Peripheral blood stem cell (PBSC)-supported high-dose melphalan 200 mg/m2 is now considered standard therapy for patients with symptomatic or progressive myeloma. During the last five years, additional new agents effecting salvage rates of 30% - 50% have been discovered and patient outcomes improved.
Standard Therapy for Myeloma
Pursuit of dose intensity with melphalan had markedly increased the frequency of complete remission and, consequently, disease-free and overall survival. The dose-limiting toxicity of melphalan as a hematopoietic stem cell-damaging agent is irreversible bone marrow damage. A procedure commonly referred to as stem cell transplant can rescue patients from the harmful effects of prolonged myelosuppression. For this purpose, patients’ own peripheral blood stem cells, collected upon induction therapy with non-stem cell-toxic regimens such as VAD, are infused back into the patient 24 hours after melphalan therapy, effecting rapid recovery of blood counts with an average duration of neutropenia < 500/dL not exceeding 7 days. As a consequence, treatment-related mortality usually does not exceed 1% to 2%. In comparison to standard-dose chemotherapy with melphalan and prednisone or combination therapies with additional alkylating agents, a single melphalan 200 mg/m2-based autotransplant has been shown to increase complete response rates from < 5% to 25%, usually associated with extension of event-free and overall survival by at least one year. Thus, despite similar total cumulative doses of melphalan with low-dose chronic versus high-dose administration, the reduction of tumor burden is substantially lower with standard dosing due to ineffective cell kill, resulting in additional gene mutations and further drug resistance.
While stem cell transplantation overcomes the harmful effects of bone marrow damage inflicted by high-dose melphalan, other side effects have become dose-limiting, especially mucositis, or inflammation of mucous membranes such as the lining of the mouth. In an effort to achieve further reduction of myeloma tumor burden, we started applying two cycles of stem cell-supported melphalan at 200 mg/m2 given within two to four months of each other for a total melphalan dose of 400 mg/m2. Such tandem autotransplants have now been shown, in a randomized clinical trial conducted by French investigators, to extend the duration of disease control and survival, while allowing mucous membrane recovery after the first transplant. With Total Therapy 1 performed at Arkansas in 231 patients, 40% achieved complete remission with an overall survival at 10 years of 35%. The dominant adverse prognostic feature was the presence of cytogenetic abnormalities prior to initiation of therapy, noted in one-third of patients. The two-thirds of patients presenting without cytogenetic abnormalities enjoyed a 10-year survival of 45%, compared to < 10% among those with cytogenetic abnormalities.
At the time of disease progression, we distinguish between primary resistance (failure to respond to initial therapy) and relapse following at least partial remission. In this latter setting, salvage therapy may not have yet been performed (untested relapse), or may have been effective (sensitive relapse) or ineffective (resistant relapse). In planning salvage therapy, these issues have to be considered along with the duration of remission, the circumstances of relapse (whether or not it occurred during therapy), and the number of autotransplants the patient has received. In addition, marrow examination, especially for cytogenetics and for evaluation of any normal marrow damage, and the possibility of secondary myelodysplasia/early leukemia must be considered. In anticipation of potential relapse after one or two autotransplants, there is a need for sufficient peripheral blood stem cell collection prior to the first transplant so that all treatment options remain open for relapse management. In our case, we typically attempt to collect 20 million CD 34 cells/kg body weight prior to first transplant.
Traditional salvage therapies include the VAD regimen, dexamethasone pulsing, thalidomide alone or combined with dexamethasone pulsing, or a highly effective regimen referred to as DT PACE, comprising dexamethasone, thalidomide, and 4-day continuous infusions of cisplatin, adriamycin, cyclophosphamide, and etoposide.
ADVANCES IN MYELOMA TREATMENT: THE PAST 10 YEARS
Several clinical factors have been linked to a poor prognosis in patients with multiple myeloma. The presence of cytogenetic abnormalities represents the most powerful adverse prognostic factor, present in one-third of newly diagnosed patients with symptomatic disease. The hazard of relapse and death with such chromosome abnormalities increases by two- to three-fold.
Thalomid®. Thalidomide was only the third compound, behind melphalan and dexamethasone, to be recognized as an independently active treatment for myeloma. One hundred and sixty-nine patients who were enrolled in a clinical trial and received up to 800 mg of the drug per day had a partial response rate of nearly 33% and extended event-free and overall survival. Thousands of myeloma patients have since benefitted from thalidomide treatment, which can be combined with chemotherapy because thalidomide does not interfere with the bone marrow production of blood cells and platelets. However, 50-80% of patients treated with thalidomide can suffer from peripheral neuropathy, a condition in which the nerves are affected, causing pain, numbness, or weakness of the extremities. In some patients, reducing the dose of thalidomide or stopping the treatment altogether will alleviate the symptoms. In a randomized clinical trial of Total Therapy II, the 4-year estimate of grade 3 or greater sensory neuropathy was 16% among 263 patients receiving thalidomide and 5% among 280 patients receiving no thalidomide. The combination of thalidomide and dexamethasone as both induction therapy (given prior to autotransplant-supported melphalan therapy) and as maintenance therapy (given after melphalan therapy) is now being examined by the Southwest Oncology Group (SWOG).
