A new generation of proteasome inhibitors, immunomodulatory agents, and deacetylase inhibitors are currently being investigated in clinical trials to treat patients with relapsed or refractory multiple myeloma.
Illustration depicts the malignant plasma cells that develop in multiple myeloma. The American Cancer Society estimates about 21,700 new cases will be diagnosed in 2012.
Treatment of multiple myeloma (MM) remains highly individualized, with multiple factors that play a role in determining the best course of therapy. Patient-specific criteria such as age of onset, whether the patient is symptomatic at the time of diagnosis, and any detected high-risk cytogenic abnormalities are all considerations when selecting a regimen. Newer agents such as bortezomib and lenalidomide in combination with lowdose steroids have replaced more toxic chemotherapeutic regimens for primary induction and have led to significant increases in progression-free survival. Depending on duration of response prior to relapse, patients may be rechallenged with the same regimen, switched to an alternative, or may undergo hematopoietic cell transplant (HCT), which remains a highly effective treatment option for patients who are candidates. However, the cost of transplantation remains high, and some patients may require a second transplantation if the initial response is incomplete. With the availability of newer agents for salvage therapies in refractory or relapsed patients, the reliance on HCT may decrease, potentially lowering healthcare costs. In addition, the availability of orally active agents may decrease the need for outpatient infusions, thus decreasing the overall costs associated with treatment and improving patient satisfaction. Finally, combination regimens that use lower doses may prove to be less toxic, as well as more effective. Even though MM only accounts for approximately 1% of all cancers in the United States, with 75 million “baby boomers” now reaching the median age of diagnosis, the increased number of cases could have a substantial impact on healthcare costs.
Although MM is a fairly uncommon cancer, it is the most commonly occurring blood cancer.1 The American Cancer Society estimates that in 2012, approximately 21,700 new cases will be diagnosed and approximately 10,710 deaths will occur as a result of MM.2 Patients with MM may present with bone pain (especially in the back), fatigue often caused by anemia, pathologic fracture, weight loss, and/or paresthesias. Some patients have no symptoms at the time of diagnosis.3 MM occurs when vast amounts of abnormal plasma cells are found in bone marrow. Additionally, there is an overproduction of IgG, IgA, IgD, IgE, or monoclonal light chains known as Bence-Jones proteins.4 Treatment of MM is complex. Patients with stage II or III MM who are considered to have good performance status are candidates for stem cell transplantation. Induction therapy with dexamethasone monotherapy or a combination of dexamethasone and thalidomide before stem cell harvesting is an option for patients; however, high-dose chemotherapy with vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine, doxorubicin, and prednisone along with bone marrow transplant has been associated with increased survival in patients. Patients who are not stem cell candidates may be treated with thalidomide, melphalan, and prednisone. Patients who are not responding or who relapse with this regimen may be treated with vincristine, doxorubicin, and dexamethasone. 5 Refractory or relapsing MM is common. Currently, regimens available for these patients contain thalidomide, lenalidomide, or bortezomib. On the horizon to treat patients with relapsed or refractory myeloma are a new generation of proteasome inhibitors, immunomodulatory agents, and deacetylase inhibitors, which are currently being investigated in clinical trials.
