Consider High-Dose Chemo in Multiple Myeloma Patients

LUGANO, Switzerland—A debate at the VII International Conference on Malignant Lymphoma proved to be less controversial than expected when the two opposing speakers came close to agreeing that the possibility of high-dose chemotherapy with hematopoietic support should be weighed in all patients with symptomatic multiple myeloma.

“Nobody should not have high-dose therapy, and everybody should be a candidate,” urged Bart Barlogie, MD, of the University of Arkansas for Medical Sciences, Little Rock. He recommended that melphalan (Al-keran) and BCNU (carmustine) be withdrawn, and patients maintained on corticosteroids to permit collection of peripheral blood stem cells for autologous transplant.

Robert Kyle, MD, of the Mayo Clinic took a somewhat more measured approach, advising that autologous stem cell transplantation be considered in multiple myeloma patients under the age of 70 years.

“I don’t go as far as Dr. Barlogie and say that every patient should have an autologous transplant, but one should at least mention this to the patient,” he said. “Stem cells should be collected before the patient has been exposed to alkylating agents because, after alkylating agents, the hematopoietic stem cells are frequently damaged,” he added.

Dr. Kyle commented that the myeloma community “spent a quarter century arguing and developing prospective studies comparing melphalan plus prednisone with a variety of alkylating agent combinations.”

However, he pointed out, a recent Oxford Trials Group meta-analysis of 20 prospective randomized studies involving nearly 5,000 patients showed that the superior response rate achieved with standard-dose combination chemotherapy did not translate into improved survival.

“Autologous stem cell transplantation is associated with a low mortality and is available for at least half of patients with multiple myeloma,” Dr. Kyle noted. “Two disadvantages,” he said, “are that the reinfused peripheral blood stem cells contain myeloma cells or their precursors, and that virtually all patients will eventually relapse.”

Thus, the two major challenges for autologous transplantation, Dr. Kyle said, are to eradicate multiple myeloma from the patient and to improve stem cell selection procedures so that myeloma cells and their precursors are removed from the peripheral blood.

“The only randomized trial of autologous transplantation to date, conducted by the French Myeloma Group, demonstrated a prolongation in median survival from 42 months to 57 months after autologous bone marrow transplantation,” Dr. Kyle noted.

He cited another French Myeloma Group trial that found no difference in 2-year event-free survival or overall survival between patients randomized to single autologous transplantation vs those assigned to double transplantation.

“Both good-risk and poor-risk patients should be transplanted,” Dr. Kyle recommended. “But it is important to realize which type of patient you are transplanting,” he continued, “because good-risk patients will do reasonably well with any therapy whereas poor-risk patients will not do well with either standard-dose chemotherapy or high-dose chemotherapy with autologous stem cell transplant.”

Promising strategies to prevent relapse following autologous stem cell transplantation include autologous dendritic cell vaccinations, he said.

Allogeneic Transplants

“Although allogeneic bone marrow transplantation has the obvious advantage of no contaminating tumor cells,” Dr. Kyle said, it is not an option for 90% to 95% of multiple myeloma patients because of age or the lack of a suitable donor. Most discouragingly, early mortality related to transplant is as high as 25% in the first 100 days. “Unfortunately, there is no evidence that these patients are actually cured, since the survival curves are not yet flat,” he cautioned.

The largest experience with allogeneic transplantation is that of the European Bone Marrow Group, which has transplanted more than 266 patients with multiple myeloma. These investigators have reported a complete response rate of 51%, a transplant-related mortality of 40%, a 4-year overall survival rate of 30%, and a 10-year overall survival rate of 20%, compared with only 5% to 10% for chemotherapy alone.

“If a patient has survived a transplant, the use of donor lymphocyte infusions is helpful, and more than half of these patients will respond,” Dr. Kyle said.

Principal remaining challenges are to reduce transplant-related mortality through such approaches as T-cell depletion or mini-allogeneic transplantation, and to improve the preparative regimen so as to destroy more myeloma cells in the patient.

