Targeting Multiple Myeloma

Oral Proteasome Inhibitor to Be Studied in Phase III Trials

MLN9708 (ixazomib), the first oral proteasome inhibitor for multiple myeloma (MM), will be studied as a component of the first all-oral triplet regimen that includes both a proteasome inhibitor and an immunomodulatory drug (IMiD). The phase III TOURMALINE- MM2 study will investigate weekly MLN9708 in combination with lenalidomide and dexamethasone for patients with newly diagnosed MM who are not candidates for transplant.¹

Two other clinical trials with MLN9708 are being launched in the approximately same time frame. TOURMALINE-MM1 is investigating MLN9708 in combination with lenalidomide and dexamethasone in patients with relapsed/refractory MM. TOURMALINE- AL1 will assess MLN9708 plus dexamethasone in patients with relapsed/ refractory light-chain amyloidosis (AL).¹

At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Shaji Kumar, MD, professor of Medicine at the Mayo Clinic, Rochester, Minnesota, presented results from a phase I study to determine the maximum tolerated dose (MTD) of once-weekly MLN9708 given as a single agent in patients with relapsed/ refractory MM.²The study enrolled 60 patients, including 32 patients in the phase I portion and 31 patients in a dose-expansion cohort of the study.

The MTD of MLN9708 was established at 2.97 mg/m²on a once-weekly dosing schedule. Of three patients who experienced dose-limiting toxicities, two were receiving the highest tested dosage of 3.95 mg/m²and one was in the 2.97-mg/m²dosage group. Two patients suffered grade 3 nausea, vomiting, and diarrhea, and one patient experienced grade 3 skin rash. (All three patients continued on the study at a lower drug dosage.) These data suggested to the investigators that weekly oral MLN9708 is generally well tolerated, with infrequent peripheral neuropathy, and that it sufficiently demonstrated activity in the study’s heavily pretreated population with prior exposure to IMiDs and bortezomib.²

In addition, in preclinical studies, MLN9708 was shown to have a shorter proteasome dissociation half-life and to offer improved pharmacokinetics, pharmacodynamics, and antitumor activity when compared with bortezomib.³

Kumar, commenting on these findings at ASCO 2013, noted that in contrast with evidence from investigational studies with bortezomib, the side-effect profile of peripheral neuropathy was “not that obvious.” Overall, he said, “20% of patients developed peripheral neuropathy; nearly onehalf had grade I peripheral neuropathy or had grade II, which worsened from preexisting pain from peripheral neuropathy.”

The fact that MLN9708 is active in this heavily pretreated patient population, said Kumar, is an encouraging sign. Among enrolled patients, the median time from diagnosis was about five years, and the median number of therapies patients had been exposed to was four. Some patients had received as many as 13 different lines of therapy.

Identifying New Targets

Given these promising results, the outcomes from the three phase III studies will be eagerly awaited. “Overall, said Kumar, “what I think we can take away from this study is that this drug is certainly active in patients with relapsed/refractory disease and it also seems to work in patients who have previously been exposed to other proteasome inhibitors, including bortezomib and carfilzomib.”Researchers have recently identified several new potential targets for MM therapy, of which the following are three encouraging options for development:

