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February 2001 Volume 4, Issue 3:
Myeloma In The Millenium
By Dr. Robert A. Kyle and Dr. Brian G.M. Durie
Oucomes of the IMF Myeloma Think Tank 2000. Participants included Drs. Mehta, Powles, Sonneveld, Kyle, Van Ness, Morgan, Oken, Durie, Blade, Urnovitz, Montagnier, Murphy, Mundy, San Miguel, Joshua and Segeren
02.01.01

Summary of Scientific Presentations

  • Dr. Brian Van Ness stated that there is increasing evidence that multiple myeloma demonstrates significant genetic heterogeneity. This genetic heterogeneity most likely contributes to disease progression and therapeutic response. He pointed out that one could develop gene expression profiles encompassing more than 30,000 genes. These profiles offer new insights into tumor classification, response to therapy and risk factors affecting survival. He said that we are approaching a genetic data explosion. He emphasized that analysis of the data is complex. He stated that pharmacogenetics might point the way to new therapeutic approaches that are tailored to the patient’s genetic background. In addition, genetic polymorphisms may provide genetic clues for chemo toxicities and the development of secondary malignancies.
  • Drs. William Murphy, Luc Montagnier, Howard Urnovitz and Brian G.M. Durie discussed viruses and genetic mechanisms in myeloma. (Clin. Diag. Lab. Immun. 6: 330-335, 1999) They reported the presence of RNA complexes with protein in the blood of patients with myeloma. They have also identified RNA in some patients with monoclonal gammopathy of undetermined significance (MGUS) and Waldenström’s macroglobulinemia. (Acta Oncologica 39: 789-796, 2000). Results need to be confirmed and extended in order to determine their importance. Dr. Durie also discussed the possible role of SV40 in the malignant transformation of B-cell precursors (JNCI 91: 1166-1167, 1999).
  • Dr. Gregory R. Mundy emphasized the role of bone disease in myeloma. Lytic lesions or fractures are present in 70% of patients at diagnosis and are responsible for the major clinical manifestations of the disease. Bone loss is a major feature and is mediated by osteoclast activity. RANK ligand plays an important role in osteoclast activation. Interleukin 1b, tumor necrosis factor (TNF) and IL-6 also play a role in bone disease. Dr. Mundy also discussed his recent data indicating stimulation of new bone formation by the cholesterol lowering drugs: statins (Science 286: 1946-1949, 1999).
  • Dr. Robert A. Kyle discussed MGUS and its progression to myeloma, Waldenstöm’s macroglobulinemia, primary amyloidosis and lymphoma. In a long-term follow-up of 1, 384 MGUS patients followed for 11,009 person years, 115 patients progressed to multiple myeloma or a related disorder (Hem/Onc. Clin. N. Am. 13: 1181-1202, 1999). The actuarial rate was 26% at 25 years – 1% per year. The presence of a small monoclonal light chain or reduction in uninvolved immunoglobulins at the time of recognition of the M-protein did not predict progression. Patients with IgM or IgA MGUS had a greater likelihood of progression than IgG. However, progression depended upon the size of the M-protein at diagnosis – an M-spike of 2.5 g/dL was 4.5-fold more likely to progress than an M-spike of .5 g/dL. It was pointed out that MGUS patients are more likely to die of unrelated disease than progression of the plasma cell proliferative disorder. Myeloma accounted for 75% of the cases that progressed.

    The cause of progression is unknown. The cytoplasm of the plasma cells of almost all patients with myeloma contains IL-1b whereas only one-fourth of patients with MGUS contain IL-1b.This cytokine alters the adhesion of the cell to bone marrow stromal cells. Genetic alterations of Ras, P53 and retinoblastoma genes play a role in cell proliferation, apoptopic signaling and therapeutic response. IL-6, a potent growth factor for plasma cells, is an important cytokine in the pathogenesis of myeloma. MGUS is a precursor of malignancy. A better understanding of the mechanism of transformation to malignant plasma cell proliferate disorders is vital in understanding myeloma as well as other malignancies. The cause of transformation to a malignancy must be sought and efforts made to interfere with the process.
  • Dr. Jesus San Miguel discussed the need for an international prognostic classification of myeloma (The Hem. J. 1: 28-36, 2000). He proposed a basic classification consisting of data readily available in all patients. This would include age, sex, performance status, type and amount of M-protein in serum and urine, percentage of bone marrow plasma cells and skeletal roentgenogram results. Other basic laboratory tests include hemoglobin, platelet, calcium, albumen, creatinine, beta 2-micro-globulin, C-reactive protein and LDH values.

    An improved classification would include the above mentioned parameters plus measurement of the proliferate activity of plasma cells by the labeling index or S-phase analysis, cytogenetics utilizing a conventional approach or FISH and plasma cell morphology.

