–46]. Like myelosuppression, risk of venous thromboembolism (VTE) also appears to be highest during the initial cycles [40]. In a pooled analysis, 60% thrombotic events occurred between the third and sixth cycle of treatment [47]. Uncommonly arterial thrombosis such as in coronary arteries leading to myocardial infarction can also occur [47]. In patients who develop VTE, it is reasonable to briefly discontinue lenalidomide and resume the treatment when full anticoagulation has been established [48]. Low-dose aspirin (81–100 mg) provides sufficient thromboprophylaxis for patients with standard risk of VTE during Len/Dex therapy, while LMWH for at least the first four cycles should be considered for patients with a higher risk of VTE, especially immobilized patients and those with a history of VTE [46, 49].

Fatigue is very frequently encountered and is a common reason for treatment discontinuation in elderly patients with MM. Common causes of fatigue, such as anemia, hypothyroidism, infection, and depression should be ruled out [49]. Infections are common and combination with dexamethasone therapy increases the risk. 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.

More than a fifth of patients suffer from neurological complications such as dizziness (20%), headache (21%), and/or insomnia (32%). Unlike bortezomib and thalidomide, neuropathy is rarely seen with lenalidomide alone, thus making it an optimal ­therapeutic choice in patients with high risk or existing neuropathy [50]. Musculoskeletal problems like arthralgia, backache, and cramp are common but rarely severe.

A variety of rashes (morbilliform, acneiform, urticarial, etc.) have been described in approximately 30% of myeloma patients treated with lenalidomide with or without dexamethasone. Severe rashes requiring permanent discontinuation of lenalidomide therapy are rare [51]. Peripheral edema, dyspnea, constipation, diarrhea, and nausea are other common toxicities of this drug. Lastly, case report of lenalidomide-induced Coomb’s positive autoimmune hemolytic anemia are also there [52].

2.3 Lenalidomide for Relapsed MM

Two large, multicenter, randomized, placebo-controlled phase III pivotal trials MM-009 (n  =  353) conducted in North America and MM-010 (n  =  351) conducted in Europe, Australia, and Israel, which collectively included 704 patients, assessed the efficacy and safety of lenalidomide plus dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma (RRMM) [26, 30, 31]. Patients were randomized to receive either oral lenalidomide 25 mg per day or placebo for three weeks along with 40 mg oral dexamethasone for four days starting 1, 9, and 17 day of each 28-day cycle (for 4 cycles) until disease progression. After four cycles, dexamethasone (40 mg/day) was limited to days 1–4 only. The results of both studies were similar, and the pooled analysis showed that treatment with lenalidomide plus dexamethasone significantly improved overall response (OR: 60.6 vs. 21.9%, P  <  0.001), complete response rate (CR: 15.0 vs. 2.0%, P  <  0.001), time to progression (TTP: median of 13.4 vs. 4.6 months, P  <  0.001), and duration of response (DOR: median of 15.8 months vs. 7 months, P  <  0.001) compared with dexamethasone-placebo. Even at a median follow-up of 48 months for surviving patients, a significant benefit in overall survival (median of 38.0 vs. 31.6 months, P  =  0.045) was retained [26]. Thus the data confirmed the significant response and survival benefit with lenalidomide and dexamethasone, and this led to approval of lenalidomide in combination with dexamethasone for the treatment of MM in patients who have received at least one earlier therapy by the US FDA in June 2006 followed by European Medicines Agency in June 2007.

Sub-analysis of MM-09 and MM-10 by Harousseau et al. revealed that half of the patients who initially had a partial response achieved a complete or very good partial response with further treatment [53]. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 vs. later); however, it still remained clinically significant. The quality of response also showed a positive prognostic impact with an extended follow-up of 48 months, as patients who achieved a CR/VGPR as their best response had significantly longer median response duration, time-to-progression, and overall survival than in those with a partial response (24.0 vs. 8.3 months, P  <  0.001; 27.7 vs. 12.0 months, P  <  0.001; not reached vs. 44.2 months, P  =  0.021, respectively), and this was regardless of when the CR/VGPR was achieved [53]. Another sub-analysis of the same studies determined that continued lenalidomide treatment until disease progression after achievement of ≥PR is associated with a significant survival advantage when controlling for patient characteristics [54].

A Dutch study showed that treatment with len-dex is highly effective and feasible in heavily pretreated multiple myeloma patients by analyzing the clinical data of more than 100 patients who had been on a median of 3 previous lines of therapy, including thalidomide in most [45]. With a median of 7 cycles of treatment, an overall response rate of 69%, including complete response in 6%, was achieved, and this was not influenced by previous thalidomide and/or bortezomib treatment. Using the recommended prophylaxis, incidence of venous thrombotic events was low (5%), but grade ≥3 myelosuppression occurred in more than a third (37%) [45].

