The Arkansas Myeloma Program, launched in 1989 at the Arkansas Cancer Research Center on the campus of the Uni-versity of Arkansas for Medical Sciences, owes its origins to the developmental therapeutics work headed by Emil J Freireich, M.D. at the University of Texas MD Anderson Cancer Center in Houston. Dr. Freireich’s work led to curative therapies for malignancies such as leukemia, lymphoma, and testicular cancer, and the proven feasibility of autologous transplant. This work and his mentorship motivated Dr. Bart Barlogie and colleagues Dr. Sundar Jagannath and Dr. Joshua Epstein to develop a research and treatment program focused on understanding the biology and advancing the treatment of a single disease, namely multiple myeloma. It is this close interplay between basic science research and clinical practice, known as translational research, that is the unique hallmark of the Myeloma Institute for Research and Therapy. The Institute is the direct result of thirteen years of the Arkansas Myeloma Program, a program that has never strayed from these roots of the ‘bench-to-bedside’ approach to solving the myeloma puzzle.
In 1983, Dr. Tim McElwain, and colleagues, had demonstrated that increasing doses of melphalan by a factor of 6 to 10 resulted in a much higher percentage of myeloma patients obtaining a complete remission, when compared to standard therapy. This was subsequently confirmed by other investigators. This new treatment was promising but it resulted in very long periods of decreased white blood cell and platelet counts, which resulted in treatment-related mortality of 15% to 20%. To decrease this treatment-related mortality, Dr. Barlogie introduced the concept of bone marrow support after high dose melphalan. With this concept the dose of melphalan could be doubled. Although it appeared unlikely that such an intervention would cure end stage patients, because the bone marrow contained residual myeloma cells, it was hoped that the normal bone marrow cells would grow much faster than the myeloma cells and that survival could be significantly prolonged. Early investigations pursued the hypothesis that survival could be markedly improved by increasing the incidence of true complete remission.
Once benefit had been demonstrated in end-stage patients with a low treatment-related mortality, this approach was offered to newly diagnosed or relatively minimally-treated myeloma patients. Most autologous transplants at that time were administered to younger patients and incorporated very intensive chemotherapy schedules; it was thought that older myeloma patients would not be able to tolerate such high doses of therapy. Therefore, it was decided to give less intensive chemotherapy with melphalan alone, but to repeat this treatment 3 to 6 months later, when patients had completely recovered from the toxicities of the first transplant. It was hoped that the two transplants with less intensive high dose chemo-therapy would be equally effective as one transplant with very intensive chemotherapy, and that the mortality associated with transplantation would be considerably lower. Thus, the concept of tandem transplants was born.
Based on the principals of St. Jude investigators led by Dr. Donald Pinkel, the Arkansas investigators developed “Total Therapy I” for newly diagnosed myeloma patients. This was based on the observation that high dose chemotherapy requiring hematopoietic stem cell support resulted in higher complete response rates and extended disease control, when compared to standard therapy. Total Therapy I incorporated induction therapy, double (tandem) autotransplant, and maintenance therapy, using a combination of agents likely in doses high enough to be effective while still preserving positive recovery.
Moving forward from Total Therapy I to its successor trial, Total Therapy II, certain phase II regimens such as DCEP and DT PACE were developed. Remission induction was intensified by treatment principles that were successful with therapies applied to post-transplant relapse. In this way, the dexamethasone-resistant tumor subpopulation, presumed to be critical to disease recurrence, could be targeted. To target angiogenesis (growth of blood vessels that feed tumors)the Arkansas program pioneered the use of thalidomide, which, among other effects, also curtails angiogenesis activity. After establishing its activity in refractory myeloma, thalidomide is now being tested up-front in Total Therapy II. Discovery of thalidomide for use in myeloma was a major milestone in that it represented an independently active agent in addition to melphalan and glucocorticoids, e.g. dexamethasone, prednisone, for the management of myeloma.
Major grant support from the National Cancer Institute has enabled the Arkansas program to continue with its extensive translational research. Research and diagnostic techniques applied to all new patients with myeloma include baseline FISH, traditional cytogenetics, gene expression profiling, analysis of telomere length and telomerase activity of myeloma cells and bone marrow cells, serum and bone marrow banking for future research, and, very important to the mix, magnetic resonance imaging (MRI). Even within the boundaries of stringently defined complete remission, focal lesions can be detected on MRI. When these lesions are subjected to CT-guided fine needle aspiration, active tumor cells, often with abnormal cytogenetics, are frequently revealed. Part of the current research at Arkansas includes determination as to whether patients whose MRIs confirm complete remission have superior event-free and overall survival.
Analysis of the first 231 patients enrolled in the Total Therapy II protocol indicates that complete and near complete remission rate has increased to >60%, that despite the more intensive therapies the treatment-related mortality is not higher than with the predecessor Total Therapy I protocol. This is especially true in the older population. In addition, event-free and overall survival curves are superior to those of Total Therapy I. Despite the use of intensive cytotoxic therapy during induction and following tandem transplants, careful scrutiny for secondary myelodysplasia, cytogenetically and by other means, has not yet revealed any case of myelodysplasia-associated karyotype (chromosomal) abnormalities.
