CHICAGO—As so often happens in medical oncology “debates,” both speakers here at one of the sessions at the American School of Oncology's Great Debates in Hematology meeting were in total agreement with one side of the argument—in this case the “no” position. Both speakers said that high-dose dexamethasone should not remain a part of most chemotherapy regimens for multiple myeloma.
Ironically, the speaker assigned to support the “yes” position, S. Vincent Rajkumar, MD, Professor of Medicine in the Departments of Hematology and Laboratory Medicine and Pathology at the Mayo Clinic, said he felt more strongly about the “no” position than his opponent, Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
“I am actually much more aggressive than Dr. Richardson in how much I feel that high-dose dexamethasone is not something we should use for treatment of multiple myeloma, particularly in the newly diagnosed setting,” Dr. Rajkumar said. “The regimen carries a very high risk of side effects and a high risk of early mortality, particularly in the elderly population.”
Low-dose dexamethasone should be the default regimen for all induction regimens, including thalidomide-dexamethasone, lenalidomide-dexamethasone, bortezomib-dexamethasone, and any others that use dexamethasone, he said.
Start of ‘Whole High-Dose Dex Mania’
Historically, he explained, the introduction of the VAD regimen (vincristine-doxorubicin-dexamethasone) started the “whole high-dose dex mania,” when trials found that VAD produced a response rate in patients with refractory disease. It was later modified into an induction regimen that did not contain melphalan but did contain dexamethasone in high doses.
It was found in the early 1990s that high-dose dexamethasone alone was as effective as the full VAD regimen, and after that, high-dose dexamethasone became the standard regimen to which other regimens were compared.
Combination trials that followed did show that adding other agents to high-dose dexamethasone was superior in efficacy to high-dose dexamethasone alone.
Dr. Rajkumar cited the Eastern Cooperative Oncology Group (ECOG)/NCI Cancer Trials Support Unit randomized Phase III E1A00 trial, for which he was first author, comparing thalidomide-dexamethasone with dexamethasone alone that showed superior response rates for thalidomide-dexamethasone—63% and 41%, respectively (JCO 2006;24:431–436).
“A lot of regimens have been derived from high-dose dexamethasone; are we going to disregard all these regimens just based on one Phase III trial that some person lead?” he said, jokingly self-deprecating his own study. “You have single-agent dex, VAD that is useful, thalidomide-dexamethasone that is the FDA-approved standard right now, len-dex, bortezomib-dex—we have a lot of regimens that are dependent on this drug and you cannot get rid of it in just one stroke.”
Moving to high-dose versus low-dose dexamethasone, he cited the ECOG Phase-III E4A03 trial of high-dose vs low-dose lenalidomide, which he also led, as the only time there was a head-to-head competition of high-dose versus low-dose (presented at the most recent ASCO Annual Meeting and updated in December at the ASH Annual Meeting).
“The high-dose regimen came up very short, with remarkably low survival rate compared with the low-dose regimen,” he said.
Dr. Rajkumar said that high-dose dexamethasone does have a role in multiple myeloma—namely, in cases of acute renal failure, in combination with thalidomide or bortezomib in patients younger than 65; in relapsed/refractory multiple myeloma; and in ongoing clinical trials.
And high-dose dexamethasone has a role in those few cases where insurers will not authorize lenalidomide until the patient has had some other treatment, he added, noting that he has given one cycle of high-dose dexamethasone and then reported unacceptable toxicity without response and then received approval to add lenalidomide to the treatment.
‘Less is More’
“I've got the much easier task of persuading you that less is more,” Dr. Richardson began, limping to the podium due to a strained ankle from an early morning run. “Dexamethasone combinations with novel therapy are here to stay; the interesting question is whether we can use less and achieve more with the combinations compared with the past, when we were forced [to use high-dose dexamethasone] by virtue of the paucity of drugs we had to maximize dose.”
Dexamethasone itself is not dead by any means, he said, and has a role in treatment from diagnosis through to the relapsed/refractory setting.
“But one quickly learns that patients detest dexamethasone in the prolonged and high-dose fashion,” he said. “Therefore we need to bear in mind that low dose at the beginning, low dose in the middle, and low dose at the end need to be considered.”
Dr. Richardson said “very convincing” evidence supporting use of low-dose dexamethasone comes from Dr. Rajkumar's landmark ECOG-E4A03 study in the induction and first-line setting. “But even in the treatment of relapsed and refractory diseases when we face patients who deal with constant morbidity, toxicity, infection risk, and so forth, I think low-dose dexamethasone will be very important,” he said.
The E4A03 trial demonstrated that when high-dose dexamethasone was combined with lenalidomide in the upfront setting, a different spectrum of side effects was seen than with high-dose dexamethasone alone. “One has to recognize that these two drugs are probably synergistic…in the context of tumor kill, so there may be synergism in terms of toxicology as well,” Dr. Richardson said.
In the upfront context, Dr. Richardson concluded that lenalidomide- and bortezomib-based approaches are enhanced with dexamethasone, but he said he strongly believed that to also be true with the low-dose context.
“It's very important as we build within this paradigm, that we recognize that less may be very much more when it comes to dexamethasone,” he said.
In the relapsed/refractory multiple myeloma setting, Dr. Richardson discussed two new regimens, both dexamethasone free. He cited a study of liposomal doxorubicin plus bortezomib versus bortezomib alone in which the combination showed a significantly longer time to progression over single-agent bortezomib—9.3 vs 6.5 months (reported at the 2006 ASH Annual Meeting by Robert Orlowski, MD, et al).
Liposomal doxorubicin-bortezomib also showed higher response rates, 52% vs 44% total response by modified European Group for Blood and Marrow Transplantation (EBMT) criteria (reported by Harousseau et al at the 2006 ASCO Annual Meeting).
Another dexamethasone-free regimen being tested for relapsed/refractory disease is bortezomib-melphalan-prednisone-thalidomide (VMPT), which in a trial of 30 patients produced a complete or very good response in 43% of patients (Palumbo A et al: Blood 2007;109:2767–2772).
“These kinds of response rates you'd expect in the upfront setting, but this is second-relapse/third-line therapy,” Dr. Richardson said.
His own favorite non-dexamethasone regimen, he said is lenalidomide-bortezomib (Rev-Vel), two drugs he said would be the “backbone gents” in multiple myeloma.
His own Rev-Vel study, presented at the 2006 ASH Annual Meeting, has shown a 58% overall response rate (by EBMT criteria) with no significant peripheral neuropathy. “My lead patient, who progressed after allogeneic transplant, is now 56 cycles into her lenalidomide-bortezomib combination, with no peripheral neuropathy” he said. “I don't think she'd be tolerating that therapy with steroids in the mix.”
A significant number of hematologists in the audience apparently heeded both speakers in their arguments against high-dose dexamethasone in newly diagnosed multiple myeloma.
Before the debate, the approximately 100 members of the audience voted by touch pad: 19% for Yes (for the use of high-dose dexamethasone) and 81% for No. Afterwards, the voting was 8% Yes and 92% No.