Chromosomal aberrations such as del (17p), t(4;14), t(14;16), and t(14;20) have been associated with poor outcome in MM. The combination of lenalidomide and dexamethasone induces durable responses among relapsed t(4;14) disease but appears to be ineffective in patients with del(17p) [55]. Also, it is postulated that lenalidomide may overcome the eventual negative impact of del(13q) on OS by reducing the relapse rate.

Although comparisons across different trials must be interpreted with caution, it appears that the response rate and the depth of response reported for lenalidomide plus dexamethasone is more favorable than that reported in phase III trials of other active treatment regimens, such as the proteasome inhibitor bortezomib in combination with pegylated liposomal doxorubicin (VPLD) [56].

Recently an expert panel published consensus statement on use of lenalidomide in RRMM [49]. Len-dex is considered to be most effective when used at first relapse and can be administered regardless of the type of previous therapy and age. The optimal starting dose of lenalidomide is 25 mg once daily orally on days 1–21 of each 28-day cycle but has to be modified according to renal function and the presence of cytopenias. 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 is 40 mg but has to be modified according to age in patients (20 mg in >75 years). Len-dex at best-tolerated dose may continue in responding patients until evidence of disease progression [49].

Toxicities from dexamethasone can sometimes be dose limiting, and this led to evaluation of the efficacy and safety of lenalidomide monotherapy in patients with RRMM by Richardson et al. [29]. This phase II study enrolled more than 200 patients of which two-third had received 3 or more prior anti-MM treatment regimens including prior autologous stem cell transplants in 45%. Lenalidomide alone for three weeks in monthly cycles induced a partial response or better in more than one-fourth of patients. Myelosuppression was reported in more than half of patients but was manageable with dose reduction [29]. Lenalidomide monotherapy was thus shown to be active in RRMM with acceptable toxicities.

Another multicenter, open-label, randomized phase II study evaluated two dose regimens of lenalidomide (30 mg once-daily or 15 mg twice-daily) in over 100 patients with RRMM [28]. Analysis showed a similar response rate (complete, partial, or minor was 25%) in the two groups, but increased grade 3/4 myelo-suppression was noted in patients receiving 15 mg twice daily (41% vs. 13%, P  =  0.03). Though lenalidomide monotherapy was effective, addition of dexamethasone in patients in whom lenalidomide either failed to achieve a response (after 2 cycles) or who subsequently progressed did induce a response in 29% and SD in 21% [28].

Combinations of lenalidomide with other chemotherapeutic agents have also been studied ( 8.2). Due to lack of overlapping toxicity, lenalidomide has been tried concomitantly with bortezomib, and the clinical evaluations showed that RVD regimen (lenalidomide, bortezomib, and dexamethasone) is well tolerated and shows promising activity with durable responses in patients with RRMM, including in patients who were prior treated with lenalidomide, bortezomib, and/or thalidomide. Two different phase II studies evaluated more than 60 patients in each and after a median of 8 cycles have reported a high ORR (84–86%) and a good depth of response (more than 20% complete response [CR]/near-complete response [nCR]) even in patients with high-risk cytogenetic profiles [57, 58]. A recent prospective study also found that the RVD regimen was able to overcome the negative impact of certain abnormalities [e.g., del(13q), t(4;14)] to a greater extent than lenalidomide plus dexamethasone alone but failed to improve outcomes for patients with del(17p) [34].

Table 8.2 Lenalidomide in RRMM
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Besides bortezomib, combinations with doxorubicin or cyclophosphamide have also shown to be safe and effective options. Combinations of lenalidomide plus dexamethasone in with novel agents such as panobinostat, bevacizumab, SGN-40, perifosine, vorinostat, dasatinib, NPI-0002, everolimus, and carfilzomib are currently being investigated in phase I and II trials. A summary of the important trials in this setting with lenalidomide are given in Table 8.2.

2.4 Lenalidomide for Newly Diagnosed Myeloma

Lenalidomide has shown high efficacy in newly diagnosed MM patients (Table 8.3). The Southwest Oncology Group conducted a randomized trial comparing lenalidomide (Len) plus dexamethasone (Dex) to dex (about 100 patients in each group) in newly diagnosed myeloma [35]. Three 35-day induction cycles followed by monthly maintenance induced superior response rates in len-dex group (1-year OS of 78% vs. 52%, P  =  0.002; ORR of 78% vs. 48%, P  <  0.001, and VGPR of 63% vs. 16%, P  <  0.001). However in initial part of this study, there was a very high incidence of thromboembolic events in len-dex group (75%). Adding aspirin prophylaxis significantly reduced this risk, but it still continued to be more than the dex group [35, 59].