• Researchers at the National Cancer Institute (NCI) discovered that all myeloma lines, regardless of subtype or genetic abnormality, require the caspase-10 enzyme for survival. This effect of caspase-10 occurs through blockage of an autophagy-dependent cell death pathway. The unexpected identification of the central role of caspase-10 emerged during a loss-offunction RNA interference screen that the researchers conducted to identify therapeutic targets in MM. Caspase-10 restricts autophagy by cleaving the BCL2-interacting protein BCLAF1, which is itself a strong inducer of autophagy, acting by displacing beclin-1 from BCL1, described by Lamy et al⁴in the April 2013 issue of the journalCancer Cell. The determination that caspase-10 modulates the autophagic response to avoid cell death in all subtypes of myeloma may provide a template for development of new drugs with potential efficacy across all MM subtypes.
• A glycolytic enzyme, pyruvate dehydrogenase kinase-1 (PDK1), is a novel therapeutic target in MM, according to a group of researchers in Japan who examined whether the Warburg Effect applied in MM as it does in other forms of cancer, and determined that it does indeed. The Warburg Effect describes the observation by Nobel laureate Otto Heinrich Warburg in the 1920s that cancer cells utilize the glycolytic pathway even when enough oxygen is present to properly respire. Cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen. Targeting glycolysis, especially via PDK1 inhibition, could serve as an effective therapeutic strategy, these researchers proposed, especially for patients with high serum levels of lactate dehydrogenase (LDH), an adverse prognostic factor in MM.⁵
• In their study, after purifying MM cells from 59 patients using CD 138-immunomagnetic beads, Fujiwara and colleagues5 determined by real-time PCR the expression level of genes that are associated with glycolysis, namelyc-MYC,GLUT1,LDHA,HIF1A, andPDK1. High LDHA expression, an indicator of poorer prognosis, was also positively correlated with expression ofPDK1,c- MYC, andGLUT1. Glycolysis inhibitors, including PDK1, induced apoptosis in MM cells.
• Investigators at Dana-Farber Cancer Institute in Boston, Massachusetts, reasoning that interactions between MM cells and the bone marrow microenvironment may play a role in the development of drug resistance by MM cells, sought to examine adhesion dynamics that involve P-selectin glycoprotein ligand (PSGL-1) and its interaction with selectins in the bone marrow. In detailed in vitro and in vivo studies, Azab et al⁶succeeded in demonstrating the important contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in the MM bone marrow microenvironment.
• The researchers also demonstrated thatPSGL-1gene expression increases with disease progression from monoclonal gammopathy of undetermined significance (MGUS) to advanced MM. In this role,PSGL-1may be a logical target for treatment of resistant and advanced cases of MM, the investigators and others suggest.^6,7
• Carfilzomib, a second-generation proteasome inhibitor, was granted accelerated approval in 2012 (bortezomib was the first in this class). Several other second-generation proteasome inhibitors are now under investigation in addition to MLN9708. New proteasome inhibitors such as marizomib, oprozomib, and delanzomib aim for a better therapeutic ratio, broader anticancer activities, and the ability to overcome inherent and acquired bortezomib resistance.^8,9

Pomalidomide for Relapsed/ Refractory MM

On February 8, 2013, the FDA granted accelerated approval for pomalidomide (Pomalyst) for the treatment of patients with MM who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease progressed within 60 days of completion of the last therapy. Pomalidomide is a IMiD and an angiogenesis inhibitor. It is in the same family of drugs as thalidomide and lenalidomide.

This action reflected a conviction within the myeloma community, expressed by Meletios Dimopoulos, MD, lead investigator in the MM-003 pomalidomide trial, that pomalidomide plus low-dose dexamethasone “should become the standard of care for patients with relapsed and refractory multiple myeloma after treatment with lenalidomide and bortezomib,” based on strongly positive data from the phase III study. Results of the MM-003 study were first reported at the December 2012 American Society of Hematology (ASH) Annual Meeting10 and updated at the 2013 ASCO Annual Meeting.¹¹

The MM-003 study enrolled 455 patients with relapsed or refractory MM. Eligible patients were refractory to their last prior therapy, had progressive disease during therapy or within 60 days after, and had failed lenalidomide and bortezomib after two or more cycles of each therapy given alone or in combination. Patients were randomized 2:1 to a combination of pomalidomide plus low-dose dexamethasone (n = 302) or high-dose dexamethasone (n = 153).

At a median follow-up of 18 weeks, progression-free survival (PFS) was significantly longer with pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone (15.7 weeks vs 8 weeks, respectively; hazard ratio [HR] = 0.45; P <.001). Overall survival (OS) at a planned interim analysis was also significantly longer with the pomalidomide/low-dose dexamethasone combination (median was not reached vs 34 weeks; HR = 0.53; P <.001).

Updated results from this international trial were presented at ASCO 2013 by Katja C. Weisel, MD, associate professor at University Hospital Tüebingen, Tüebingen, Germany.¹¹At a median follow-up of 10 months, PFS and OS continued to favor treatment with pomalidomide plus low-dose dexamethasone (median PFS, 4 months vs 1.9 months; HR = 0.48; P <.001; median OS, 12.7 months vs 8.1 months; HR = 0.74; P =.028).

The investigator-assessed overall response rate (ORR) for patients in the pomalidomide-plus-low-dose-dexamethasone arm was significantly improved, at 31% versus 10% in the highdose dexamethasone arm (P <.001), and 24% versus 3% for patients who were randomized 6 months or more after enrollment (P <.001).

At 48%, neutropenia was the most frequent grade 3/4 adverse event for the combination of pomalidomide plus low-dose dexamethasone, but there were very few febrile complications, Weisel said.

