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Myeloma: Novel Agents Combined with Standard Therapy Show Promise for Bortezomib-Refractory Patients

Fuerst, Mark

doi: 10.1097/01.COT.0000415888.85877.20

Novel agents in combination with standard multiple myeloma therapies show considerable promise in treating the poor-risk group of patients who have disease that is bortezomib-refractory or who have relapsed after bortezomib treatment.

Three abstracts reported at the ASCO Annual Meeting show the potential impact of novel agents, including panobinostat, a histone deactylase (HDAC) inhibitor; pomalidomide, an immunomodulatory drug (IMiD); and elotuzumab, a monoclonal antibody, after failure of bortezomib therapy.

There are a cornucopia of new drugs for relapsed/refractory multiple myeloma, noted Robert Z. Orlowski, PhD, MD, Director of the Myeloma Section at the University of Texas MD Anderson Cancer Center. These include, he noted in a telephone interview a few days before the meeting, small molecules and novel signal transduction inhibitors, second-generation proteasome inhibitors, second- and third-generation immunomodulators, HDAC inhibitors, heat shock protein 90 inhibitors, and monoclonal antibodies (siltuximab, elotuzumab, and lorvotuzumab mertansine).

“Novel agents can have an impact when myeloma patients relapse, and drugs with novel mechanisms of action are showing promise alone or in combination,” he said. The benefits of vorinostat in combination with bortezomib are unclear, he said, but other HDAC inhibitors, such as panobinostat, are moving forward. Also, the next generation of proteasome inhibitors (carfilmozib, marizomib, and MLN9708) and IMiDs (pomalidomide) are coming to registration studies.

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HDAC Inhibitor Plus Bortezomib and Dexamethasone

Melissa Alsina, MD, Head of the Multiple Myeloma Transplant Program at H. Lee Moffitt Cancer Center & Research Institute, updated data from the Phase II PANORAMA 2 trial in relapsed and bortezomib-refractory patients (Abstract 8012), demonstrating that more than half of patients treated with a combination of panobinostat, bortezomib, and dexamethasone show clinical benefit.

Patients with multiple myeloma who are refractory to bortezomib and an IMiD have limited treatment options and a poor prognosis, she noted. In a Phase I study of patients with relapsed or relapsed/refractory multiple myeloma, panobinostat-plus-bortezomib treatments led to clinical responses overall and in patients with bortezomib-refractory disease.

PANORAMA 2 is a single-arm, Phase II study of panobinostat plus bortezomib plus dexamethasone in this patient population. Initial treatment consisted of eight three-week cycles of oral panobinostat plus intravenous bortezomib plus oral dexamethasone. Patients who showed clinical benefit entered a second treatment phase consisting of four six-week cycles of the three-drug combination.

The ASCO report was on 55 patients, median age of 61, who were heavily pretreated, with a median of four prior regimens. Two-thirds of the patients received prior autologous stem cell transplant.

Seventeen patients achieved at least a partial response, for an overall response rate of 31 percent, and 11 patients achieved a minor response for a clinical benefit rate of 51%. Five patients have completed at least 12 cycles.

“Panobinostat when combined with bortezomib can recapture responses in heavily pretreated bortezomib-refractory multiple myeloma patients,” she concluded. “Overall, the combination of panobinostat with bortezomib and dexamethasone was tolerable with manageable toxicities.” Those included thrombocytopenia, fatigue, diarrhea, nausea, dyspnea, anemia, decreased appetite, and dizziness. Common Grade 3/4 adverse events included thrombocytopenia, fatigue, anemia, pneumonia, neutropenia, and diarrhea. One patient had Grade 3/4 peripheral neuropathy.

A randomized Phase III trial (PANORAMA I) will further define the role of panobinostat combined with bortezomib and dexamethasone in relapsed/refractory multiple myeloma patients. Panobinostat is also being explored in combination with other agents for multiple myeloma treatment, including a combination of lenalidomide/bortezomib/dexamethasone; pomalidomide; carfilmozib; and thalidomide.

In an interview at the ASCO meeting after her presentation, Alsina said, “I would definitely consider adding an HDAC inhibitor to patients who are refractory to bortezomib. When they get to that stage of myeloma it's a huge challenge. Usually they do not respond to anything. Having a drug like this that recaptures response to bortezomib would help patients buy time.”

Panobinostat is not a cure, she said, but “it will be an additional tool to treat patients that we didn't have before and give us another alternative.”

The study's Discussant, Asher Chanan-Khan, MD, Chairman of Hematology/Oncology at the Mayo Clinic, said, “Clearly there is a need to develop new drugs. Myeloma remains incurable, and all patients eventually relapse,” adding that dysregulation of HDAC has been established in multiple myeloma.

Panobinostat as a single agent, even though it showed strong preclinical data, is not effective in myeloma patients, Chanan-Khan noted. “It is more compelling in combination. Dr. Alsina presented interesting combination data in this patient population that is refractory to bortezomib.”

Patient heterogeneity precludes practice-changing conclusions from the data, he said. “The exact role of panobinostat in multiple myeloma and the extent of its potential benefit remain to be addressed through larger randomized studies.”

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Enhance Activity

Ravi Vij, MD, Associate Professor of Medicine in the Division of Oncology at Washington University in St. Louis, said in an interview that HDAC inhibitors are theoretically appealing as a class for the treatment of relapsed/refractory multiple myeloma: “HDAC inhibitors do not by themselves produce robust responses, but they enhance the activity of bortezomib or lenalidomide.”

