Myeloma Drug Arsenal Expanding to New Classes

February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology - Multiple Myeloma
Caroline Helwick

New Orleans, LA—Emerging agents for multiple myeloma (MM) are promising as future treatment options. The arsenal now includes many new classes of agents beyond the standard immunomodulatory drugs (IMiDs) and proteasome inhibitors. Here is a look at the key studies presented at ASH 2013.

Oral Proteasome Inhibitors
In newly diagnosed patients with MM, the oral proteasome inhibitor MLN9708, now known as ixazomib, combined with lenalidomide plus dexamethasone, led to high response rates with extended treatment duration, reported Paul G. Richardson, MD, Clinical Director, Jerome Lipper Center for Multiple Myeloma, Dana-­Farber Cancer Institute, Boston.

“This is the first all-oral proteasome inhibitor/IMiD combination under investigation in this setting to date, and the data support its feasibility and activity,” Dr Richardson said.

The study of treatment-naïve patients included 14 patients in the dose-finding phase 1 trial and 57 patients in the phase 2 study, who received ixazomib 3 mg every 21 days for up to 16 cycles. The objective response rate (ORR) was 94%, and complete responses (CRs) plus very good partial responses (VGPRs) were achieved by 76% of patients. Of the 11 evaluable patients who achieved a stringent CR plus CR, 9 patients had no minimal residual disease. Drug-related serious adverse events (AEs) were seen in 28% of patients; grade 3 drug-related AEs were reported in 58%, and no grade 4 events were reported.

In another presentation, Shaji K. Kumar, MD, of the Division of Hematology, Mayo Clinic, Rochester, MN, presented data from a phase 2 trial of ixazomib as a single agent in 69 patients with relapsed MM who had not received bortezomib or received <6 cycles of bortezomib and had a PR or better without progression.

For the 32 patients remaining on study, the ORR was 34%. Among the patients, who were followed for 12 months, 77.5% have not progressed and 59% are alive without progression at 12 months.

“MLN9708 has single-agent activity, with deep responses seen in some patients. The addition of dexamethasone for lack of response or progression leads to improved response,” Dr Kumar concluded.

Another oral proteasome inhibitor, oprozomib, is demonstrating activity. In an ongoing dose-finding study in 42 relapsed patients, approximately 1 in 4 patients is responding to treatment with oprozomib.

Histone Deacetylase Inhibitors
The combination of proteasome and histone deacetylase (HDAC) inhibitors is predicted to become a viable treatment for patients with MM, attributed to the dual inhibition of the proteasome and aggresome pathways.

Dr Richardson presented an update of the phase 2 PANORAMA 2 trial, which evaluated the oral HDAC inhibitor panobinostat paired with bortezomib and dexamethasone in 55 patients with relapsed, bortezomib-­refractory disease.

The ORR was 35%, including VGPRs in 5.5% of patients, with a median response of 6 months. Including patients with stable disease, the clinical benefit rate was 53%.

“In this patient population, high-risk cytogenetics did not negatively impact response rates,” said Dr Richardson. In the 14 patients with high-risk cytogenetics, the ORR was 42.9%, and the clinical benefit was 71.4%.

The median progression-free survival (PFS) was 5.4 months, and the median overall survival (OS) was 17.5 months, with longer remissions among responders. The safety profile was “manageable.”

Another multicenter phase 2 study evaluated panobinostat in combination with the proteasome inhibitor carfilzomib in 44 patients with relapsed/refractory MM. The median PFS was 6.8 months altogether—7.6 months for patients with previous bortezomib therapy and 4.8 months in patients refractory to bortezomib. The 12-month PFS rate was 41%, and the OS rate was 85%; the median OS was not yet reached.

“The combination of panobinostat and carfilzomib is feasible and effective in the relapsed or relapsed/refractory population,” said lead investigator Jesus G. Berdeja, MD, Director of Myeloma Research, Sarah Cannon Research Institute, Nashville, TN. The main grade 3 to 4 treatment-related AEs were thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, diarrhea, dyspnea, and hypertension. Frequent dose reductions were required for panobinostat.