“I predict that within the next 1 to 2 decades, we will not be disagreeing about autologous or allogeneic transplantation,” Dr. Kyle forecast. “We will have better therapy that is dependent not on tumor kill, but on biologic changes that reverse myeloma to the MGUS [monoclonal gammopathy of unknown significance] stage.”

Tandem Transplant Trials

In the last decade, Dr. Barlogie and his colleagues have treated more than 1,000 patients with multiple myeloma in tandem (double) transplant trials using melphalan, 200 mg/m².

In contrast to the 5% complete remission rate achieved with standard chemotherapy, he said, biopsy-confirmed complete remission rates jumped to 40% with high-dose therapy. For previously untreated patients under the age of 65, event-free survival was 3.6 years, with overall survival reaching 6.7 years.

“The most important point that I’m trying to drive home is that we should employ the best that we have in a disease that is notoriously resistant to currently available drugs; one strategy to exert growth control is dose escalation, which we can do very safely with melphalan,” Dr. Barlogie said.

Of the 40% of patients who have a complete remission, two thirds who do not have a chromosome 13 deletion and who do have a low ß2-microglobulin level will continue in complete remission for as long as 6 years, he said.

According to Dr. Barlogie, disease associated with a chromosome 13 deletion represents a distinct new entity in the spectrum of multiple myeloma conditions. Multivariate analysis has pinpointed this cytogenetic aberration as a key determinant of adverse outcome, along with elevated ß2-microglobulin levels, duration of prior therapy, high C-reactive protein levels, and the IgA isotype.

For the 20% of patients in Dr. Barlogie’s series who had none of the standard risk factors, event-free survival at 6 to 7 years was 60%. On the other hand, he said, among patients exhibiting all of these risk factors, median survival was only 2 years.

“If you add chromosome 13 information to the standard risk model,” Dr. Barlogie said, “you can see that, for each and every risk category, the presence of deletion 13, pertinent to about 10% to 15% of patients, is a very unfavorable feature indeed.”

He noted that among patients with no other risk factors, median overall survival is 7.8 years in the absence of a chromosome 13 deletion, but only one third as long in the presence of a chromosome 13 deletion.

“Two additional determinants of long-term event-free survival,” Dr. Barlogie said, “were the achievement of a complete remission and the timely administration of a second course of high-dose therapy within 9 months of the first.”

DCEP for Recurrences

For patients who experience recurrences despite high-dose therapy, Dr. Barlogie and his team have developed the DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) combination chemotherapy regimen. “This is a very effective salvage regimen for post-high-dose-therapy relapses,” he said.

In a pilot study, 54 high-risk patients received DCEP as a post-high-dose consolidation strategy. DCEP converted 16 of these patients from a partial remission to a complete remission and yielded a 2-year event-free survival rate of more than 80%, compared with less than 16% for matched controls.

Turning to noncytotoxic approaches, Dr. Barlogie told the audience that treating the bone marrow microenvironment with bisphosphonates not only delays the onset and severity of bone complications but also may produce occasional tumor responses.

Single-agent thalidomide (Thalomid) may also bring about dramatic, nearly complete remission after transplant failure, he said. In a study of 89 patients in the post-transplant setting, about 25% responded to this antiangiogenic agent.

Remission Is the Goal

“If complete and sustained remission is the goal, it is important to try to push the incidence of complete remission beyond 50% and build on these additional observations,” Dr. Barlogie said. “Right now cytotoxic therapy seems to bring about complete responses and seems to contribute, with a consolidation regimen such as DCEP, to durable remissions.”

He described an ongoing trial that is attempting to clarify the role of thalidomide and compare two consolidation regimens of different intensity. Patients are being randomized to thalidomide or no thalidomide, then treated with two cycles of melphalan, and subsequently randomized to either DCEP or DCEP/VAD (vincristine, doxorubicin, dexamethasone).