New Life for an Old Drug

by Angelique Siy

Thalidomide became infamous worldwide for causing thousands of serious birth defects in the late 1950s and early 1960s. But in the years since it was pulled from the market, researchers have found new ways to capitalize on its properties—some of which are inseparable from the ones that gave the drug its bad reputation.

In recent years, thalidomide has been shown to be successful in treating erythema nodosium related to leprosy as well as some hematologic cancers, such as myelodysplastic syndrome (MDS) and multiple myeloma. In fact, thalidomide led researchers to discover an entire class of promising related drugs: IMiDs, or immunomodulatory agents, which along with other novel agents, have revolutionized the treatment of multiple myeloma. One of the IMiDs, lenalidomide (Revlimid), performed so well in trial after trial that it was licensed for use in multiple myeloma and one form of MDS within 6 years of entering clinical trials. Lenalidomide is more potent against cell lines and has a different toxicity profile than thalidomide—in particular, it does not appear to have the teratogenic effects that led to thalidomide’s downfall.

The way IMiDs modify or regulate the functioning of the immune system is not known, but they have been documented as effective anti-angiogenics and antiinflammatories, with direct cytotoxic effects on myeloma cells—both in vitro and in patient-derived primary myeloma cells—and some effects on the microenvironment of the bone marrow that affects myeloma cell growth. In addition to being anti-angiogenic, lenalidomide seems to affect myeloma cells by inducing apoptosis, inhibiting growth, and reducing adhesion to bone marrow stromal cells. Clinical investigators have realized that other IMiDs share these traits to different degrees and with different adverse effects, which they hope means that less toxic and more effective drug combinations can be discovered. Trials of IMiDs given in combination with other proven antimyeloma agents such as bortezomib, a proteasome inhibitor, and other chemotherapeutics like cyclophosphamide, melphalan, dexamethasone, and doxorubicin have provided alternative and improved regimens for myeloma. Future studies with biphosphonates (pamidronate and zoledronic acid), an anti-CD40 monoclonal antibody, and even the “proto- IMiD,” thalidomide, may provide even more options for patients with this multiple myeloma.

Donna Weber, M.D., who has been involved in multiple myeloma clinical research, is an associate professor in the Department of Lymphoma at The University of Texas M. D. Anderson Cancer Center. “We are finding more and more active novel agents. With thalidomide, lenalidomide, and bortezomib, there is additive, and probably synergistic, interaction, so that even if patients are resistant to these drugs as single agents, they can be combined with each other, as well as with conventional agents, providing many more effective alternative combinations for the treatment of myeloma.

“The IMiDs are unique; there’s an entire range of possibilities with them,” Dr. Weber continued. “The old and new agents are being used together in the same regimens. Each novel agent has shown survival benefits. It’s a whole new world for myeloma patients. I’ll give you an example of the impact it has had on just one patient.”

Good timing pays off

“In 1992, I had a patient who was diagnosed with multiple myeloma,” Dr. Weber said. “The standard of care in 1992 was essentially combinations of alkylating agents or anthracyclines, like melphalan and prednisone, or vincristine, Adriamycin, dexamethasone (VAD), followed by myeloablative therapy with stem cell transplant. When these and other treatment options began to fail in slowing the disease, we tried intensive therapy supported by autologous hematopoietic stem cell transplantation. When that also failed and we couldn’t find a match for an allogeneic transplant, the patient was running out of options.

“That’s when (1997) Dr. Bart Barlogie’s initial findings of thalidomide’s apparent effectiveness against multiple myeloma were reported at the International Myeloma Workshop,” said Dr. Weber. “Fortunately, we were among the first to begin trials to confirm its efficacy. This patient did well on thalidomide, and subsequent thalidomide combinations controlled the disease until about 2 years ago. By that time the field of myeloma was in a new phase of discovery and we were able to try another new agent, bortezomib.” Bortezomib (Velcade) is one of a new class of drugs called proteasome inhibitors and was approved by the FDA for resistant multiple myeloma in May 2003.

And the patient? “He achieved his best response ever, a complete remission, on bortezomib,” said Dr. Weber.