Monoclonal Antibodies
There is no monoclonal antibody yet approved for MM, but more than 10 candidates are in development. Elotuzumab, which targets CS1, and daratumumab, which targets CD38, are furthest along in development and are considered the most promising.

Daratumumab received the US Food and Drug Administration Breakthrough Therapy designation in 2013 for patients with disease that is refractory to proteasome inhibitors and IMiDs. In an evaluation of 11 patients who received up to 16 mg of daratum­umab, 8 patients achieved a PR or better after single-agent treatment (up to 16 mg/kg), including CRs in 3 patients, VGPRs in 2 patients, and PRs in 3 patients. Two patients achieved a minimal response, and 1 had stable disease; no patients progressed. Corresponding to these responses was a marked reduction in M-protein.

The drug was generally well tolerated. Grade ≥3 AEs occurred in 17 patients, 70% of which were hematologic; some infusion reactions were observed, primarily bronchospasm, and typically early in the trial. This was managed well with supportive medications. The maximum tolerated dose has not yet been established.

SAR650984 is another promising monoclonal antibody, although it is still in early phase. In a phase 1 study of SAR650984 as a single agent, the ORR in heavily pretreated patients was 25%, with 8% CRs, and 17% PRs. At higher doses, the response rate was 31%. The maximum tolerated dose is still being determined.

Kinesin Spindle Protein Inhibitors
Filanesib (ARRY-520) is a highly selective, targeted kinesin spindle protein (KSP) inhibitor with a mechanism of action distinct from currently available drugs for MM, such as IMiDs and proteasome inhibitors. Mature data from a phase 2 trial in heavily pretreated patients (median, 6 previous therapies) were reported at the meeting. The response rates with this KSP agent were 16% for single-agent filanesib and 15% among patients whose disease was dual refractory to bortezomib and lenalidomide.

In addition, the retrospective use of acute-phase protein alpha-1-acidic gly­coprotein (AAG) levels as a biomarker improved response rates and OS. In AAG-low patients, the response rate was 24% with single-agent filanesib, and 19% with filanesib plus dexamethasone in patients with dual-refractory disease; no responses were observed in patients with high AAG levels. The median OS in AAG-low patients was 23.3 months.

Also of note, filanesib demonstrated clinical activity in patients previously treated with newer MM agents, including carfilzomib, ixazomib, and/or pomalidomide, suggesting that filanesib maintains activity in patients who are resistant to multiple standard agents and new myeloma agents. In this population, filanesib had an ORR of 21%, which improved to 33% in an AAG-selected population. The incidence of nonhematologic adverse events was low, including an absence of peripheral neuropathy. Hematologic toxicities were transient, and were managed with supportive measures.

“Filanesib has shown clinical activity in relapsed/refractory multiple myeloma patients, both as a single agent, and in separate combination trials with carfilzomib and bortezomib,” said Jatin J. Shah, MD, Assistant Professor, Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX. “These results support advancing filanesib into pivotal trials.”

Novel Classes in Early Development
Preliminary data were presented for several interesting new classes of anti-MM drugs. Indatuximab ravtansine is a compound that combines a chemotherapeutic drug (ravtansine) with an antibody (indatuximab) that helps deliver the drug to myeloma cells and other cancer cells. When the compound enters a cancer cell, it releases the chemotherapy drug that ultimately kills the cell.

The phase 1/2 study included 15 patients with relapsed/refractory disease who had received a median of 4 previous lines of therapy. Patients received indatuximab ravtansine in combination with lenalidomide and dexamethasone. Among the 9 patients who are currently available for response, the ORR was 78%, with 11% patients achieving CRs, 11% achieving VGPRs, and 55% reaching PRs. The remaining 22% achieved stable disease.

ImMucin is a myeloma vaccine being developed in Israel that is based on the protein MUC1, which is found on the surface of cancer cells. The study presented at the meeting included 15 patients with MM who had received a median of 2 previous lines of therapy, and who had residual or progressive disease after stem-cell transplantation. All participants had myeloma cells with the protein MUC1 on the surface. Participants received 6 or 12 biweekly ImMucin injections plus growth factors. Most patients achieved significant reductions in MUC1 levels, and most had stable disease lasting up to 29 months after study completion.

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