October 25, 2010
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Impressive response rate seen with three-drug regimen for multiple myeloma

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For the first time ever, a three-drug regimen resulted in a 100% response rate and a favorable tolerability profile in patients with multiple myeloma, according to new findings.

The combination of lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium Pharm) and dexamethasone proved highly effective for previously untreated multiple myeloma, and these findings may change future standards of care in this setting, the investigators reported in their study recently published in Blood.

There are numerous exciting upfront treatment options that appear to be promising, said the study’s lead author, Paul G. Richardson, MD, clinical director, Jerome Lipper Center for Multiple Myeloma at Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.

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Paul G. Richardson, MD and colleagues are evaluating the benefit of early autologous stem cell transplantation combined with the three-drug regimen for multiple myeloma.

Photo by Dana-Farber Cancer Institute

“The bortezomib/lenalidomide combination is especially exciting because of the depth and quality of response, together with a manageable tolerability profile,” Richardson told HemOnc Today. “The bottom line is that the bortezomib-based or lenalidomide-based therapies show the greatest promise in my view, with the combination of the two generating the best results to date in several studies.”

The phase 1/2 study was the first prospective multicenter investigation of the lenalidomide/bortezomib/dexamethasone regimen, otherwise known as RVD, in newly diagnosed multiple myeloma patients. In addition to showing impressive activity in treated patients, RVD also demonstrated favorable tolerability over a lengthy period with no treatment-related mortality.

Patients received 3-week cycles of bortezomib dosed between 1 mg/m2 or 1.3 mg/m2 on days 1, 4, 8 and 11; lenalidomide 15 mg to 25 mg on days 1 to 14; and dexamethasone 40 mg or 20 mg given on the day of and day after bortezomib. Responding patients received maintenance therapy with weekly bortezomib and lenalidomide given on the same 2-week-on, 1-week-off schedule, or proceeded to transplantation, according to physician and patient choice. Phase 2 dosing was determined to be bortezomib 1.3 mg/m2, lenalidomide 25 mg and dexamethasone 20 mg.

The rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Complete or near-complete response was seen in 54% of patients treated at the phase 2 dosing. Twenty-eight patients (42%) subsequently underwent transplantation successfully and without any unusual events reported.

The median length of follow-up was 21 months, with an estimated 18-month PFS and OS for the combination treatment with/without transplantation of 75% and 97%, respectively.

Phase 3 studies are in progress to compare lenalidomide-dexamethasone with or without bortezomib to assess the benefit of the three-drug approach, as well as in other sequences. In addition, an international randomized, prospective study led by Dana-Farber Cancer Institute in partnership with the Intergroupe Myelome Francophone is now under way to assess this combination with or without autologous stem cell transplantation, followed by maintenance.

According to A. Keith Stewart, MB, ChB, professor of medicine, Mayo Clinic Arizona, the RVD regimen represents a leap forward in the treatment of multiple myeloma and will likely serve as an important platform on which to continue building treatment strategies, as well as a new standard of care.

“Nevertheless, there were still significant issues [with RVD]. The combination is complicated by painful sensory neuropathy in 32% of patients; 40% of patients required dose reductions, missed doses, or had to discontinue therapy due to toxicity,” Stewart said in an editorial accompanying the Richardson study, although peripheral neuropathy was mild to moderate in almost all patients affected, with only one grade 3 event reported, and proved reversible in the majority.

In younger patients who are eligible for transplant, Stewart said he prefers to use combination induction therapies like RVD that will likely offer a rapid and deep response. Maximizing initial response will translate into better long-term disease control and survival for most patients, and therapy should not be saved.

“I think the majority of evidence supports using a multiple drug combination of three or maybe four drugs,” Stewart said.

The EVOLUTION trial is currently examining which combination therapy to use, according to Stewart, and highlights potential benefits of combination therapy in newly diagnosed patients.

The randomized, phase 1/2 trial compares cyclophosphamide combined with bortezomib, dexamethasone and lenalidomide (VDCR) with RVD and VCD (bortezomib, cyclophosphamide and dexamethasone). In the phase 1 portion of the study, cohorts of three to six patients received a cyclophosphamide dosage of 100 mg, 200 mg, 300 mg, 400 mg or 500 mg/m2 (on days 1 and 8) plus bortezomib 1.3mg/m2 (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1–14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m2, on days 1, 8, 15 and 22).

