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Current Advances in Non–Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma

Current Advances in Non–Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma

In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)—and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid). Several novel classes of drugs, including the histone deacetylase (HDAC) inhibitors, heat shock protein (HSP) inhibitors, and monoclonal antibodies have been shown to have activity in myeloma in early-stage clinical trials. HDAC inhibitors, including vorinostat (Zolinza), panobinostat, and romidepsin (Istodax) are thought to affect multiple pathways involved in MM and correct the deregulation of genes involved in apoptosis and cell cycle arrest, thus potentially sensitizing MM cells to apoptosis. HSP inhibitors (eg, tanespimycin) decrease MM proliferation and suppress the long-term replicative potential of MM cells; they may also sensitize MM cells to other anticancer agents. The humanized monoclonal antibody elotuzumab induces antibody-dependent cell cytotoxicity–mediated apoptosis. It is likely that in the near future the treatment armamentarium for MM will undergo significant expansion as some of these additional target pathways become validated.


Multiple myeloma (MM) remains incurable despite the current approaches used in initial therapy, including more effective induction therapy, one or more autologous stem-cell transplants, and consolidation/maintenance strategies. The improved survival of patients with myeloma and the incurable nature of the disease have led to an increased number of patients with relapsed disease who require treatment for continued control of their disease. Treatment of relapsed disease has improved considerably in the past decade and has resulted in improved outcomes in this group of patients.[1] Therapeutic advances during this decade have included thalidomide (Thalomid) and its immunomodulatory derivatives lenalidomide (Revlimid) and pomalidomide, as well as the proteasome inhibitor bortezomib (Velcade). Immunomodulatory drugs (IMiDs) represent a series of compounds that were developed based on thalidomide. Thalidomide was initially introduced as a sedative and used for morning sickness, but was withdrawn from the market in the early 1960s after it was found to be a teratogen. Given its antiangiogenic properties, it was evaluated in the treatment of several cancers, including myeloma. Based on promising initial results, thalidomide was evaluated in several phase II and phase III studies in the setting of relapsed and newly diagnosed disease. These studies demonstrated clear activity for the drug, and several combinations that include thalidomide have been developed since then. However, thalidomide was associated with significant toxicity, including peripheral neuropathy (PN), constipation, sedation, and deep venous thrombosis. Moreover, the teratogenic effect of the drug required that it be prescribed under strict regulations. Attempts to develop analogs with more acceptable toxicity and possibly improved activity led to the development of the IMiDs lenalidomide and pomalidomide.[2] More recently, several novel classes of drugs have been shown to have activity in myeloma in early-stage clinical trials. These include the histone deacetylase (HDAC) inhibitors, heat shock protein (HSP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, phosphoinositide 3-kinase (PI3k)/AKT inhibitors, and monoclonal antibodies. Here we review the recent developments and potential future options for management of relapsed/refractory MM.


Mechanisms of action

Lenalidomide is often referred to as an IMiD, but its mechanisms of action in myeloma have not been fully elucidated. It is likely that its antimyeloma activity is dependent on many effects, including direct cytotoxicity as well as indirect effects associated with modulation of the different cytokines, inhibition of angiogenesis, regulation of T-cell activity, and augmentation of natural killer (NK)-cell cytotoxicity.

Direct cytotoxic effects. Lenalidomide clearly has direct antiproliferative and apoptotic effects on MM cells, as has been shown with cell lines and primary myeloma cells.[3-5] Lenalidomide affects cyclin-dependent kinase (CDK) inhibitors through regulation of p21waf-1, a key cell-cycle regulator that modulates the activity of CDKs. Various mechanisms have been proposed for the apoptotic effects, including increased potentiation of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), inhibition of apoptosis protein-2, increased sensitivity to Fas-mediated cell death, upregulation of caspase-8 activation, down-regulation of caspase-8 inhibitors (FLIP, cIAP2), downregulation of nuclear factor kappa B (NFκB) activity, and inhibition of prosurvival effects of insulin-like growth factor (IGF)-1.[6] More recently, studies have shown that lenalidomide may act through CCAAT/enhancer binding protein (CEBP)-beta, a transcription factor that regulates the activity of interferon regulatory factor (IRF)-4, which appears to be a critical survival factor for myeloma cells.