Despite MM being an incurable disease, immunomodulatory drugs (IMiDs) have demonstrated effectiveness in the treatment of MM. IMiDs have been investigated for both first-line and maintenance therapies.6 Thalidomide was the first drug in this class and subsequently lenalidomide was approved by the FDA.6 Pomalidomide is the newest IMiD under investigation and several phase I and II trials have been completed. While the drug is a chemical analogue of thalidomide, it appears to have a much greater potency in stimulating the proliferation of T-cells as well as increasing natural killer cell activity.6 Additionally, the drug works through inhibition of blood cell growth and modulates the levels of inflammatory and regulatory cytokines. IMiDs have also been shown to directly induce apoptosis in plasma cells.6 Phase I, II, and III clinical trials are currently under way to evaluate the drug in combination with dexamethasone, as well as in combination with bortezomib, doxorubicin, and cyclophosphamide.7
Proteasomes serve as valuable chemotherapeutic targets due to the integral role they play in protein homeostasis, degradation of cytotoxic proteins, and clearance of misfolded and/or unfolded proteins.8 Key proteins regulated by proteasomes that are involved in cell-cycle progression and apoptosis include cyclins, caspases, B-cell lymphoma 2 (BCL2), and NF-B activation.8 It is believed that malignant cells are more dependent on this cellular housekeeping, and this is supported by several studies indicating that cancer cells are more susceptible to proteasome inhibition. 8 In 2003, bortezomib became the first drug in this class to be approved by the FDA for initial MM treatment and relapsed/refractory MM; however, drug resistance and dose-limiting toxicities such as peripheral neuropathy remain a concern with bortezomib treatment.9,10
Carfilzomib, an epoxyketone, is a structural analogue of the natural microbial product epoxomycin-3.11 This novel proteasome inhibitor has a structure and mechanism different from bortezomib.11 Carfilzomib differs by being an irreversible inhibitor, as opposed to the reversible inhibition seen with bortezomib, which gives carfilzomib a longer duration of inhibition.11 It also appears to be more specific in its affinity for chymotrypsin-like protease, with lesser activity seen for the trypsin and caspase-like proteases in the 26S proteasome.11 In July, the FDA approved carfilzomib for relapsed MM. It also is being evaluated in phase III clinical trials with lenalidomide and low-dose dexamethasone in patients with relapsed MM.12
MLN9708 is an orally active, reversible proteasome inhibitor chemically distinct from bortezomib that is currently in multiple phase I and II clinical trials.13 In vitro and in vivo studies revealed MLN9708 had an improved volume of distribution, greater inhibition of the proteasome, and thus a greater antitumor effect than bortezomib.13 It works by increasing the number of ubiquinated proteins selected for destruction, leading to cell cycle disruption and the activation of apoptotic pathways. MLN9708 caused cell death in both a time-dependent and dose-dependent fashion, and the drug increased survival with continuous or intermittent administration. Further studies are needed to assess its place in therapeutic regimens, but currently recruiting phase I and II studies are evaluating MLN9708 with lenalidomide and dexamethasone, melphalan, and prednisone, and in patients who have relapsed with bortezomib treatment.14
Marizomib is an orally active, novel, irreversible proteasome inhibitor that is also distinct from bortezomib. In preclinical trials, marizomib demonstrated a synergistic cytotoxic effect when used in combination with IMiDs such as lenalidomide. Toxicity has been a concern with bortezomib therapy; however, lower doses of IMiDs and marizomib used together in studies revealed minimal toxic effects. Marizomib has shown that it can trigger cell death in MM cells in the presence of bortezomib resistance.10 Phase I marizomib studies are ongoing and include patients with relapsed or refractory MM.15
CEP-18770 is a reversible proteasome inhibitor with the potential to be administered orally, but was also dosed via the intravenous route during studies. Preclinical trials have been done with the drug when used as monotherapy, as well as in combination with bortezomib and melphalan. Synergy was demonstrated in studies with the combination regimens. Investigators were able to show that sensitization of previously resistant tumors was induced by co-administration of CEP-18770. CEP-18770 studies have established a good safety profile, with 10-fold greater than therapeutic concentrations showing little or no effect on normal human epithelial cells, bone marrow progenitors, bone marrow-derived stromal cells, and PBMCs.16 CEP-18770 has two studies on clinicaltrials.gov enrolling at the time of this article, with one study involving combination treatment with dexamethasone and lenalidomide and the other to further investigate maximum tolerated dose (MTD) as well as safety and efficacy in relapsed MM refractory to the most recent therapy.17
This slide depicts an IgA k monoclonal protein characteristic of multiple myeloma that was revealed through immunofixation.
