Immunomodulatory Compounds (IMIDS®) in the Treatment of Multiple Myeloma

Th e design of innovative, more eff ective, less toxic therapy of multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Th alidomide has changed the treatment paradigm of patients with MM. Its effi cacy, however, has been compromised by signifi cant side eff ects. IMiDs® (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifi cally designed to create new agents with enhanced immunomodulatory and anticancer properties and better tolerability profi les. In this article, we review the clinical trial development of the second-generation IMiDs®, lenalidomide and pomalidomide. Both agents demonstrate potent activity and are highly eff ective and well tolerated treatment options for patients with MM.


Introduction
Multiple myeloma (MM) is the second most common hematologic malignancy and is invariably fatal (, ).Each year, , new cases of MM are diagnosed, resulting in nearly , deaths annually ().Despite available therapies such as high-dose chemotherapy and autologous stem cell transplantation (ASCT), MM remains an incurable disease with a median survival of  to  years depending on disease stage (), and a -year relative survival rate of approximately  ().Th e role of high-dose chemotherapy and ASCT continues to be controversial, with overall survival (OS) only minimally improved if any (, ).Patients with progressive disease can achieve a - response rate to salvage regimens such as vincristine, doxorubicin, and dexamethasone (VAD) (, ); however, these responses are often short-lived.Th erefore, the need for novel agents and therapeutic modalities in MM remains critical.Th e introduction of the IMiDs®, such as lenalidomide and pomalidomide, for the treatment of various malignancies has gained momentum, especially in the management of MM ().Th e re-discovery of thalidomide not only improved response rates and provided a new class of agents for MM patients, but also instigated a wide range of bench and clinical research activities that enriched the understanding of MM pathophysiology ().

Th alidomide
Th e discovery that thalidomide had anti-angiogenic () and T-cell co-stimulatory () activity led to the clinical investigation of thalidomide for therapy in MM.In relapsed and refractory MM, thalidomide produced response rates of approximately  as a single agent ().In newly diagnosed patients, thalidomide achieved response rates of  alone and - in combination with dexamethasone (, ).As a result, thalidomide in combination with dexamethasone received United States Food and Drug Administration (US FDA) approval for the treatment of newly diagnosed MM in .In addition, recent phase III studies have investigated various thalidomide-containing regimens and reported improvements in quality of response with: thalidomide, adriamycine and dexamethasone compared to VAD (); bortezomib, melphalan, prednisone and thalidomide (VMPT) compared to bortezomib, melphalan and prednisone (VMP) (), melphalan, prednisone and thalidomide (MPT) compared to melphalan and prednisone (MP) (), and bortezomib, thalidomide and dexamethasone (VTD) compared to thalidomide and dexamethasone (TD) ().However, the encouraging eff ects of thalidomide are hampered by toxicity, which often compromises the dose or leads to discontinuation of therapy.Common adverse events include fatigue, somnolence, constipation, fl uid retention, peripheral neuropathy, venous thromboembolism (VTE), and rash (, ).Given the promising activity of thalidomide, synthetic analogs were developed and introduced in an eff ort to provide equal or greater immunomodulation, but a better tolerability profile.Clinical data indicate that the incidence of peripheral neuropathy, which is common with thalidomide, is low with lenalidomide and pomalidomide, (-).