Table 8.3 Lenalidomide in newly diagnosed
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A case–control retrospective study by Mayo clinic involving more than 400 newly diagnosed patients revealed len-dex to be well-tolerated and more effective than thal-dex as initial therapy for newly diagnosed myeloma [37]. The incidence of one grade 3/4 adverse event was similar (57.5% vs. 54.6%, P  =  0.568) in the two groups, but the main grade 3/4 toxicities of len-dex were hematologic while that in thal-dex were venous thromboembolism and peripheral neuropathy [37].

In an open-label randomized controlled trial by Eastern Cooperative Oncology Group (ECOG), 445 patients with untreated symptomatic myeloma were randomly treated with lenalidomide 25 mg for three weeks along with either high-dose dexamethasone (40 mg on days 1–4, 9–12, and 17–20) or low-dose (40 mg weekly) in monthly cycles [36]. Within four cycles, 79% of patients receiving high-dose therapy and 68% of patients on low-dose therapy had complete or partial response (odds ratio 1·75, 80% CI 1·30–2·32; P  =  0.008). At the second interim analysis at 1 year, overall survival was 96% (95% CI 94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high-dose group (P  =  0.0002). Even though patients on high dose of dex showed a better response rate, they experienced much more toxicity and mortality (12 of 222 on high dose and one of 220 on low-dose) compared to those on the low-dose regimen [36].

Role of lenalidomide as a monotherapy in this group is still unknown. However, recently, a retrospective study observed an overall response rate (≥partial remission) to be 47% at a median follow-up of 7 months (range 1–26) to lenalidomide alone [60]. Though the study was limited by the small size (n  =  17), it reassures that lenalidomide alone has the potential to induce significant clinical response in newly diagnosed patients as well.

Combinations with various chemotherapeutic agents in front-line myeloma have also been evaluated (Table 8.3). The combination of melphalan-prednisone-lenalidomide (MPR) has shown promising results in elderly newly diagnosed myeloma patients [38, 61]. Combinations with bortezomib, clarithromycin, or cyclophosphamide have shown overall response rates of more than 80% with acceptable toxicity. A recent phase I/II study using lenalidomide-bortezomib-dexamethasone has shown a partial response of 100% [32].

2.5 Maintenance

Being orally available, IMiDs have a distinct advantage over intravenous drugs such as bortezomib as maintenance therapy. Thalidomide has been proven to improve OS as well as time to progress in three separate phase III studies in post transplant patients [62–65]. Despite these findings, concerns about cumulative toxicity have limited the use of thalidomide for maintenance.

Recently maintenance therapy with oral lenalidomide in multiple myeloma patients who had undergone stem cell transplantation has shown a significant reduction in the risk for relapse in two separate phase III trials—one conducted in the USA and the other in France. The American study reported result of 460 randomized patients which showed that after 17.5 months of follow-up, only 20% of patients in the lenalidomide group had experienced an event (progression or death), compared with 41% of those in the placebo group. Estimated hazard ratio was 0.40, thus a 60% reduction in the risk of disease progression with lenalidomide. The estimated median TTP was 42.3 months in lenalidomide group vs. 21.8 months for the placebo arm [66].

The other set of results come from an interim analysis of a French study involving 614 patients which revealed that lenalidomide maintenance halved the risk for relapse. The 3-year progression-free survival was 68% with maintenance lenalidomide, compared with 35% with placebo (hazard ratio, 0.46; P  <  10–6), reducing the rate of relapse by 54% [67].

The two studies were similar, but the French study used a consolidation phase of therapy before moving on to maintenance with lenalidomide. Both trials showed a significant improvement in time to disease progression, although no significant data available is yet for overall survival. However, since the time to progression of disease is dramatically increased, lenalidomide maintenance therapy could become the new standard of care for these patients.

2.6 Early Stage Disease (Smoldering Myeloma)

Smoldering MM (SMM) is a MM precursor defined by an M-protein of ≥3 g/dL and/or ≥10% bone marrow plasma cells with no evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions [CRAB]) (Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working group 2003 [68]). SMM is differentiated from MGUS based on the size of the M protein and the level of bone marrow involvement. The natural history of SMM varies greatly, and the overall risk of progression is approximately 10% per year for the first 5 years, 3% per year for the next 5 years, and 1% per year for the last 10 years with the cumulative probability of progression being 73% at 15 years [69].

Standard management of smoldering myeloma at present consists of monitoring the patient every 3–6 months until the disease has progressed to a point at which intervention is warranted. Three phase II studies showed that thalidomide could prolong the TTP; however, proven benefit in prospective randomized trials is required before approval [70–72]. The activity of lenalidomide and its acceptable safety profile has prompted evaluation of its efficacy in preventing or delaying progression of high-risk smoldering myeloma to symptomatic myeloma. A multicenter, phase III study compared the efficacy of induction therapy with lenalidomide (25 mg daily for 21 days every 28-day cycle, for 9 cycles) plus dexamethasone (20 mg on days 1–4 and days 12–15 every 28 days, for 9 cycles) and maintenance therapy with lenalidomide (10 mg/day for 21 days every 2 months) with that of therapeutic abstention in patients with high-risk smoldering myeloma [73]. After a median of four cycles, the overall response rate in the lenalidomide arm was 81% (n  =  47), which increased to 91% after nine cycles. After a median follow-up of 14 months, the median TTP was not reached in the lenalidomide group (n  =  47) and was 19.3 months in the abstention arm (n  =  47). OS at 2 years was 100% for lenalidomide-treated patients and 96% for those abstaining from treatment [73].