It should be noted that the success of phase II efforts leading up to the Total Therapy II protocol was instrumental in convincing the Health Care Financing Administration (HCFA) that age, per se, was not an adverse feature for autologous transplant, neither from a safety or a disease point of view. This led to HCFA approval for autologous transplantation for Medicare patients (one autologous transplant is covered by Medicare; a second transplant, which the Arkansas clinicians considers critical for long-term disease control, is not covered by Medicare). This was a major milestone, similar to earlier efforts to demonstrate that high dose chemotherapy followed by autologous stem cell transplant was safe also in patients with renal failure.
Major Findings Drive Research
- Bone Marrow Microenvironment
It is clear that the bone marrow microenvironment affects the ability of myeloma cells to thrive, to survive and to become resistant to chemotherapy, especially if delivered at standard doses. Using a unique mouse model, Dr. Epstein and colleague Dr. Shmuel Yaccoby have been able to unravel the characteristics of the bone marrow microenvironment, such that therapies to make the microenvironment inhospitable to myeloma cells can be developed. A current study compares the gene expression in cells of the bone marrow environment that has been infiltrated with myeloma cells to the gene expression in cells of normal, healthy bone marrow. It is expected that this study will yield information as to whether gene chip analysis (to determine gene expression) will aid in 1) defining clinical disease manifestation; 2) predicting response and long-term prognosis; and 3) deciphering the molecular mechanisms of agents active in myeloma.
- Molecular Genetics Research
Dr. John Shaughnessy heads up the Lambert Laboratory for Molecular Genetics at Arkansas. His work is dedicated to identifying the critical molecular mechanisms and characteristics that affect patient prognosis. Through collaborative communication between basic scientists and clinical researchers, Dr. Shaughnessy’s lab has performed gene chip analysis on almost 600 patients with various stages of myeloma, individuals with plasma cell dyscrasias such as Waldenström Macroglobulinemia and other B cell tumors including Chronic Lymphocytic Leukemia and non-Hodgkin’s Lymphoma, as well as normal donors. Comparative gene expression profiling using sophisticated computer models has clearly distinguished normal from malignant plasma cells and plasma cells from patients with MGUS versus those with active myeloma.
With the clinical course of myeloma differing greatly, with some patients living a few months and others more than 10 years, DNA microarray technology gives a global profile of gene expression. Applying this technology to myeloma permit examination of genes that are pertinent to tumor growth and drug resistance; it will so help identify new molecular targets for new drugs. Dr. Shaughnessy has found that within the myeloma samples of 100 patients, differences in gene expression existed and , based on this, patient samples could be grouped into poor-, intermediate-, and high-risk groups. We will further these investigations into the genetic nature of myeloma by using microarray analysis to predict the disease course of myeloma, identify mechanisms of disease progression, and discover molecular targets that lend themselves to therapeutic intervention. This information could elucidate the mechanisms of plasma cell transformation, revolutionize diagnostic classification, and provide important directions for development of new therapeutics for myeloma patients.
Dr. Jeffery Sawyer, Director of the Cytogenetics Laboratory, has demonstrated that cytogenetic abnormalities in multiple myeloma are enormously complex and important, with an average of 7 to 8 different chromosomes involved in only a few distinct recurring simple translocations. This genomic chaos, similar to abnormalities seen in solid tumors, is perhaps reflective of a strong environmental exposure over time, although even some very young patients exhibit these abnormalities. More than any other laboratory feature, the knowledge of a patient’s karyotype has become the single most important staging tool in the Institute’s clinical practice.
In “knowing the enemy” it is important to recognize markers that are powerful, such as chromosome 13 deletion and high LDH, which are critical features associated with high risk of relapse.
- Immunotherapy, Vaccine Trials, and Other New Treatment Strategies
Under the leadership of Dr. Guido Tricot, Dr. Frits van Rhee and Dr. Qing Yi are actively pursuing research investigating the hypothesis that developing a cure for myeloma requires multi-agent therapy directed at both tumor cells and accessory elements that support myeloma cell growth. New therapies under development for previously treated patients include cytotoxics, immunotherapy (idiotype or dendritic cell vaccination and donor lymphocyte infusions), antiangiogenic therapy (thalidomide), and anti-stromal cell treatments (bisphosphonates).
Further evidence that translational research is most successful when applied to large patient populations, Dr. Tricot and colleagues are addressing the potential consequence of therapy (Myelodysplastic Syndrome) using CD34 Gene Expression Profiling, FISH, telomere and in vitro stromal co-cultures along with SNP analysis to identify genetic predisposition. This research has obvious implications for understanding primary MDS as well. Vaccination research takes advantage of Cancer Testis Antigen expression (present in 30-50% of MM cells) to determine immune response and clinical efficacy. Continuing research over several areas will help close important gaps in understanding myelomagenesis, treatment mechanisms and paradigms, and the development of secondary malignancies. This continued research can translate into therapeutic prevention and intervention strategies that can work toward cure for myeloma in the 21st century.