Deacetylase (DAC) inhibitors, previously referred to as histone deacetylase inhibitors, demonstrate much farther reaching effects than histone deacetylation (HDAC) alone.8 There are four classes of DAC enzymes that have been classified, with 18 specific enzymes that were identified in humans.8 Class I DAC enzymes are found locally within the nucleus of the cell, whereas class II can be found in multiple locations, including the nucleus and cytoplasm.8 Preclinical studies using several DAC inhibitors in both in vitro and in vivo mouse xenograft models have demonstrated inhibition of cell proliferation and induction of apoptosis of MM cells.8 However, phase I trials have shown limited viability of the class to be useful in single-agent treatment of MM.8
Romidepsin is a cyclic tetrapeptide FDA-approved for the treatment of T-cell lymphoma.8,18 Previously, it was thought to affect only class I DAC enzymes, but at higher concentrations it inhibits activity of the class II enzymes as well.18 Early preclinical trials have demonstrated romidepsin’s efficacy against a variety of MM cell lines. An investigation has now been completed using romidepsin in combination with dexamethasone and bortezomib.18 Results from this small study indicate that the combination had sustained results, with a median time to progression of 7.2 months, and three patients who exceeded 20 months. While the groundbreaking APEX bortezomib trial had a median survival of 29.8 months, at the time of the publication the cohort had a median survival of greater than 36 months, with the one-year survival in a heavily pretreated group being 76%.18 Enrollment is currently being sought for a phase I/II clinical trial involving bortezomib and romidepsin in patients with relapsed myeloma.19
Panobinostat is a novel, hydroxamic acid—based DAC inhibitor that exhibits broad inhibitory activity. It has shown activity toward class I, II, and IV HDAC and is perhaps the most potent inhibitor identified to date.8 Benefits have been seen in patients with refractory hematologic malignancies, and currently, a phase III clinical trial is under way to evaluate panobinostat in combination with bortezomib and dexamethasone in relapsed MM patients.20,21 Additional phase I and II trials are also under way, including combinations with immunomodulators and other proteasome inhibitors.21
Mechanism of Action
Recombinant fusion protein
Merck Serona SA
(The Merck Group)
Kyowa Hakko Kirin Pharma
Millennium Pharmaceuticals (Takeda Pharmaceuticals)
Janssen Pharmaceuticals, Inc (Johnson & Johnson)
DNA alkylating agent
Merck & Co
aCarfilzomib (Krypolis) is approved for multiple myeloma that has progressed after prior therapy.
bRomidepsin (Istodax) is approved for cutaneous and peripheral T-cell lymphoma after prior therapy.
cVorinostat (Zolinza) is approved for cutaneous T-cell lymphoma progressive or recurrent after prior therapy.
Vorinostat is a DAC inhibitor that is FDA-approved for certain lymphomas and has a broad spectrum of activity toward class I, II, and IV HDACs.8 The drug works by decreasing the rate of myeloma cell proliferation and induces apoptosis by increasing the production of proteins involved in those processes. However, results from a large phase III clinical trial and a phase IIB trial demonstrated disappointing results, raising doubts whether vorinostat will get FDA approval for MM indications.22
Monoclonal antibodies (mAbs) have demonstrated favorable results in a variety of cancers (eg, trastuzumab in breast cancer, bevacizumab in renal cell carcinoma, and cetuximab in squamous cell carcinoma).23 While the mechanism of action of the mAbs has not been fully elucidated, they have been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and directly cause cell death through signal transduction.23
Siltuximab is a chimeric human-mouse mAb that works by neutralizing interleukin-6 (IL-6). IL-6 is secreted predominantly by bone marrow stromal cells (BMSCs), which activate a series of survival and proliferative pathways in myeloma cells.23,24 Patients who have high serum levels of IL-6 have been shown to have a poor prognosis. Within the microenvironment of the bone marrow, MM cells attach to BMSCs, and the adhesion stimulates the secretion of IL-6 and other pro-survival cytokines.23,24 In preclinical trials, siltuximab has demonstrated positive results when tested together with bortezomib, dexamethasone, and melphalan.23 However, a phase III trial evaluating siltuximab with bortezomib and dexamethasone was withdrawn from ClinicalTrials.gov before recruitment began.25
Elotuzumab is a humanized mAb targeted against the cell surface glycoprotein CS1, which is highly expressed on MM cell lines, including over 97% of the cells of patients with MM. The primary mechanism of action of elotuzumab is through NK cell-mediated ADCC. Studies have also indicated that elotuzumab works by blocking myeloma cell binding to BMSCs, which is believed to diminish the stimulatory effects on the growth and survival of MM cells. Results from a phase I trial that evaluated the combination of elotuzumab and bortezomib suggest that the combination warrants further investigation due to the positive results demonstrated in the study, and a phase II trial is planned. Currently, a phase III clinical trial (ELOQUENT-2) is under way to assess the combination of elotuzumab with lenalidomide and dexamethasone in patients with relapsed MM.26
