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Novel Proteasome Inhibitor and HDAC Inhibitor for Myeloma Shine at ASH 2013

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

New Orleans, LA—Emerging agents for multiple myeloma are looking more and more promising as future treatment options for relapsed or refractory patients. Here is a look at a few of the studies of novel agents presented at the 2013 American Society of Hematology (ASH) annual meeting.

Ixazomib: First All-Oral Regimen for Patients with Newly Diagnosed Disease
In patients with newly diagnosed myeloma, use of the oral proteasome inhibitor ixazomib citrate (also known as MLN9708), combined with lenalidomide and dexamethasone, led to high response rates and increased depth of response with extended treatment duration, reported Paul G. Richardson, MD, Clinical Director, Center for Multiple Myeloma, Dana-Farber Cancer Institute, Boston, at the ASH meeting.

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

Ixazomib was given twice weekly with lenalidomide and dexamethasone to treatment-naïve patients, including 14 patients in the dose-finding phase 1 trial (3.0 mg and 3.7 mg), and 57 patients in the phase 2 study (3.0 mg). The patients received up to 16 cycles of the triplet regimen, which was taken every 21 days. At the data cutoff time, the median number of treatment cycles was 9; overall, 16% of the patients received at least 16 courses of treatment.

The overall response rate was 94%, and the rate of complete response (CR) plus very good partial response (VGPR) was 76%. A stringent CR was reached in 75% of the patients who attained a CR.   

Based on 56 patients who received the recommended dose and had an evaluable response, the responses improved over the course of treatment, with 93% of patients responding after 4 cycles (≥VGPR in 61% of patients), and 95% responding overall (≥VGPR in 71% of patients). Among the 11 evaluable patients who achieved a stringent CR plus a CR, minimal residual disease was observed, and 9 of these patients were negative for myeloma.

Of the patients who received the recommended phase 2 dose, 26% continued therapy at data cutoff.

Drug-related serious adverse events were seen in 28% of patients; grade 3 drug-related adverse events were reported in 58%, and there were no grade 4 events.

In another presentation, Shaji K. Kumar, MD, Professor of Medicine, Mayo Clinic, Rochester, MN, presented phase 2 data for ixazomib citrate as a single agent in 69 patients with relapsed myeloma who had not received bortezomib or who received <6 cycles of bortezomib and had at least a partial response without disease progression. Patients whose disease progressed or had an inadequate response had dexamethasone added.

Overall, 30 patients are no longer in the study, because of different reasons, including disease progression (55%), refusing further treatment (25%), adverse events (15%), or other reasons. For the 32 patients remaining in the study, the overall response rate was 34%, with dexamethasone added as needed. Of the patients who were followed for 12 months, 77.5% did not have disease progression 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.

Panobinostat plus a Proteasome Inhibitor Combination
The combination of a proteasome inhibitor and a histone deacetylase (HDAC) inhibitor is predicted to become a viable treatment regimen in multiple myeloma, attributed to the dual inhibition mechanisms.

“Inhibition of the aggresome and proteasome pathways causes a buildup of intracellular misfolded cytotoxic proteins, leading to myeloma-cell apoptosis,” explained Dr Richardson, who led the PANORAMA 2 (Panobinostat in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and Bortezomib-Refractory Multiple Myeloma) trial.

At ASH 2013, Dr Richardson presented an updated analysis of the phase 2 study, which evaluated the oral HDAC inhibitor panobinostat, paired with bortezomib and dexamethasone, in 55 patients with relapsed and bortezomib-refractory disease. Patients received up to 8 cycles (21 days per cycle) of the combination, and patients showing clinical benefit continued with 4 cycles (42 days per cycle) until disease progression. The median duration of exposure was approximately 5 months.

The objective response rate was 35%, and the clinical benefit rate was 53%. VGPRs were observed in 5.5% of patients. In the 19 patients achieving a response, the median time to response was 1.4 months, and the median duration was 6 months.

“In this patient population, high-risk cytogenetics did not negatively impact response rates,” Dr Richardson reported. “Among the 14 patients with high-risk cytogenetics, the objective response rate was 42.9%, and clinical benefit rate was 71.4%.” The safety profile of the combination was “manageable,” Dr Richardson said.

“These results, and those from the ongoing phase 3 trial of panobinostat, bortezomib, and dexamethasone in relapsed and relapsed/refractory myeloma (PANORAMA 1), will better elucidate the role of this combination,” he said.

Another multicenter phase 2 study evaluated panobinostat in combination with the proteasome inhibitor carfilzomib in 44 relapsed/refractory patients. Patients received carfilzomib and panobinostat on a 28-day cycle until disease progression. Four doses of each drug were evaluated.

“The combination of panobinostat and carfilzomib is feasible and effective in the relapsed or relapsed/refractory population, and prior exposure to proteasome inhibitors or IMiDs does not seem to affect the response rate or overall survival of patients on this combination,” according to lead investigator Jesus G. Berdeja, MD, of Sarah Cannon Cancer Center, Nashville, TN.

Overall, the median PFS was 6.8 months, with 7.6 months for patients who had previously received a proteasome inhibitor, and 4.8 months in patients with disease refractory to a proteasome inhibitor. The 12-month PFS probability was 41%. Median OS was not reached, and the 12-month OS probability was 85%, Dr Berdeja said.

The main grade 3 or 4 treatment-related adverse events were thrombocytopenia (34%), neutropenia (20%), fatigue (11%), anemia (9%), leucopenia (7%), diarrhea (7%), dyspnea (7%), and hypertension (5%). There were 12 serious adverse events among 44 patients, and 8 hospitalizations.

Dr Berdeja added that frequent (62%) dose reductions were required for panobinostat, so further dosing schedules will be explored to find the optimal dose for this encouraging combination.

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Last modified: May 20, 2015
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