The overall response rate was 96%, including 20% stringent complete response, 40% complete response/near-complete response and 68% very good partial response. VDCR was generally well tolerated and highly active in this population, but was associated with more myelosuppression and infection than RVD, as well as two cases of possible treatment-related mortality plus potentially more severe peripheral neuropathy seen with the addition of the alkylating agent.

“The results of all these combination regimens are better than anything that anyone else has reported outside of transplant studies. I think this is an important advance,” Stewart told HemOnc Today.

The combination of bortezomib, thalidomide and dexamethasone (VTD) is similarly one of the most impressive frontline treatments to arise during the past decade, according to William I. Bensinger, MD, member of the Fred Hutchinson Clinical Research Center and professor at University of Washington School of Medicine, Seattle. The Fred Hutchinson Clinical Research Center uses the VTD regimen for patients not participating in a clinical trial, Bensinger said.

A similar trial that used smaller doses of bortezomib also had interesting results, Bensinger told HemOnc Today.

“The so-called ‘little vTD’ trial compared the dose with standard bortezomib/dexamethasone. That showed better overall response and less neuropathy than what is generally seen with the standard dose of bortezomib,” he said.

Less intensive options

Although data on the combination drugs appear impressive, some clinicians still advocate the use of less aggressive therapy, particularly for patients who are at a lower risk for progression.

James R. Berenson, MD, medical and scientific director, as well the CEO of Oncotherapeutics and the Institute for Myeloma & Bone Cancer Research, West Hollywood, Calif., said for frontline treatment, he generally uses alkylate-based therapy, either melphalan or cyclophosphamide (Cytoxan, Bristol-Myers Squibb — Mead Johnson) with 1-mg metered dose of bortezomib on a 4-week schedule.

“I strongly believe in lower doses and longer cycles,” Berenson told HemOnc Today. “I’m not convinced at this point that in most low- and standard-risk myeloma that combination therapy — although it yields a higher response rate — necessarily improves the most important outcome, which is quality of life and length of life. I think, in general, we may have overtreated this disease, much to the disservice of the quality of life of our patients.”

Brian G. M. Durie, MD, chair and medical director of the International Myeloma Foundation in Los Angeles, and director of research and myeloma programs at Cedars-Sinai Comprehensive Cancer Center in Los Angeles, said he also prefers to use the minimal amount of treatment and then retreat when a patient relapses to achieve a later response.

Brian G. M. Durie, MD
Brian G. M. Durie

“There are those who would say that you should automatically start with three to four drugs. I prefer to start with two to three drugs and only use the other drugs if you need to — either initially or save them for later,” Durie said.

Right treatment for each patient

Most experts in the field agree there is no clear-cut answer regarding which frontline therapy is best for treating patients with multiple myeloma, because it depends on the patient. Patients must be evaluated individually and therapy based on the health and age of each patient.

“If a patient has diabetes and neuropathy, you may want to treat them with a different drug than you would for a patient with renal issues,” said Morton Coleman, MD, director of the Center for Lymphoma and Myeloma, New York Presbyterian Hospital-Cornell Medical Center, and HemOnc Today Editorial Board member. “You must tailor the therapy to suit the patient.”

Durie said it is helpful to have an age cutoff to use as a guide for choosing treatment, and uses 65 years as a tentative cutoff.

“There’s under age 65, then 65-75 and then over 75. You can definitely stratify what you consider related to age,” Durie said. “Under age 65, you’re looking at things related to the philosophy of your approach at the present time. That philosophy is mostly impacted by what you think about the role of transplant, both autologous and allogeneic.”

Treatment-related morbidity is another important issue to consider when choosing a treatment.

Data from the large phase 3 randomized MRC IX trial from the United Kingdom presented in Barcelona at the European Hematology Association Congress in June indicated that median survival for patients who received zoledronic acid was 6.5 months longer than in those who received clodronate plus similar forms of chemotherapy administered to both arms. The investigators gave the zoledronic acid continuously until disease progression, rather than the 1 to 2 years currently recommended. The study enrolled 2,000 patients, making it the largest of its kind to date.