Immunomodulatory effects. Lenalidomide inhibits the production of proinflammatory cytokines TNF-α, interleukin (IL)-1, IL-6, and IL-12 and increases the production of anti-inflammatory cytokine IL-10 from human peripheral blood mononuclear cells.[7,8] IL-6 is a critical cytokine in myeloma; it plays a role in cell proliferation and survival and is secreted both by myeloma cells and cells in the marrow microenvironment.[9] Lenalidomide down-regulates the production of IL-6 directly and also inhibits MM–bone marrow stromal cell (BMSC) interaction, leading to increased apoptosis of myeloma cells.[10,11] Lenalidomide is a much more potent inhibitor of TNF-α secretion—up to 50,000 times more potent than thalidomide—which may, to some extent, explain the differences in the clinical activity of these two agents.[2] Lenalidomide can lead to increased Th1-type cytokine response, resulting in increased expression of IL-2 and interferon (IFN)-γ, thereby enhancing T-cell and NK-cell-mediated lysis of myeloma cells.[7] CD28 is a co-stimulatory molecule that augments the T-cell response, and lenalidomide can induce tyrosine phosphorylation of CD28 on T cells, leading to activation of downstream targets such as PI3K, Grb2-SOS, and NFκB.[12,13] IMiDs have been shown to stimulate both cytotoxic CD8+ and helper CD4+ cells.[14] In vitro studies have shown an important role for NK-cell–mediated cytotoxicity against myeloma cells. Increased NK-cell numbers are seen following treatment with IMiDs and may be a result of increased IL-2 secretion.[15]

Antiangiogenic properties. Multiple in vitro and in vivo studies have demonstrated strong antiangiogenic properties of thalidomide and the IMiDs, but it remains unclear what the exact contribution of this effect is to antimyeloma activity.[16,17] Tumor-associated endothelial cells are more dependent on vascular endothelial growth factor (VEGF)-receptor signaling for growth and survival than are normal endothelial cells.[18,19] Lenalidomide significantly decreases the expression of angiogenic factors VEGF and IL-6 in MM, an effect that is still present when the myeloma cells are in the tumor microenvironment.[7,20] 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 AKT1.[21,22] It is likely that multiple mechanisms underlie the antiangiogenic properties of lenalidomide and other IMiDs.

Effects on the microenvironment. In addition to the effect on myeloma cells and immune cells, lenalidomide can also have different effects on cells in the microenvironment. Interaction between osteoclasts and myeloma cells leads to increased production of IL-6 and other growth factors for MM cells as well as osteoclasts.[23] Lenalidomide affects the marrow microenvironment by decreasing the formation of osteoclasts.[10] It downregulates the important mediators of osteoclastogenesis, such as transcription factor PU.1 and pERK, and it reduces the levels of bone remodeling factor RANK. IMiDs also decrease cell surface adhesion molecules such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, and they inhibit the adhesion of MM cells to bone marrow stromal cells.[24]

Adverse effects of lenalidomide

In general, lenalidomide is well tolerated and does not have many of the more bothersome adverse effects associated with thalidomide. There is no direct evidence of teratogenicity in humans, but lenalidomide’s structural similarity to thalidomide[25] calls for caution while using the drug in women with childbearing potential and in sexually active male patients.[26]

The most common grade 3 (or higher) adverse events reported in phase III trials were neutropenia, thromboembolic events, thrombocytopenia, anemia, and pneumonia.[27] Myelosuppression remains the most common problem associated with lenalidomide, with neutropenia much more common than thrombocytopenia and anemia. However, the frequency of febrile neutropenia is quite low.[28] Myelosuppression can usually be managed with growth factor support and/or lenalidomide dose reductions but may require discontinuation of treatment.[29]

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 high-dose dexamethasone, or when used with erythropoietic agents.[30-32] The risk is also higher when lenalidomide is used in combination with cytotoxic chemotherapy, particularly anthracyclines.[32] The incidence of VTE was 16% in patients treated with lenalidomide + dexamethasone without thromboprophylaxis in phase III trials.[27] Recent studies support the use of aspirin prophylaxis, which reduces the risk of VTE to less than 5%—with low-molecular-weight heparin reserved for those at high risk for thrombosis, especially immobilized patients and those with a history of VTE.[32-36]

Fatigue is another frequent side effect and is often the reason for treatment discontinuation.[37] This is usually manageable with dose reduction. Another bothersome complaint reported by many patients is muscle cramping. Nearly 20% of patients experience neurologic complications such as dizziness, headache, and/or insomnia. Unlike with thalidomide, new-onset neuropathy is rarely seen with lenalidomide alone, and worsening of preexisting neuropathy has not been widely reported.[38] Rashes have been described in 20% to 30% of patients with myeloma treated with lenalidomide with or without dexamethasone. Severe rashes requiring permanent discontinuation of lenalidomide therapy are rare.[39] Peripheral edema, dyspnea, constipation, diarrhea, and nausea are other common toxicities seen with this drug.