Lenalidomide and pomalidomide
The IMiDs® are a group of unique, orally bioavailable agents that have been refined, using thalidomide as a structural template (Figure ).
Modification of the thalidomide structure through removal of a carbonyl on the ring formed lenalidomide (CC-, Revlimid®), and addition of an amino group at the  position of the phthaloyl ring formed pomalidomide (CC-).These IMiDs® were specifically designed to enhance immunomodulatory and anticancer properties of thalidomide with fewer side effects.Preclinical studies have shown that lenalidomide and pomalidomide are   times more potent, in vitro, than thalidomide at inhibiting tumor necrosis factor alpha (TNF-α) (, ).
Studies have revealed that IMiDs® not only inhibit angiogenesis, but also stimulate T-cell proliferation and induce apoptosis and growth arrest in resistant myeloma cells (Table ) (-).Th ese compounds also prevent the adhesion of myeloma cells to bone marrow stromal cells, and thereby inhibit the enhanced secretion of migratory factors, such as interleukin (IL)-, TNF-α, and vascular endothelial growth factor (VEGF) (-).Lenalidomide has more potent activity than thalidomide in the preclinical setting (, ), and has also demonstrated impressive clinical activity in both newly diagnosed and relapsed or refractory MM (, -).Pomalidomide also demonstrates potent activity against TNF-α in vitro, indicating greater synergy than lenalidomide with rituximab in vivo ().It also promotes T-cell differentiation and cytokine production via the transcription factor T-bet (), and has demonstrated promising activity in clinical trials (, ).
Studies among patients with relapsed or refractory MM have demonstrated that lenalidomide can overcome resistance to prior MM therapy, including thalidomide (-).In addition, time to progression (TTP) and progression-free survival (PFS) are superior when lenalidomide is given at fi rst relapse rather than given later as salvage therapy ().Two phase I trials of lenalidomide have demonstrated promising activity as well as decreased toxicity in heavily pretreated patients with relapsed or refractory MM [, ].In the MM- and MM- studies, grade / hematologic adverse events were more common with With successful responses and better tolerability obtained from early trials, lenalidomide is rapidly being incorporated into front-line regimens.Th e Southwest Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) have ongoing randomized, phase III trials assessing Len+Dex as primary therapy in the front-line setting.The SWOG trial compared Len+Dex to dexamethasone alone in patients with newly diagnosed MM ().In this study,  patients were randomized,  received lenalidomide  mg/ day ( of  days for  induction cycles, then  of  days as maintenance thereafter) plus dexamethasone  mg/day (days -, -, and - as induction, then days -, and - as maintenance) and  received dexamethasone plus placebo.In the  patients who were assessable for response, the ORR was signifi cantly higher (, vs. ,; p=,) and -year PFS was signifi cantly longer ( vs. , p=,) with Len+Dex.Th e -year OS was high and there was no diff erence between arms ( vs. ).Grade / neutropenia (, vs. ,, p=,) and infections (all grades:  vs. ; grade  or higher:  vs. , p=,) were more common with Len+Dex.VTE was reported in  of patients treated with Len+Dex vs.  of patients treated with dexamethasone alone; most patients () who experienced VTE received aspirin as thromboprophylaxis, however it is to be noted that those patients received the full dose of aspirin at  mg daily which his known to be thrombogenic as it inhibits the prostacyclin activ-ity this negating its anti-platelet role (, ).Patients in the dexamethasone arm who progressed were allowed to cross over to the Len+Dex arm.Of  patients who crossed over, the ORR in  who were assessable for response was ,.Th ese data confi rm the superior effi cacy with Len+Dex in newly diagnosed patients.Th e ECOG trial compared lenalidomide plus standarddose dexamethasone (RD) to lenalidomide plus lowdose dexamethasone (Rd), in an attempt to further diminish adverse events while maintaining the response rate.In this study, patients in the RD arm were treated with lenalidomide  mg/day on days - of each day cycle and dexamethasone  mg/day on days -, -, and - of each -day cycle, and patients in the Rd arm received dexamethasone  mg on days , , , and  of each -day cycle ().A total of  patients were randomized,  to RD and  to Rd. Grade  or higher adverse events were more common in the RD arm ( vs. ; p<,), including neutropenia ( vs. ; p=,), VTE ( vs. ; p<,), and infections ( vs. ; p<,).Although response rates during the fi rst  cycles were higher with RD (ORR:  vs. ; p=,; CR + VGPR:  vs. ; p=,), OS was signifi cantly higher in the Rd arm, p=,, (-year OS:  vs. ; -year OS:  vs. ).Th e -year OS rate for the  patients who underwent stem cell transplant () was comparable to the -year OS for patients in the Rd arm who continued primary therapy beyond  cycles ().These data demonstrated superior outcome with lenalidomide plus low-dose dexamethasone in patients with newly diagnosed MM compared to lenalidomide plus high-dose dexamethasone.Th e dose and schedule of dexamethasone will need to be evaluated further in light of the diff erences between the results of the SWOG and ECOG studies.Th ere is probably a group of patients that could benefi t from high dose dexamethasone administered according to the SWOG schedule and for others a lower dose may achieve similar disease outcome with less toxicity and mortality.Baz et al. combined pegylated liposomal doxorubicin, vincristine, and dexamethasone (DVd) regimen with lenalidomide (DVd-R) in a phase I/II study among patients with relapsed or refractory MM ().Th e study objectives were to determine the MTD and evaluate the safety and efficacy of DVd-R.Lenalidomide was administered orally at doses of , , and  mg/day for  days of each -day cycle in cohorts of - patients.Patients were treated for at least  cycles, and a maximum of  cycles after best response.Maintenance therapy included continuation of lenalidomide with the addition of prednisone  mg every other day un-til disease progression.Low-dose aspirin ( mg) was administered as VTE prophylaxis.Sixty-two patients were enrolled in the study ( refractory to prior therapy).The MTD of lenalidomide with DVd chemotherapy was  mg.Th e ORR was  with CR or near CR in .After a median follow-up of . months, the median PFS was  months and the median OS had not been reached.Grade / adverse events included neutropenia (), febrile neutropenia (), peripheral neuropathy (), and VTE ().Th is novel combination appears to be well tolerated, and resulted in a high response rate in a group of patients with MM, most of whome were refractory to prior therapy.
In addition to the ability of lenalidomide to exert an effective anti-tumor activity through direct anti-malignant plasma cell eff ects, it also exerts immune modulatory effects.Lenalidomide stimulates the immune cellular system leading to a benefi cial impact on infectious complications, especially those that rely on the cellular immune system.One of the major viral infections in patients with multiple myeloma is herpes zoster that occurs in  of multiple myeloma patients over the course of the disease.Herpes zoster has high morbidity especially in this age group where post herpetic neuralgia could be crippling to the patients.With lenalidomide based therapy the incidence of herpes zoster is less than  as compared to other regimens that include proteasome inhibitors, where the incidence ranges from -.(, ) Th e clinical activity of pomalidomide was fi rst demonstrated in a phase I study in which  patients with relapsed or refractory MM were treated with pomalidomide as a single agent ().