Dacetuzumab is a humanized mAb that is targeted against the CD-40 receptor, which has been noted to be overexpressed on MM cells, as well as BMSCs.23,27 Dacetuzumab works through multiple mechanisms of action, including the induction of cell death through direct signal transduction, as well as antibody-dependent cellular cytotoxicity and phagocytosis.27 Results of phase I trials suggest that, while the drug is relatively safe and well tolerated, its role as monotherapy has only shown modest promise. In vitro trials demonstrated a synergistic effect with lenalidomide that perhaps will lead to better response rates.27
Atacicept is a unique fusion protein consisting of both the extracellular ligand-binding portion of the transmembrane activator and CAML interactor (TACI) receptor and the Fc portion of human IgG. The drug acts by neutralizing two key proteins of the tumor necrosis factor (TNF) ligand family that are vital for the growth and development of B cells. Interaction of atacicept with the target receptors has antiproliferative effects and leads to apoptosis of myeloma cells. Primary receptor targets are B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL). Both of these receptors produced in significant amounts in the microenvironment of the bone marrow and myeloma cells abnormally express BLyS and APRIL mRNA. TACI and B-cell maturation antigen (BCMA), which are found on most myeloma cell lines, are receptors shared by both BLyS and APRIL. In preclinical trials, subcutaneous atacicept was well tolerated and found to be relatively safe. However, due to the suppression of polyclonal B cells, infection remains a possible serious adverse effect despite the lack of occurrence during the initial trial. Currently, there are no clinical trials under way; however, the drug remains a target of interest.28
Increased plasma cells in marrow are visible amid normal hematopoietic elements in relapsed multiple myeloma.
Perifosine belongs to a new class of antineoplastic agents that work through Akt inhibition in the PI3K pathway. The drug is a synthetically derived alkylphospholipid that is currently in phase I clinical trials. It has been found to be orally active and works at the cell membrane of MM cells to trigger apoptosis. Apoptotic pathways initiated by perifosine are believed to be facilitated by caspase-8, caspase-9, poly (ADP-ribose) polymerase (PARP) cleavage. In studies, it has been shown to enhance inhibition of cell growth and cytotoxicity in combination models, including the mainstay of treatment with dexamethasone, as well as doxorubicin, melphalan, and bortezomib. Two key mechanisms of drug resistance that limit effectiveness of dexamethasone are the upregulation of IL-6 and IGF-1. However, in vitro studies using these exogenous cytokines were unable to diminish the cytotoxic effect of perifosine. Additionally, the protective effect seen with the attachment of myeloma cells to BMSCs was not demonstrated with perifosine exposure. Combined with in vivo studies using mouse models showing inhibitory cell growth and prolonged survival, the drug shows great promise both as monotherapy and in combination with other agents.29 Currently, phase I trials are seeking enrollment to evaluate perifosine in combination with dexamethasone and bortezomib, and another trial will investigate perifosine used in combination with dexamethasone and lenalidomide.30
Heat shock protein 90 (Hsp90) has long been recognized as a molecular target for drug development, but has only recently aroused significant clinical and pharmaceutical interest.31 Hsp90 is an ATP-dependent chaperone protein that plays an important role in the promotion of proliferation, as well as malignant cell survival. 32 Through activation, stabilization, and assistance in the correct conformation of client proteins, Hsp90 plays a key role in oncogenesis.33 Inhibition of Hsp90 causes the breakdown of its client proteins through the ubiquitin-proteasome pathway.33 Earlier studies of HSP inhibitors demonstrated only modest therapeutic effects as single agents.31 Liver toxicity was noted as a limitation of the early molecules studied, as well as suboptimal degradation of client proteins, possibly due to suboptimal dosing or schedules. Additionally, a resistance mechanism was observed with tanespimycin mediated through P-glycoprotein efflux.31
Recent in vitro and in vivo studies utilizing AUY922, a novel Hsp90 inhibitor, in combination with panobinostat, vorinostat, melphalan, or doxorubicin showed primarily synergistic effects.32 Of particular note was the ability of the investigators to show that the best result was seen when the drug was continued for another 48 hours after 24 hours of the combination regimens.32 While resistance was seen in one MM cell line and several primary cell samples from patients when AUY922 was used only as monotherapy, the remarkable results of the combination regimens pave the way for future studies However, a phase I/II study of AUY922 alone and in combination with bortezomib with or without dexamethasone was recently terminated.
