NEW YORK CITY—A Phase II study testing clarithromycin, the immunomodulator lenalidomide, and dexamethasone in combination as induction therapy for multiple myeloma is showing response rates above 90% among newly diagnosed patients, according to data reported here at the “2006 Lymphoma & Myeloma” meeting.
The principal investigator, Ruben Niesvizky, MD, Clinical Director of the Multiple Myeloma Service in the Center for Lymphoma and Myeloma at Weill Cornell College of Cornell University, presented data from the ongoing Phase II trial of the BiRD regimen (Biaxin/, clarithromycin, Revlimid/lenalidomide, and dexamethasone).
“The regimen demonstrated an overall response rate of 90 percent with a remarkable combined complete response/near-complete response rate of 42 percent,” Dr. Niesvizky said. “Furthermore, this combination did not appear to interfere with hematopoietic stem cell harvest.”
He speculated that combinations of novel agents such as lenalidomide and bortezomib with dexamethasone might one day obviate the need for stem cell transplant in newly diagnosed patients with myeloma.
Dr. Niesvizky, principal investigator of the study and a co-chair of the conference, reported on the first 62 patients in the study.
First 40 Patients Reported at ASCO Meeting
When he reported on the first 40 patients in a poster discussion session at the most recent American Society of Clinical Oncology Annual Meeting, the objective response rate was 95% and the complete response rate was 43% compared with a response rate of 90% and a combined complete response rate of 42% four months later.
Patients entered in the study had received no earlier treatment, and had advanced disease (more than Durie-Salomon Stage II), measurable disease, and a serum creatinine level of less than 2.5 mg/dL. Median age was 62.
Trial sponsors and collaborators are listed on the ClinicalTrials.gov Web site as Weill Medical College and Celgene Corp.
The protocol regimen was oral lenalidomide at 25 mg daily and oral clarithromycin at 500 mg twice daily, each given on Days 1 to 21 of a 28-day cycle. Oral dexamethasone at 40 mg was given once weekly. Patients also received low-dose aspirin as thrombosis prophylaxis.
Dr. Niesvizky said at the Myeloma meeting that the response rates for 62 patients were 29% complete response and 13% near complete response (total of 42%), a partial response rate of 53% and a stable disease rate of 5%.
With a follow-up of approximately 10 months, the researchers have found it possible to achieve the maximum possible response after five to six months of therapy, he said. “And at this point no patient has progressed.”
Major toxicities observed have been thrombotic events and cytopenias. There have been at least two lethal events due to thrombosis, he said, and Grade 3/4 anemia, thrombocytopenia, and neutropenia have been seen.
Dr. Niesvizky concluded that BiRD is very effective in patients with newly diagnosed myeloma, demonstrating a complete near-complete response rate of more than 40%. “But the bad news is that 60 percent of patients do not achieve a CR [or near CR],” he said.
Dr. Niesvizky recommended that lenalidomide and as well as bortezomib continue to be tested as primary therapy in multiple myeloma, and that regimens containing these two drugs in combinations or in sequence eventually should be tested against autologous stem cell transplant.
“The sequential use of non-cross-resistant bortezomib and lenalidomide might one day serve as a tandem induction effective in breaking the plateau typical of patients receiving standard induction therapy,” he said. “And perhaps they can be used in lieu of stem cell transplantation.”
Dr. Niesvizky also touched briefly on other trials testing combinations of novel agents as front-line therapy for myeloma.
Thalidomide-dexamethasone has been shown to be superior to the VAD regimen (vincristine, doxorubicin, and dexamethasone) in a recent case-controlled study (Cavo et al: Blood 2005;106:35–39), and that other researchers have reported response rates between 64% and 76% for the combination, he said.
But the Grade 3/4 toxicities associated with the thalidomide-containing regimen, particularly neuropathy, thrombosis, and Cushing's syndrome, have led researchers to search for immunomodulatory agents with fewer side effects.
Lenalidomide is both more potent and less toxic than thalidomide, he said, and is effective even in patients who have failed to respond to single-agent thalidomide (Richardson et al: Blood. 2006, July 18 e-publication ahead of print). But lenalidomide is associated with Grade 3/4 nonhematological toxicities, Dr. Niesvizky said.
And bortezomib (Velcade) combined with dexamethasone is superior to dexamethasone alone for refractory/relapsed multiple myeloma. He said a 2004 study showed bortezomib-dexamethasone highly active as an induction regimen (Chauhan et al: Blood. 2004;104:2458–2466).
Dr. Niesvizky said his group has begun looking for non-cross-resistant agents to increase the complete response rate, and has initiated a pilot study for patients in partial remission with initial induction regimens of bortezomib-dexamethasone with/without pegylated liposomal doxorubicin (DoVeD).
To date, five of 11 patients have achieved complete responses by standard criteria, including a patient who had the (4,14) translocation and four others with the chromosome 13 deletion, he said.
Dr. Niesvizky said it is known from the literature that clarithromycin increases the area under the curve of selected corticosteroids by virtue of its ability to inhibit the p450 system. There may also be other immunomodulatory aspects of clarithromycin that affect myeloma, he said.
A Phase II study testing clarithromycin, lenalidomide, and dexamethasone in combination as induction therapy for multiple myeloma is showing response rates above 90% among newly diagnosed patients,
The Chair of the session, Sundar Jagannath, MD, Chief of the Multiple Myeloma and Bone Transplant Program and Professor of Medicine at New York Medical College, said that clarithromycin appears to add to the efficacy of dexamethasone, but that he believes this is additive.
“But [clarithromycin] is not the key drug [in the BiRD combination]—the key drug is lenalidomide,” Dr. Jagannath said.
Novel Agents Are the Future
The meeting's organizer and chair, Morton Coleman, MD, of the Center for Lymphoma and Myeloma at Weill Cornell College of Cornell University and the New York-Presbyterian Hospitals, noted in an interview after the meeting that the three novel agents in myeloma therapy today—thalidomide, bortezomib, or lenalidomide, each given with dexamethasone—are all approved for treatment of relapsed myeloma.
“But in practical terms these drugs are being used earlier and earlier about the country,” Dr. Coleman said.
Dr. Jagannath said that novel agents are “here to stay” as treatment in newly diagnosed myeloma patients.
“That's the message [from this session]: People will be using novel agents rather than conventional chemotherapy,” Dr. Jagannath said in an interview after the session. ''Thalidomide-dexamethasone is already accepted and FDA approved as front-line therapy, and right at its heels is bortezomib-dexamethasone.
“And then there is Revlimid-dexamethasone, which is also showing very good promise as induction therapy for newly diagnosed myeloma patients. So that will be the future.”