April 2002

Novel Regimens Emerging for Myeloma
by Lilian Delmonte, D.Sc.

Editor’s Note: This article is condensed from “Oncology Times” magazine and reprinted in “UAMS Update” by permission of the publisher. Many colleagues, cancer patients, and members of the UAMS institutional family already know about the significance of the work of Dr. Barlogie’s research team, but it’s nice to hear it from an exterior source.

Bart Barlogie, M.D., Ph.D., director of the Myeloma Institute for Research and Therapy and professor of medicine at the UAMS College of Medicine in Little Rock, spoke in New York City at a recent Chemotherapy Foundation Symposium. He said, “Over the past two decades, with the introduction of the tandem transplant treatment concept and the entry of thalidomide into the multiple myeloma clinic, enormous strides have been made in the treatment of the disease. The incidence of complete remission, stringently defined by immunologic and bone marrow criteria, has risen from five percent to 60 to 70 percent, and event-free and overall survival have been extended markedly,” he noted.

“Using the tandem transplant concept — high-dose melphalan followed by two autologous bone marrow transplants (BMT) — we pushed complete remissions from five percent to 40 percent,” Dr. Barlogie said. “Is it important to point out that we did not use total body irradiation in the conditioning regimen. Among 231 patients treated between 1989 and 1994, therapy-related mortality was in the range of one to two percent. At 10- to 11-year follow-up, we are seeing about 40 percent overall survival, with 25 percent event-free survival.”

In the late 1990s, Barlogie made the seminal discovery that thalidomide monotherapy has major efficacy in multiple myeloma, even in patients relapsing after two autologous BMT. Of the 169 patients in the original Phase II study, 40 percent are still alive at three years, and about 20 percent are event-free.

Currently, Barlogie’s team is evaluating the potential of adding thalidomide to the best available protocol (called Total Therapy I) for treating newly diagnosed multiple myeloma. The new protocol, Total Therapy II, consists of four sequential phases: (1) induction with dose-intense chemotherapy, utilizing alternating regimens; (2) two consecutive autologous blood stem cell transplants; (3) one-year consolidation chemotherapy; and (4) long-term maintenance with alfa-interferon. Upfront, patients are randomized to receive or not to receive thalidomide.

Barlogie compared the results of the first 231 patients receiving Total Therapy II with 231 patients on the earlier Total Therapy I protocol. At the two-year follow-up, the incidence of complete remission and near-complete remission was 65 percent with Total Therapy II, versus 40 percent with Total Therapy I.

Survival comparison between the two groups revealed significantly superior overall and event-free survival with Total Therapy II, he reported. Data are still blinded with regard to thalidomide randomization. Interestingly, Barlogie noted, treatment-related mortality with the new and more dose-intense protocol was significantly lower than the earlier Total Therapy I protocol.

His team has also studied gene-expression changes in about 30 patients following single-agent intervention, looking at critical drugs including dexamethasone, thalidomide, or Imid (a new thalidomide analog with considerably less neurotoxicity and fewer sedative effects than thalidomide itself).

The gene-expression studies allow a better understanding of the molecular genetics of multiple myeloma and the mechanism of action of critical drugs and a better understanding of the basis for responsiveness and non-responsiveness of multiple myeloma cells to specific agents. The technology has also begun to uncover potential targets for new therapies.

He also highlighted the cutting-edge data of gene-expression profiling by DNA microarray technology, developed by his colleague Dr. John Shaugnessy. An article has been scheduled for publication in the journal, Blood, about this research. Another colleague, Dr. Maurizio Zangari, found that therapeutic doses of an anticoagulant such as coumadin could largely prevent formation of deep venous thromboses. Dr. Zangari has also demonstrated that multiple myeloma patients have a higher incidence of acquired protein resistance, which contributes to the higher incidence of deep venous thromboses.

Many more treatment modalities that appear to be active in advanced and refractory disease are now in the pipeline, Barlogie said, adding that they will need to be evaluated cautiously in the clinical trial setting. Also at issue, he pointed out, is how best to incorporate them into front-line management of these patients.

“There have been major advances in the treatment of multiple myeloma through the pursuit of dose-intensive therapies, and the discovery of new agents including thalidomide, its analog Imid, and the investigational drug PS 341,” Barlogie concluded.