KW-2478 is also an Hsp90 inhibitor that has been identified as a viable therapeutic moiety and has been studied to further characterize its properties and place as a suitable therapeutic agent. In animal studies using the drug, there were no identified cases of hepatotoxicity, as seen with other structural analogues.31,33 Additionally, the drug had a favorable pharmacokinetic profile, was found to be soluble in saline, and showed no metabolism through the CYP3A4 pathway.33 Additional studies are under way in human subjects, with KW-2478 being used in combination with bortezomib.34
TH-302 is a modified prodrug derived from ifosfamide and belongs to the alkylating agent drug class.35 MM cells can be found together in extreme oxygen-deprived environments in the bone marrow. Hypoxic environments are seldom found in healthy tissues, making them a viable target for tumor-specific therapy. TH- 302 potency was enhanced 10-fold through chemical modification and is uniquely activated under hypoxic conditions. It causes G0/G1 cell-cycle arrest by downregulating cyclinD 1/2/3, CDK 4/6, p21clp-1, p27klp-1, and pRb expression in in vitro studies.35 This translates into the apoptosis of MM cells by upregulating the cleaved proapoptotic caspase-3, -8, -9, and poly ADPribose polymerase while having no significant effects under normal oxygen conditions. Further studies in mice models demonstrated apoptosis within the bone marrow microenvironment, including other markers of activity such as decreases in paraprotein secretion and decreases in microvesical density. Preclinical trials examined TH-302 monotherapy and in combination with gemcitabine, pemetrexed, doxorubicin, and docetaxel. As monotherapy, TH-302 has demonstrated dose-dependent effects and low toxicity under normal oxygen conditions, warranting further study in human trials.35
While MM has remained an incurable disease, new therapeutic agents have provided viable treatment options with encouraging results despite the fact that all patients relapse at some point. Research and development surrounding MM targets remain very active, with a number of drugs under evaluation for the treatment of MM.
However, only a few of these drugs are currently in phase III trials, and results of some recent trials have been disappointing. The most promising agents emerging include the so-called second generation proteasome inhibitors, with some that are orally active and have better pharmacokinetic profiles, more potent therapeutic effects, and the ability to overcome resistance. Additional treatment options that may become available as they are undergoing phase III trials are a more potent IMiD (pomalidomide),7 a new mAb that is directed at cell surface glycoprotein CS1 (elotuzumab),26 and an orally administered Akt inhibitor (perifosine).30 Other therapeutic agents are in the earlier stages of development, but a large percentage of studies have demonstrated that further trials are warranted. Despite these new agents on the horizon, MM needs to remain a target for new drug development to help overcome the high relapse rates and refractory disease associated with this cancer.
Our Lady of the Lake Regional Medical Center (MMM), Baton Rouge, LA; and University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus (BLM), Baton Rouge, LA.
Funding Source: None.
Author Disclosures: Dr M. M. Mohundro reports receiving payment for involvement in the preparation of this manuscript. Dr B. L. Mohundro reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Concept and design (BLM); acquisition of data (BLM); analysis and interpretation of data (MMM, BLM); drafting of the manuscript (MMM, BLM); and critical revision of the manuscript for important intellectual content (MMM, BLM).