He noted that initial data on another HDAC inhibitor, vorinostat, presented at the most recent American Society of Hematology Annual Meeting in December met statistical goals, although there is still a debate about whether these results are clinically meaningful.

“This Phase II study of panobinostat suggests the drug has activity when combined with bortezomib and dexamethasone, but we still need to scrutinize data from the Phase III trial,” which has completed accrual but has not yet been reported, he said.

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IMiD Plus Low-Dose Dexamethasone

Vij presented updated data from the MM02 trial of pomalidomide with or without low-dose dexamethasone in myeloma patients who are refractory to lenalidomide and/or bortezomib (Abstract 8016).

“Pomalidomide is an exciting compound that could get accelerated FDA approval later this year. It will be an important addition to our armamentarium to improve outcomes in multiple myeloma,” he said.

In the study, half of the patients (108) received pomalidomide at 4 mg/day on days 1–21 of each 28-day cycle alone and the other half (113) received pomalidomide plus dexamethasone at 40 mg/week. Patients who received the dual combination were refractory to lenalidomide (77%), bortezomib (73%), or both (61%). Nearly half of the patients (42%) were refractory to both lenalidomide and bortezomib and had received a prior transplant.

The results found that 20% of patients achieved at least a partial response, with a median progression-free survival (PFS) of 3.5 months and a one-year survival rate of 59%. Vij noted that response rates and duration were comparable in patients with disease refractory to lenalidomide, bortezomib, or both, and in patients who had received prior transplant.

Survival outcomes were also similar across the groups, with a median PFS of 3.8 to 4.6 months and a one-year survival rate ranging from 60% to 67%.

Additional updated data on the concurrent arm showed that the “responses are more worthwhile,” he said.

He predicted that if pomalidomide is approved by the FDA, that it will be used in patients who have previously been exposed to lenalidomide and bortezomib. “I think the data are impressive for dual-refractory patients, and it certainly meets an unmet need in this population,” said Vij, adding that it is unlikely the drug will be used in lenalidomide-naïve patients since there are no trials to date in that population. “The fact that it appears to work in patients who have failed lenalidomide and bortezomib shows the potential exists to use the drug even earlier in therapy.”

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Monoclonal Antibody Plus Lenalidomide and Low-Dose Dexamethasone

At a Clinical Science Symposium at the ASCO meeting on Monday, Philippe Moreau, MD, from the Hematology Department of University Hospital in Nantes, France, presented data from a randomized Phase II study of elotuzumab with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (Abstract 8020).

Elotuzumab is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein. The abstract notes that CS1 is highly expressed on more than 95% of multiple myeloma cells, with lower expression on natural killer cells and little to no expression on normal tissues.

A Phase I trial of elotuzumab plus lenalidomide and low-dose dexamethasone demonstrated an 82% objective response rate (ORR) in patients with relapsed/refractory multiple myeloma, and Moreau will report the results of a Phase II study of previously treated myeloma patients who were randomized to receive elotuzumab at either 10 or 20 mg/kg intravenously on days 1, 8, 15, and 22 every 28 days in the first two cycles and on days 1 and 15 of subsequent cycles, lenalidomide at 25 mg orally on days 1–21, and dexamethasone at 40 mg orally weekly. Prophylaxis for infusion-related reactions was administered prior to each elotuzumab infusion.

About half of the 73 patients (median age of 63), had received at least two prior therapies; 60% had received prior bortezomib and 62% prior thalidomide. The ORR was 82% for all patients, including 48% with at least a very good partial response. The ORRs were 92% in the 10 mg/kg group (36 patients) and 73% in the 20 mg/kg group (37 patients). The median time to best response was 2.2 months.

After a median follow-up of more than 14 months, the patients' median progression-free survival time has not been reached, with PFS rates of 75% (10 mg/kg dose) and 65% (20 mg/kg dose). The triple-drug combination also showed “encouraging activity,” the researchers said, in patients with high-risk cytogenetics (ORR 80%) and/or Stage 2–3 multiple myeloma (ORR 81%).

The most common Grade 3/4 toxicities were neutropenia, lymphopenia, and thrombocytopenia. Infusion reactions were reported in 12% of patients, with one patient having a Grade 3 rash.

Moreau and colleagues conclude that “the combination of elotuzumab/lenalidomide/dexamethasone was generally well tolerated and resulted in a high ORR, and PFS not reached after 14 months of median follow-up in patients with relapsed/refractory multiple myeloma.” He provided updated results at the meeting, including information on two ongoing Phase III trials of 10 mg/kg elotuzumab plus lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients.

“Elotuzumab is another exciting drug,” said Vij. “The data of elotuzumab in combination with lenalidomide and dexamethasone in the Phase I and II experience suggest that elotuzumab adds substantial activity to the other two drugs in this population, with durable responses.” In addition, he said, the Phase III studies in previously treated and untreated patients look promising.

When asked about the plethora of new drugs for relapsed/refractory multiple myeloma, Orlowski noted that novel agents with activity in this setting include inhibitors of HDAC, KSP, CdK, Bcl-2 family, Crm, and Akt, as well as monoclonal antibodies.

He said that in the future, he foresees biomarker-guided combinations that will include an IMiD and/or a proteasome inhibitor that overcomes patient-specific mechanisms of resistance, such as a proteasome inhibitor plus an IFG-1 inhibitor or an IMiD plus an inhibitor of Wnt/beta-catenin or agents that reactivate Cereblon expression.

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.
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