That patient was far from alone in having so few treatment choices against so lethal a cancer. Multiple myeloma, also called myeloma or plasma cell myeloma, accounts for 13% to 33% of all hematologic cancers and affects 50,000 people in the U.S. alone. A patient diagnosed with multiple myeloma is typically 65-75 years old and faces a mean survival time of 3 to 5 years. The disease’s 5-year survival rate of 32% has remained virtually unchanged for over 45 years. Although relapses are common, nearly half the patients diagnosed with multiple myeloma will, as a result of these new treatments, achieve complete remission, and with time many doctors expect to see the benefit of novel agents in terms of survival.

Treatment breakthroughs

Now, with the approval of thalidomide, bortezomib, and lenalidomide for multiple myeloma, there is a whole new treatment paradigm for multiple myeloma. Lenalidomide’s potential would not likely have been discovered had it not piggybacked on thalidomide’s rediscovery. Fortunately, several very persistent and innovative thinkers, over the course of 30 years, connected the ideas that angiogenesis might be important to the growth and spread of cancer; that thalidomide was possibly anti-angiogenic; and that multiple myeloma, a disease for which treatment progress was slow, might respond to anti-angiogenic treatment, given that the bone marrow of patients with multiple myeloma had been shown to have significant vascularization. This was followed by the realization that IMiDs had many other effects on processes that drive myeloma cell growth.

By the early 2000s, Dr. Weber and colleagues had completed several studies that confirmed and expanded upon the results of Dr. Barlogie’s (University of Arkansas for Medical Sciences [UAMS] in Little Rock, Arkansas) original thalidomide trial in patients with advanced multiple myeloma.

Dr. Weber recalls a series of discoveries that led to a great deal of attention: “After the original thalidomide discovery, it was kind of a fluke that we gave one-tenth the standard myeloma dose of dexamethasone to treat a rash in a patient with VAD-resistant disease being treated with thalidomide. The patient went into remission and this led to an observation that 45% of patients responded to the combination of thalidomide and dexamethasone despite prior resistance to both drugs given as single agents. This opened the door for many new combinations for novel and established agents for treatment of myeloma. In August 2001, the UAMS lead researcher told the American Cancer Society that because preliminary studies of thalidomide were so promising, many oncologists weren’t waiting; they were using it off-label in patients whose cancer had failed to respond to other therapies. He estimated that about 10,000 patients worldwide with multiple myeloma had received the drug, which meant there was much more evidence to publish.

“After that, many trials confirmed the initial findings for resistant myeloma. It was very exciting because of the dramatic results for resistant disease, and it was natural for investigation to expand to untreated patients with myeloma. Two concomitant trials (M. D. Anderson, Mayo Clinic) demonstrated 65% to 70% response rates in previously untreated patients with potentially serious but manageable side effects, which led to a 2001 randomized trial that confirmed thalidomide and dexamethasone’s superiority compared with dexamethasone alone and subsequent approval of thalidomide in 2004 for use in treating previously untreated myeloma patients.

“For the field of myeloma, finding a new single agent whose activity is nearly as great as steroids is monumental,” Dr. Weber said. “When thalidomide made its reappearance, it changed a lot of patients’ lives. Myeloma became the field to watch, and in the last decade, three new novel agents have been approved. The growth of the field has been amazing.”

In 2000, phase I and II clinical trials demonstrated activity of lenalidomide in myeloma patients. Dr. Weber and her team were the national principal investigators, and two trials proved lenalidomide had a manageable adverse effect profile. At high doses, lenalidomide’s most common toxicities included thrombocytopenia, neutropenia, and skin rash. Based on these results, the FDA awarded the drug a fast track designation for relapsed and refractory myeloma in February 2003.

Dr. Weber and her team were the investigators for a North American phase III trial that proved superiority of lenalidomide-dexamethasone over dexamethasone alone for patients with relapsed multiple myeloma. The results of this trial were nearly identical to a concomitant sister trial in Europe, Australia, and Israel led by Dr. Meletios Dimopoulos. By March 2005, these two ongoing phase III clinical trials demonstrated lenalidomide-dexamethasone to be more effective than dexamethasone alone. The trials were unblinded early, and patients who had not been given lenalidomide were given the option of adding it to their regimen, if warranted. In June of this year, lenalidomide received FDA approval for use in combination with dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy.

And next?

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, September 2006 issue:

• Zeroing in on a Moving Target
• In Brief: Research News from the Laboratories and Clinics of M. D. Anderson
• House Call: Managing Your Medications
• DiaLog: Adjuvant Therapy for Aggressive Kidney Cancer

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