NEW YORK CITY—Combination regimens of two, three, and four drugs, tested in the several stages of multiple myeloma, generally achieve better responses than single-drug regimens.
But more might not be better, according to two internationally known speakers who gave their views on combination regimens in the first session here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies.
The four-drug combinations may be more efficacious but also bring added toxicities whether patients are transplant-eligible or -ineligible.
Less than Total
Tackling the subject of first-line treatment for transplant eligible patients, Jean-Luc Harousseau, MD, Professor and Head of the Department of Clinical Hematology at Hôtel Dieu in Nantes, France, said the best regimen without question is the multi-drug regimen in Total Therapy 3 (TT3), which includes all active available agents.
While TT3 is well tolerated, it is a very intense, complex regimen, Dr. Harousseau said, and it might be possible to achieve the same results with a simpler regimen.
For induction, a simpler protocol would be the three-drug regimen of VTD (bortezomib [Velcade], thalidomide, and dexamethasone), or vTD with a lower dose of bortezomib for less neuropathy—data he reported at the 2009 ASH Annual Meeting (Abstract 354).
“Bortezomib and dexamethasone form a platform to which different agents can be added to improve outcomes,” he said, adding that bortezomib-based induction regimens are effective in high-risk disease as well.
Because of that tradeoff with increased toxicity, the role of four-drug combinations is still undefined, he said.
Way to Go Forward'
In an interview after the meeting, another speaker, Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Center for Multiple Myeloma at Dana-Farber Cancer Institute, said, “We are all moving toward combinations as the way to go forward.
“The issue is, what combination is best tolerated and most active, and in that regard less is more, so lower doses of each combined may be better.”
Dr. Richardson noted that as reported at the ASH 2009 Annual Meeting (Kumar et al, Abstract 127), the randomized, Phase II EVOLUTION study of front-line therapy for transplant-eligible patients showed that a four-drug combination could deliver response rates similar to two three-drug regimens, but with more toxicity.
That three-arm randomized trial of newly diagnosed patients compared lenalidomide-bortezomib-dexamethasone (RVD) against bortezomib-dexamethasone-cyclophosphamide (VDC) against the four-drug regimen of bortezomib-dexamethasone-cyclophosphamide-lenalidomide (VDCR).
“It is difficult to make an efficacy call [in EVOLUTION] because the numbers are not big enough, but when you look at toxicities it is much more informative, with the four-drug regimen associated with more fatigue, myelosuppression, infection, and higher grades of neuropathy versus the three-drug regimen,” Dr. Richardson said.
Dr. Richardson, in his own presentation at the Lymphoma/Myeloma meeting, said that better treatments for patients with relapsed and/or refractory disease are a fundamental priority and a substantial challenge.
“Even with our tremendous advances in treatment, once bortezomib or lenalidomide or thalidomide has failed [the relapsed/refractory patient], their time to progression and overall survival remain dismal,” he said. “Progression-free survival is three to six months, and overall survival beyond nine months does not occur.”
There are special populations within this group, whose clinical features are associated with poor prognosis: age over 65; increased beta-2m, decreased serum albumin, low platelet count, acquired cytogenetic abnormalities such as chromosome 13 deletion and t(4;14) translocation; renal dysfunction; extensive bone disease; and extramedullary disease.
Clinical factors when choosing therapy for relapsed disease include comorbid conditions, previous therapy, time from previous therapy, mode of drug administration, risk profile, and the potential for a second autologous stem cell transplant or an allogeneic stem cell transplant.
Dr. Richardson said that bortezomib (Velcade) clearly is the most powerful single agent for myeloma today, but a combination of lenalidomide (Revlimid) and dexamethasone is also very powerful. And using all three together or in different combinations, “clearly has more appeal.”
An emerging side effect of long-term bortezomib is diarrhea, but peripheral neuropathy remains the single biggest challenge with bortezomib—the main idea is that you have choices.
“It's not one size fits' all anymore, so you would use the classical platforms that help—immunomodulatory therapy and glucocorticoids, plus proteosome inhibition. Then you would add to it rationally depending on what the patient previously had, on what would most likely engender response, and what would be less toxic.”