3 Pomalidomide

Pomalidomide (CC-4047) is yet another derivative of thalidomide with similar mechanism of action and is considered to be most potent of the IMiDs [21, 74]. Preclinical studies showed that it significantly increases serum IL-2 receptor and IL-12 levels serum within a month, which correlated with the percentage decrease in paraprotein [75]. A decrease in CD8+/CD45RA+ cells and CD4+/CD45RA+ during the first month of study was also accompanied by a corresponding increase in CD8+/CD45RO+ cells and CD4+/CD45RO+, which suggests a switch from naive cells to activated effector T cells [75]. This drug also potently blocks osteoclasts differentiation and thus, might also have a role in preventing or treating myeloma bone disease [76]. Pomalidomide also affects inflammation via transcriptional inhibition of cyclooxygenase-2 (COX-2) production, which is associated with increased prostaglandins in human lipopolysaccharide (LPS)-stimulated monocytes [77].

Like thalidomide, pomalidomide may have the potential for severe birth defects, and caution in reproductive age group is advised. Myelosuppression is the major and dose-limiting toxicity noted in all clinical trials. Grade 3/4 neutropenia has been seen in about 30–60% of patients and is more common than thrombocytopenia or anemia (Table 8.4). Thromboembolic complications occurred with a frequency similar to that reported with other IMiDs. Neuropathy is infrequent, but worsening of neuropathy has been reported by previously heavily pretreated patients. Noninfectious acute lung injury is a rare but serious drug complication. Fortunately it responds well to the use of corticosteroids. Other common side effects include orthostatic hypotension, skin rash, and constipation.

Table 8.4 Pomalidomide in RRMM
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Low-dose pomalidomide is effective in the treatment of anemia associated with JAK2V617F-positive myelofibrosis [83]. Among patients with multiple myeloma, pomalidomide has been tried in only relapsed cases. Initial phase I trials established pomalidomide as well tolerated in maximum tolerated dose (MTD) of 2 mg QD or 5 mg on alternate days and demonstrated a potent immune-activating effect of this agent in myeloma [75, 78]. These studies using pomalidomide predominantly as monotherapy have shown excellent long-term responses with an overall response rate of 52% [84].

The first phase II trial conducted by Lacy and colleagues presented data on a cohort of 60 relapsed patients who were administered 2 mg of oral pomalidomide daily along with weekly 40 mg oral dexamethasone [79]. About two-third patients achieved confirmed response including complete response in 5%. Responses were shown even among 40% of patients who were lenalidomide and 60% of patients who were bortezomib-refractory. Also, 74% of patients with high-risk cytogenetic or molecular markers (hypodiploidy or karyotypic deletion of chromosome 13, FISH showing presence of translocations t(4;14) or t(14;16) or deletion 17p, or plasma cell labeling index ≥3%) showed a response. This observation carries great importance since lenalidomide and its combinations have so far being unsuccessful in improving the outcomes of patients with deletion 17p [34]. Pomalidomide was well tolerated with primary issue being grade 3/4 hematologic toxicity in about a third [79]. To better define its efficacy in lenalidomide refractory disease, Lacy et al. also treated a cohort of 34 of these patients with the same regime of pom-dex, and the overall response (PR or better) was near 50% [80].

Dual refractory myeloma (refractory to both bortezomib and lenalidomide) is a great challenge in current scenario, and ongoing studies have established pomalidomide to be effective in this group of patients with an overall response of 25% or more [33, 81, 82]. Also, it is being postulated that its effectivity goes beyond marrow pathology as it has been also shown effective in treatment of extramedullary disease with a response rate of ∼30% including the extramedullary component [85].

The optimal dose of pomalidomide is still unclear. While earlier studies advocated 2 mg daily as the maximum tolerated dose, Richardson and colleagues in a recent phase I/II dose escalation study proved 4 mg pomalidomide daily to be well tolerated as well [33]. In the study by Lacy et al., eight patients with suboptimal response were escalated from 2 to 4 mg daily, and one patient improved from stable disease to PR [80]. However, in an ongoing trial by Lacy et al. starting with higher pomalidomide dose (4 mg) has not shown any superiority of response over starting with 2 mg dose and is associated with higher risk of myelosuppression [81].