Conclusion
Th e treatment paradigm for MM has evolved rapidly in recent years, with signifi cant advances in the translation of novel biologically derived therapies from research to clinical application.Studies of lenalidomide and pomalidomide have demonstrated signifi cant clinical benefi ts in patients with MM, along with an improved safety profi le compared to thalidomide.Both IMiDs® are signifi cant additions to the therapeutic armamentarium for MM therapy due to their more potent immunomodulatory properties, as well as their improved tolerability.Further studies of these orally bioavailable IMiDs® in MM patients are warranted, not only in combination with other biologics and chemotherapeutic agents, but with thalidomide as well.
G. Srkalovic has no potential confl ict of interest relevant to this article.M.A. Hussein is employee of Celgene Corporation, manufacturer of IMiDs® Th ese studies established  mg/day as the maximum tolerated dose (MTD) for lenalidomide in relapsed or refractory MM, and provided a firm foundation for continuing trials with lenalidomide, either alone or in combination with other active agents in MM.Two large, randomized, phase III, double-blind, placebocontrolled clinical trials (North American MM- and European MM-) have compared the efficacy and safety of lenalidomide plus dexamethasone (Len+Dex) with placebo plus dexamethasone in patients with relapsed or refractory MM (, ).In both trials, lenalidomide  mg/day or placebo was administered on days - of each -day cycle and oral dexamethasone  mg was administered on days -, -, - of each -day cycle.Th e MM- trial enrolled  patients (Len+Dex n=; placebo+Dex n=) and the MM- trial enrolled  patients (Len+Dex n=; placebo+Dex n=).Th e Len+Dex combination achieved a significantly higher overall response rate (ORR) (MM-:  vs. ; MM-:  vs. ; both p<,) and complete response (CR) rate (MM-: , vs. ,; MM-: , vs. ,; both p<,), (Figure ).The median TTP was significantly prolonged by the addition of lenalidomide to dexamethasone (MM-: , months vs. , months; MM-: , months vs. , months; both p<,), (Figure ) and the median OS was significantly longer in the Len+Dex arm (MM-: , months vs. , months; p<,; MM-: not reached vs. ,; p=,).
Len+Dex and included neutropenia(, and ,  vs. , and ,, respectively), anemia(, and  , vs. , and ,), thrombocytopenia(, and  , vs. , and ,), and febrile neutropenia (, vs. ).Other common grade / adverse events included infection(, and , vs. , and ,,  respectively), and fatigue(, and , vs. , and  ,).Th e incidence of VTE in the MM- and MM- studies was higher in the Len+Dex arm (, and , vs. , and ,, respectively); however, it was comparable to the incidence of  observed for the general MM population in retrospective analyses().On the basis of these studies, lenalidomide was approved by the US FDA in June  and by the European Medicines Agency in June  for use in combination with dexamethasone in the treatment of MM in patients who have received at least one prior therapy.Due to encouraging results in the relapsed or refractory setting, a phase II trial was undertaken to assess the efficacy and safety of the Len+Dex combination therapy in the front-line setting().In this phase II trial, lenalidomide ( mg/day orally on days - of each -day cycle) was combined with dexamethasone ( mg/day orally on days -, -, and - of each -day cycle) in  newly diagnosed, previously untreated MM patients.The ORR was , with CR in  and very good partial response (VGPR) and near CR in .Grade  or greater non-hematologic adverse events were reported in  of patients and included fatigue (), muscle weakness (), anxiety (), pneumonitis (), and rash ().Myelosuppression was minimal, most likely refl ecting the preserved bone marrow reserve in this group of previously untreated patients.All patients were placed on low dose aspirin prophylaxis, based on the effi cacy of low dose aspirin in preventing VTE among patients treated on the thalidomide plus dexamethasone regimen(), and only one patient developed a VTE.In addition, Len+Dex combination therapy appeared to be a useful pre-transplant conditioning regimen, as there was no adverse eff ect on stem cell mobilization among these patients.
Objective responses were also reported  of  patients () who were refractory to lenalidomide.Grade  hematologic adverse events included neutropenia (), thrombocytopenia (), and anemia ().There was no grade  neuropathy, but grade - neuropathy was reported in  of patients.Due to the incidence of VTE in the phase I study, all patients received aspirin as thromboprophylaxis and there were no cases of VTE.Pomalidomide appears to be another promising agent with a role for further studies as an immunostimulatory modality of treatment among patients with relapsed or refractory MM.