Clinical results with lenalidomide in the treatment of relapsed MM

Following the promising results seen in phase II trials in relapsed disease, two large, multicenter, randomized, placebo-controlled phase III trials were conducted comparing lenalidomide + dexamethasone with dexamethasone alone in patients with relapsed and/or refractory (R/R) MM: MM-009 (N = 353) in North America, and MM-010 (N = 351) in Europe, Australia, and Israel.[27,40,41] Patients were randomly assigned to receive either oral lenalidomide, 25 mg/d, or placebo for 3 weeks, along with 40 mg of oral dexamethasone for 4 days starting on days 1, 9, and 17 of each 28-day cycle for four cycles or until disease progression. After four cycles, dexamethasone (40 mg/d) was limited to days 1 through 4 only. The results of the two studies were largely the same, demonstrating similar and significant improvement in overall survival with lenalidomide + dexamethasone (with a median of 38.0 vs 31.6 months, P = .045).[27] In June 2006, based on the results of these trials, the US Food and Drug Administration (FDA) approved lenalidomide in combination with dexamethasone for the treatment of MM in patients who have received at least one earlier therapy. The European Medicines Agency (EMA) followed suit in June 2007. Subsequently, a large expanded-access study was performed in patients with relapsed MM; the results were in accord with those seen in the phase III studies.[29]

A large number of subsequent analyses have been done using data from these studies, addressing several important aspects of treatment with lenalidomide. Significant numbers of patients who initially had a partial response (PR) achieved a complete response (CR) or very good partial response (VGPR) with further treatment, especially among those who achieved a PR within the first four cycles.[42] Patients who achieved a CR/VGPR as their best response had significantly longer median response duration, time to progression, and overall survival compared with those with a PR.[42] Continuation of lenalidomide treatment until disease progression in patients who achieve a PR was associated with a significant survival advantage.[43]

Chromosomal aberrations such as deletion (17p) and translocations t(4;14), t(14;16), and t(14;20) are poor prognostic factors in MM and have been associated with poorer outcomes. The combination lenalidomide + dexamethasone can result in durable res-ponses in patients with relapsed t(4;14) disease but provides a limited duration of disease control in patients with del(17p).[44] Existing data suggest that lenalidomide may overcome the negative prognosis associated with del(13q).

Recently an expert panel published a consensus statement on the use of lenalidomide in R/R MM.[37] The panel stated that lenalidomide + dexamethasone is most effective when used at first relapse, a phenomenon unlikely to be specific for any one type of therapy. The optimal starting dosage of lenalidomide is 25 mg orally once daily on days 1 through 21 of each 28-day cycle, but should be modified in patients with renal dysfunction. The use of low-dose dexamethasone in combination with lenalidomide may 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 weekly, but this dose can be modified based on toxicity.[37]

While most studies used lenalidomide in combination with dexamethasone, Richardson et al studied the efficacy and safety of lenalidomide monotherapy in relapsed myeloma.[45] This phase II study enrolled more than 200 patients, among whom two-thirds had experienced three or more prior anti-MM treatment regimens, including prior autologous stem-cell transplants in 45% of the patients. Lenalidomide alone on days 1 through 21 of 28-day cycles induced a PR or better in more than 25% of patients. Myelosuppression was the most common adverse event and was manageable with dose reduction.[45]


Clinical Studies of Lenalidomide in Relapsed Multiple Myeloma

Another multicenter, open-label, randomized phase II study evaluated two dosing regimens of lenalidomide (30 mg once daily or 15 mg twice daily) in relapsed MM.[46] Analysis showed a similar response rate (minor response [MR] or better in 25%) in the two groups, but grade 3/4 myelosuppression was noted more often in patients receiving 15 mg twice daily (80% vs 69%). However, this difference was not statistically significant. Although lenalidomide monotherapy was effective, the addition of dexamethasone in patients in whom lenalidomide either failed to achieve a response after two cycles or who subsequently progressed induced a response in 29% and stable disease in 21%.[46]

Lenalidomide has been combined with a variety of other drugs that were commonly used in myeloma, including anthracyclines and alkylating agents as well as newer drugs like bortezomib (Table 1). In particular, the combination of lenalidomide and bortezomib (VRD) has significant activity in relapsed disease and is well-tolerated. In addition to bortezomib, combinations with doxorubicin or cyclophosphamide have also been shown to be safe and effective with clinically relevant responses. Combinations of lenalidomide with novel agents such as panobinostat, bevacizumab (Avastin), SGN-40, perifosine, vorinostat (Zolinza), dasatinib (Sprycel), NPI-0002, everolimus (Afinitor), and carfilzomib are currently being investigated in phase I and phase II trials. Table 1 provides a summary of the important trials in this setting with lenalidomide.


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