Revimid®. The thalidomide derivative, Revimid or CC-5013, can beneficially alter the patient’s immune system and kill myeloma cells both directly and indirectly by altering the bone marrow microenvironment. One-third of patients with advanced and refractory myeloma respond with at least a 50% reduction in measurable myeloma protein, typically associated with marked improvement or normalization of bone marrow. Revimid is essentially devoid of neurotoxic side effects but produces myelosuppression that is readily reversible, unless there is major bone marrow compromise from extensive prior alkylating agent therapy.
Velcade®. Velcade has been shown to have remarkable activity in patients with myeloma that has not responded to other regimens, including thalidomide. Also referred to as PS 341, this is one of a new class of agents for the treatment of myeloma, known as proteasome inhibitors. We are currently testing a combination of Velcade plus thalidomide for patients relapsing after melphalan-based autotransplants. Nearly 70% of more than 60 patients with sufficient follow-up achieved at least a partial response at the end of the third cycle of therapy, including nearly 20% who achieved complete remission.
Other Agents. Arsenic trioxide is another treatment under investigation. This compound targets mitochondria, the energy power houses in our cells, and thus may be able to initiate programmed cell death of myeloma cells. Other compounds under investigation by ourselves and others include monoclonal antibodies to interleukin-6 receptor and CD20, farnesyl transferase inhibitors, and STI 571 (Gleevec®).
Interferon was the first biologically-based treatment for myeloma. Randomized trials have revealed that patients receiving interferon as maintenance therapy had slightly improved event-free and overall survival compared with those receiving no maintenance therapy. Trials are also underway to determine whether vaccinations that have been developed from patients’ myeloma cells may be another means of treating the disease. We have begun an exciting trial employing cancer testis antigen peptide vaccination. These tumor-specific antigens, not present on normal tissue except testis, are expressed in over one-half of patients with myeloma, especially at the time of relapse in the high-risk setting of cytogenetic abnormalities.
Allogeneic transplants use stem cells from a donor, usually from a matched sibling. Only 1 of 7 patients potentially benefit from allogeneic sibling transplant. Major complications include graft-versus-host disease and opportunistic infections, which cause high first-year treatment-related mortality of about 50%. However, survivors of allogeneic transplants may experience fewer late relapses than survivors of autotransplants. The “mini-allo” transplant differs from the standard myeloablative regimens in that lower doses of conditioning treatment are employed, such as total body irradiation at 2 Gy or melphalan at 100 to 140 mg/m2 with or without fludarabine. Mini-allogeneic transplants are much better tolerated because of a virtual absence of mucositis and other toxicities, resulting in a marked drop in treatment-related mortality, from approximately 50% with standard allotransplants to the 10%-15% range. In view of the marked efficacy of donor lymphocytes in killing recipient myeloma cells, and in cases of cytogenetic abnormalities, we are offering this approach to high-risk patients following maximum disease control achieved safely with a single autotransplant (tandem auto/mini-allotransplant).
Targeting the Bone Marrow Microenvironment
Myeloma cell survival depends on interactions with the bone marrow “neighborhood,” the microenvironment. Thus, researchers have demonstrated that with treatment targeting the microenvironment by way of 1) osteoclast-inactivating bisphosphonates (Aredia or Zometa); 2) disrupting myeloma-stromal cell interaction (thalidomide, Revimid, Velcade); or 3) inhibiting angiogenesis; myeloma cells die and bone is preserved.
Myeloma researchers agree that, in order to control multiple myeloma, achieving a high frequency of complete remission early in the management is important for long-term benefit. Because of its potential for inducing a complete remission in nearly half of our patients, autotransplant-supported high-dose melphalan, especially in the setting of tandem transplants, has emerged as a safe platform of treatment upon which improvements can be anticipated by introducing thalidomide, Revimid and Velcade for remission induction prior to, and for maintenance after, autotransplants. Reduced melphalan doses at 100 to 140 mg/m2 with autologous hematopoietic stem cell support have recently been shown to be effective and safe in patients presenting with renal failure or advanced age (> 70 years), so that the majority of patients with myeloma can now be offered this highly effective therapy. We recommend that all patients with newly diagnosed myeloma be considered for appropriately dose-adjusted high-dose melphalan with stem cell support. The discovery of active new drugs, the immunomodulatory agents thalidomide and Revimid, as well as the proteasome inhibitor Velcade, has given hope to patients with refractory end-stage disease. MT
Note: The International Myeloma Foundation is proud to present its second Robert A. Kyle Lifetime Achievement Award to Bart Barlogie, MD, PhD, Professor of Medicine and Pathology, and Director of the Myeloma Institute for Research and Therapy in Little Rock, Arkansas. Dr. Barlogie is being honored for his outstanding body of work, both clinical and research, in the field of myeloma. The IMF is giving this award to recognize his tireless work to significantly improve care, treatment, and prognosis for many myeloma patients.
The IMF's Robert A. Kyle Lifetime Achievement Award was established to honor an individual whose lifetime body of work furthers the ultimate goal of finding a cure for myeloma. The accolade is named for Dr. Robert A. Kyle, noted physician and founder of the Myeloma and Related Diseases Research Group at the Mayo Clinic in Rochester, Minnesota.