David Siegel, MD, PhD

Early Stage Data for Daratumumab

Speaking about the potential of pomalidomide, David Siegel, MD, PhD, from John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, and an investigator for pomalidomide, said that the drug&rsquo;s potent activity &ldquo;&hellip;means that it can overcome resistance to other immunomodulatory agents,&rdquo; and thus offers a treatment option for patients who no longer respond to thalidomide and lenalidomide.The performance of the investigational CD38 monoclonal antibody (mAb) daratumumab was unprecedented for a single agent in patients with relapsed/ refractory MM in a phase I/II dose-escalation study reported at ASCO 2013 by Henk Lokhorst, MD, PhD, University Medical Center Utrecht, Utrecht, The Netherlands.¹²

In early May, the FDA granted Breakthrough Therapy designation for daratumumab for the treatment of patients with MM who have received at least three prior lines of therapy, including a proteasome inhibitor and an IMiD, or for patients who are double-refractory to both classes of drugs.

The international group of researchers reported finalized part 1 and preliminary safety data from an ongoing part 2 of a study enrolling patients aged 18 years and older with MM that was relapsed or refractory to at least two prior lines of therapy. Patients must also have been ineligible for transplant.

At dosages &ge;4 mg/kg (n = 12), daratumumab induced a marked reduction in paraprotein and bone marrow plasma cells in the group of heavily pretreated patients. In patients receiving the &ge;4- mg/kg dosage, five partial responses and three minimal responses were observed. Seven of 12 patients had a 50% to 100% concomitant reduction in bone marrow plasma cells.

In remarks to the meeting audience, Lokhorst noted that, &ldquo;Most paraprotein reductions were seen in the high-dosage groups, but even in patients with very low doses of daratumumab, stable or mild responses were observed.&rdquo; Overall, 47% of patients who were heavily pretreated had a reduction in paraprotein. Median PFS in the &ge;4- mg/kg dosage groups was not reached by a data cut-off of 3.8 months.¹²

Updated Phase I and II Results for Elotuzumab

The future of daratumumab may not be as a single-agent treatment. Because of a synergy between MAbs and chemotherapy, it will most likely be a component of this form of combination. &ldquo;In vitro studies have shown that if we combine lenalidomide with daratumumab, we get enormous killing of myeloma cells,&rdquo; said Lokhorst.The combination of humanized anti- CS1 mAb elotuzumab plus lenalidomide/ dexamethasone (Len/dex) resulted in a high ORR and encouraging PFS in patients with relapsed/refractory MM, and was generally well tolerated, according to an update of phase II and phase I/II long-term safety results reported by investigator Sagar Lonial, MD, from Emory University in Atlanta, Georgia.¹³

The study included a dose-finding phase I cohort (N = 28) and a phase II cohort (N = 73). The ORR in the phase II cohort (median age, 63 years) was 84%, 92% with 10 mg/kg (n = 36), and 76% with 20 mg/kg (n = 37). At a median follow-up of 20.8 months, median PFS was not reached for the 10-mg/kg group (18.6 months with 20 mg/kg).¹³

References

A phase III study will assess whether the addition of elotuzumab to lenalidomide and low-dose dexamethasone will enhance PFS among patients with newly diagnosed, previously untreated MM.

1. Millennium: The Takeda Oncology Company. Newsroom. Available at: http://www.takeda. com. Accessed July 15, 2013.
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3. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer.Cancer Res. 2010;70(5):1970-1980.
4. Lamy L, Ngo VN, Emre NC, et al. Control of autophagic cell death by caspase-10 in multiple myeloma.Cancer Cell. 2013;23(4):435-449.
5. Fujiwara S, Kawano Y, Yuki H, et al. PDK1 inhibition is a novel therapeutic target in multiple myeloma.Br J Cancer. 2013;108(1):170-178.
6. Azab AK, Quang P, Azab F, et al. P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment.Blood. 2012;119(6):1468- 1478.
7. Haznedar R. A new target for myeloma therapy.Blood. 2012;119(6):1325-1326.
8. McBride A, Ryan PY. Proteasome inhibitors in the treatment of multiple myeloma.Expert Rev Anticancer Ther. 2013;13(3):339-358.
9. Potts C, Albitar X, Anderson C, et al. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.Curr Cancer Drug Targets. 2011;11(3):254-284.
10. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone demonstrates a significant progression-free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study.Blood. 2012;120:abstr LBA6.
11. San-Miguel JF, Weisel KC, Moreau P, et al. MM-003: A phase III, multicenter, randomized, open-label study of pomalidomode (POM) plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/ refractory multiple myeloma (RRMM).J Clin Oncol. 2013;31(suppl; abstr 8510).
12. Lokhorst HM, Plesner T, Gimsing P, et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma.J Clin Oncol. 2013;31(suppl; abstr 8512).
13. Lonial S, Jagannath S, Moreau P, et al. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): updated Ph II results and Ph I/II longterm safety.J Clin Oncol. 2013;31(suppl; abstr 8542).