Carlson, Robert H.
NEW ORLEANS—Many new agents were discussed at the ASH Annual Meeting, of course, but one expert saw a trend in the presentations on new treatments for multiple myeloma.
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“We saw investigators looking at the treatment paradigm all the way from smoldering myeloma through induction, consolidation, transplant, and ultimately long-term remission, to see where these new drugs are going to find an appropriate niche,” said Brian G.M. Durie, MD, Chairman and Medical Director of the International Myeloma Foundation and attending physician at Cedars-Sinai Medical Center in Los Angeles.
Activating Osteoblasts in Myeloma
Treatments for bone disease in patients with multiple myeloma tend to concentrate on reducing activity of osteoclasts. But taking a different approach is BHQ880, a novel osteoblast-activating anti-DKK1 human monoclonal antibody that allows bone remodeling inhibited by myeloma.
“This human monoclonal antibody has a very specific target, TKK1, and this target essentially is the culprit for not allowing bone remodeling to occur in multiple myeloma,” explained Swaminathan Padmanabhan, MD, of the Institute for Drug Development, Cancer Treatment and Research Center, at the University of Texas Health Science Center at San Antonio.
He said BHQ880 is unlike the bisphosphonates, which add calcium back to bone to prevent bony destruction but don't address the bone formation issue: “For the first time a drug is addressing the bone formation problem, which I think is a fundamental issue in the bone disease in multiple myeloma.”
He presented results of a multi-institution BHQ880 Phase I/II study in relapsed and refractory multiple myeloma that included 34 patients, receiving BHQ880 on the first day of a 21-day schedule, followed by the bisphosphonate zoledronic acid on Day 2 and antimyeloma therapy with lenalidomide and/or dexamethasone on Day 3 (but not bortezomib, which has bone-anabolic properties).
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“The zoledronic acid decreases bone resorption, and BHQ880 increases new bone formation, so this combination, along with an antimyeloma drug, may provide an effective treatment strategy for multiple myeloma bone disease,” Dr. Padmanabhan said.
Seven of the 34 patients have relapsed disease and four have refractory disease.
Among the 11 patients evaluable for safety there has been no infusion-related toxicity so far, Dr. Padmanabhan said, and no toxicities related to the drug. One patient still receiving BHQ880 is currently in the ninth cycle.
“Dexa scans have shown positive increases in bone mineral density in several of the patients, with changes ranging from +.02% to +6.0%, in as early as three months,” Dr. Padmanabhan said. But there has been no evidence that BHQ880 has any effect on the myeloma disease.
The Phase II portion of the study was expected to begin early this year.
Dr. Durie said in a telephone interview after the meeting that he was familiar with the development of BHQ880, stemming from work in gene expression profiling by John D. Shaughnessy, Jr., PhD, Professor of Medicine at the University of Arkansas.
There has been a lot of drug development work on shutting down osteoclasts, Dr. Durie said, calling BHQ880 a very interesting approach to the problem of getting increased activity of osteoblasts to have bone healing.
Carfilzomib, Second-Generation Proteosome Inhibitor
A serious side effect of bortezomib treatment in relapsed myeloma has been neurotoxicity. In one study presented in the “Myeloma Therapy” session at the meeting, the second-generation proteosome inhibitor carfilzomib (at 20 mg/m2) was substituted for bortezomib in a three-drug combination with lenalidomide (25 gm) and low-dose dexamethasone to treat patients with relapsed or refractory myeloma.
In this dose-escalating Phase Ib study, 32 patients were enrolled in the first five cohorts.
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Principal investigator Ruben Niesvizky, MD, of Weill/Cornell Medical College, said the lack of overlapping toxicities of carfilzomib and lenalidomide allowed the use of these agents at full doses and for extended durations of more than 10 months in several cases, despite relapsed or refractory disease.
No drug-related serious adverse events, peripheral neuropathy, or renal events were reported, he said. Hematological adverse events have been reversible and manageable in 26 patients evaluable for safety, including Grade 3/4 thrombocytopenia (four patients), anemia (four), and neutropenia (two). All but one of these events were Grade 3; the Grade 4 problem was thrombocytopenia, lasting less than seven days.