A potential downside to using zoledronic acid is a rare but important complication known as osteonecrosis of the jaw (ONJ). The risk of ONJ was 3.5% in this prospective trial, but the rate may also depend on the patient population and the underlying dental health of the patients. In the United States, the risk of ONJ can be as high as 12% to 15%, according to Durie, but these data have generally been retrospective and so subject to attribution bias.

“ONJ is a serious problem that could cause a huge disability with the off-chance that the patient might live a few months longer, especially when there are other treatments that could accomplish that without the debilitating side effect,” he said. “The MRC data are not convincing enough to suggest continuous use of Zometa. I would stick to the old protocol that calls for using Zometa for a maximum of 1 year or possibly 2 years.”

Morton Coleman, MD
Morton Coleman

In contrast, Berenson said he never believed in the fixed time. He began using zoledronic acid in clinical trials in 1995, generally keeps patients on zoledronic acid for as long as they are responsive.

“I am certainly a true believer in the drug to not only improve bone disease — which is disappearing, thanks to that drug — but also to improve the overall survival of patients,” Berenson said. “I do believe it should be a chronically used drug, with the awareness that the drug can, on occasion, cause ONJ.”

Richardson agreed with Berenson regarding the benefits of zolendronic acid.

“My sense of this is that it brings into question the whole strategy of abandoning bisphosphonate after 2 years. It also lays to rest the debate that bisphosphonates are at best a mixed blessing. They clearly are not,” Richardson said. “They are a vital part of myeloma care, in my opinion, and while the side effects are important to be aware of, they are generally manageable and reversible with appropriate supportive care.”

With regard to patients older than 65 years, a well-tolerated oral regimen is generally best, according to Durie, and several regimens should be discussed with the patient.

“You need to consider the logistics for an individual patient, and also the cost. These days you need to pay attention to what the patient’s health plan will cover. You need to be cautious and know what the situation is before you start discussing the options,” Durie said. “You’re looking for the most effective oral combination for older patients. There’s a lot to be said for Revlimid plus low-dose dexamethasone, which has a high response rate and it’s very well tolerated for an older patient.”

Bensinger said data from several randomized trials comparing melphalan and prednisone to melphalan, prednisone and thalidomide (MPT) as well as trials comparing melphalan and prednisone with bortezomib (MPV) all clearly show that either of those two regimens is effective for treating multiple myeloma.

Findings from studies of lenalidomide and low-dose dexamethasone also show promise, Bensinger said. However, there is a lack of data that compares the lenalidomide/low-dose dexamethasone regimen to other treatment regimens.

“While the data look good, without randomized studies, it’s hard to know if Revlimid-dexamethasone is better or worse than MPT or better or worse than MPV,” Bensinger said.

Fast Facts

Is transplant still necessary?

The goal of frontline therapy for multiple myeloma is complete remission and/or long-term disease control. While most centers in the United States offer transplant to younger patients, the issue of whether autologous stem cell transplantation contributes to the depth and duration of remission is being evaluated by Richardson and colleagues. The trial is designed to determine whether the new drug combination of RVD will benefit from early transplant or be sufficient with transplant being kept in reserve, Stewart said.

“I think that most people still think that auto transplant would be a standard of care and would automatically consider recommending it for a patient under 65 years,” Durie said. “We don’t know that in the era of novel agents. What is the added value of doing an auto transplant for someone who is already in a complete remission with something like Velcade, Revlimid and dexamethasone, for example? That combination is a top-of-the-line sort of treatment that some consider has the best response rate as a first-line choice.”

Although some patients may be considered eligible for transplant, the patient and/or clinician may not choose that treatment. Durie said the most recent numbers for the United States show that only one-third of eligible patients actually proceed with transplantation.

“That’s partly a physician preference in that the other treatments have improved so much that it’s not an absolute necessity,” he said. “Also, the patient must be considered. A transplant does help achieve a better response with drug therapy but it does not guarantee a longer remission. So many patients are willing to stay on drug therapy without transplant.” – by Cassandra Richards

POINT/COUNTER
Should maintenance therapy now be a standard of care after autologous transplantation?

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