		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.

 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.

 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.

 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.

 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.

 Thalidomide was the first drug in this class and subsequently lenalidomide was approved by the FDA.

 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.

 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.

 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.

	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.

 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.

 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. 

 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.

	Carfilzomib, an epoxyketone, is a structural analogue of the natural microbial product epoxomycin-3.

 This novel proteasome inhibitor has a structure and mechanism different from bortezomib.

 Carfilzomib differs by being an irreversible inhibitor, as opposed to the reversible inhibition seen with bortezomib, which gives carfilzomib a longer duration of inhibition.

 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.

 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.

	MLN9708 is an orally active, reversible proteasome inhibitor chemically distinct from bortezomib that is currently in multiple phase I and II clinical trials.

 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.

 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.

	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.

 Phase I marizomib studies are ongoing and include patients with relapsed or refractory MM.

	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.

 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.

		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.

 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.

 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.

 However, phase I trials have shown limited viability of the class to be useful in single-agent treatment of MM.

	Romidepsin is a cyclic tetrapeptide FDA-approved for the treatment of T-cell lymphoma.

 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.

 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.

 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.

	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.

 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.

 Additional phase I and II trials are also under way, including combinations with immunomodulators and other proteasome inhibitors.

					Millennium Pharmaceuticals (Takeda Pharmaceuticals)

					Janssen Pharmaceuticals, Inc (Johnson & Johnson)

Articles

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.

Michael Marlan Mohundro, PharmD

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On the Horizon for Multiple Myeloma: Update on Novel Agents, Bone Therapies