Dr. Niesvizky called the responses among 20 evaluable patients robust, with a 55% overall response rate across all cohorts. Initial responses were rapid and occurred within the first two cycles, and improved with continuing therapy.
The 26 patients evaluable for safety were heavily pretreated: 89% had received steroids, 77% bortezomib, 85% alkylating agents, 54% lenalidomide, 46% thalidomide, 31% anthracyclines, 81% stem cell transplant, 54% had received both lenalidomide and bortezomib, and 50% were refractory or had disease progression on one or more prior therapies.
“It's encouraging that we have another novel proteosome inhibitor that may be effective, even in the context of refractory myeloma,” Dr. Niesvizky said in an OT Broadcast News podcast interview at the meeting.
‘Key Question Is…’
Asked for his opinion, Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and Associate Professor of Medicine in the Department of Medical Oncology at Harvard Medical School, said that in some previous studies carfilzomib showed response rates very similar to those of bortezomib, but with a safer toxicity profile.
“Because of that, it will have the ability to help patients who are, for example, intolerant of bortezomib,” he said.
“The key question is, whilst it may have a better side effect profile, do we see some tradeoff in terms of quality of response? From the data presented with carfilzomib alone, it is difficult to know whether or not we're seeing differences in CRs and so forth. That may mean that it may be better tolerated but it may not be as powerful.
“I think we have to be very careful about saying carfilzomib is a better proteosome inhibitor than bortezomib; I think they're very different.”
Dr. Richardson said Dr. Niesvizky's study was very exciting combining carfilzomib with lenalidomide doses higher than what has been used in the relapse setting when lenalidomide was combined with bortezomib.
“He was able to do that without a very substantial side effect penalty, and he showed very encouraging response rates. To me that was a very important presentation.”
“At the moment myeloma is not curable, so what we have to have is serial lines of therapy that can control disease and restore response when resistance emerges,” he said. “And what you're seeing is that we've got some rational combinations we can go to, with acceptable side effect profiles, that can allow us to continue to treat patients. And the more tolerable your treatment, the longer you can stay on it, and the more benefit you can derive from it.”
Panobinostat Synergy with Bortezomib
A Phase Ib, multicenter, open-label dose-escalation study of oral panobinostat (LBH589) and intravenous bortezomib in patients with relapsed multiple myeloma showed encouraging clinical anti-myeloma synergism between panobinostat and bortezomib.
Jesús F. San Miguel, MD, PhD, Professor of Hematology and Head of the Department of Hematology at the University of Salamanca in Spain, said that the combination warrants further clinical investigation in patients with refractory and relapsed disease.
“Given the frequency of thrombocytopenia and dose adjustments, the dosing schedule in subsequent Phase II/III studies will be modified to take the safety profile and dose-reduction/-interruption pattern into account,” he said.
Panobinostat is a pan-deacetylase inhibitor (pan-DACi) that disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates, and triggers myeloma cell death, he explained. The primary objective of the trial was to determine the maximum tolerated dose of oral panobinostat when combined with bortezomib.
There was a median of three prior regimens among the 29 patients treated, and 25 had at least one prior autologous stem cell transplant. Patients were treated in four cohorts with escalating doses of both drugs.
“Overall, the combination of panobinostat and bortezomib was safe and tolerated in Cohorts I to III, with one dose-limiting toxicity, a Grade 4 afebrile neutropenia in Cohort II,” Dr. San Miguel reported. In Cohort IV, there were four dose-limiting toxicities: two Grade 4 thrombocytopenias requiring platelet transfusions, one Grade 3 pneumonia, and one Grade 3 fatigue.
Among 28 evaluable patients, 14 had a partial response or better, including four with an immunofixation-negative complete response. Four additional patients achieved minor responses, resulting in a 64% overall response rate.
The researchers also saw responses in the subset of patients refractory to prior bortezomib, suggesting a strong clinical correlate for synergism of the panobinostat-bortezomib combination, he concluded.
Ruben Niesvizky talks more about his research with the novel proteasome inhibitor carfilzomib, used in combination with lenalidomide and dexamethasone to treat relapsed/refractory multiple myeloma, in a “Live from ASH” OT Broadcast News podcast (Program #4) available at oncology-times.com and on iTunes.
© 2010 Lippincott Williams & Wilkins, Inc.