    He recommended that ECOG, SWOG, MRC, Nordic, French, Italian, Spanish, Australian, and German cooperative groups submit data from patients treated with conventional chemotherapy as well as those receiving an autologous stem cell transplant.
  • Dr. Joan Bladé stated that renal failure was present in 20% of patients with myeloma at diagnosis (Arch. Int. Med. 158: 1889-1893, 1998). He reported that the 94 patients with myeloma presenting with a serum creatinine > 2 mg/dL had a median survival of 9 months vs. 33 months for those with normal renal function. In thirty patients with myeloma requiring hemodialysis, only 1 recovered partial function while one other received a renal transplant. The median survival of the 30 patients was 20 months (Brit. J, Haem. 91: 854-859, 1995). He felt that patients with renal failure severe enough to require dialysis were unlikely to respond to the plasma exchange. Dr. Martin Oken reported that patients given prophylactic antibiotics during the first two months of chemotherapy had a significant reduction of infection (Am. J. Med. 100: 624-628, 1996).
  • Dr. Pieter Sonneveld discussed the role of cellular multi-drug resistance (MDR) in multiple myeloma. Although several drugs such as cyclosporine and derivatives (e.g. PSC831) have been evaluated in the clinic in an effort to overcome drug resistance, thus far the results have been rather disappointing. One problem is the presence of multiple 
    resistance mechanisms and pathways. Dr. Sonneveld discussed new research in this area and potential new therapeutic strategies to achieve improved clinical outcome. 
  • Dr. Ray Powles presented results of high dose therapy in multiple myeloma with now up to 15 years follow-up (Abst. Blood 96: 11, #2215, Nov 2000). He focused particularly on a series of what he called "operationally cured" patients who were in continued complete remission for over 10 years. As of June 2000 the Myeloma Unit of the Royal Marsden database, contained 327 living patients with diagnosis dating back to 1979.

    Fourteen patients (4.3%) were in first complete remission lasting > 10 years. Important features of these 14 patients were: 
    – Young age: 31-56 years old (median 45 yrs)
    – Low serum b 2 microglobulin; good renal function
    – Excellent response to induction (e.g. CR with infusional VAMP in 7 patients) pre high dose melphalan.

    Further work is underway with molecular and other studies to better classify and identify such good risk patients with good quality long remissions.
    Broader areas of high dose therapy and transplantation were also presented and discussed including: very good outcome for very young patients (age < 35 years), the role of up-front stem cell harvesting pre-induction therapy, new preparative regimens, the role of allo and "mini-allo" transplantation as well as the value of post-transplant maintenance with alpha interferon, prednisone, vaccines or other approaches.
  • Dr. Douglas Joshua presented results of T-lymphocyte studies in myeloma patients (see prior work: Leukemia: 11, 1312-1317, 1997). New studies in 38 patients showed frequent expansion of clonal cytoxic T-lymphocytes with a typical CD8high, CD57high, and CD28low phenotype. The number of such cells increased from D/S stage I to D/S Stage III. The exact role and significance of these cells remains unexplained. Dr. Joshua also presented results indicating expression of B7-2 (CD86) in 54% of myeloma patients at diagnosis. This increased expression was associated with shorter survival (median 28 versus 57 months) and higher tumor burden. This finding can have implication for immunotherapy protocols, especially involving hu CD40 LT which up regulates CD80 without affecting CD86. 

    It was clear from the discussions that much more needs to be learned about antigen expression and immune responses to develop appropriate immunotherapy for myeloma patients. 
  • Dr. Gareth Morgan from the University of Leeds in the U.K. discussed briefly the importance of studying genetic polymorphisms. In a recent study, Dr. Morgan’s group has shown that myeloma patients are more likely to have a "high producer" TNF-alpha phenotype that may have significant implications for understanding the biology of myeloma. Further studies are underway to assess polymorphisms of other cytokines and within several signal transduction pathways such as NFkB. 

Summary Discussions & Recommendations

After the formal presentations, there were discussions about overall priorities for myeloma research. Discussions focused upon the following:

TYPES OR AREAS OF RESEARCH

A. DNA array and related technology: The greatest interest and enthusiasm related to the application of genomic and proteinomic technologies in myeloma research. As outlined by Dr. Brian Van Ness, the identification of aberrant gene expression and/or patterns of genes associated with myeloma can become the basis for staging, prognostic classification as well as treatment selection and analysis. There was much discussion both about the most pertinent areas of research as well as potential technical and other difficulties with gene expression studies. 

Firstly, only a fraction of identified genes are currently known. Therefore, extensive ancillary research is required to fully characterize new genes. Secondly, the criteria for identifying aberrant and/or abnormal gene expression has spawned the huge fields of bioinformatics and proteinomics. Is “aberrancy” when one or two genes are massively over expressed? Or is it more related to changes in pattern with more subtle increases and decreases of gene expression involving many genes? Will DNA array technology searching at the DNA/RNA level be sufficient or fully relevant? Don’t we need to know the changes in the amount and function of expressed proteins? Does DNA, RNA and proteinomic research need to be done in parallel to be meaningful?

These and other issues pointed to the strong likelihood of many years of research to reach any final conclusions. For example, the separation (e.g., by sorting or micro-dissection) and identification of target myeloma cell populations are quite a challenge, but essential as a baseline for gene expression analysis of the initial malignant (or pre-malignant) cell population. 

There was much discussion re: the value and significance of studies using myeloma cell lines versus direct human material versus animal model studies. Animal models are clearly important, particularly, since the direct human material of the greatest interest is the most difficult to obtain and analyze. For example, difficulties in comparing MGUS with active myeloma include purifying plasma cells from MGUS bone marrow samples as well as identifying patients during or before and after the transition to active myeloma. Likewise, studying treatment sensitive and resistant patients requires careful serial monitoring. To compare patients with solitary plasmacytoma with multiple myeloma, again, one needs to obtain solitary plasmacytoma material, which is a difficult task. New animal model systems can therefore prove very useful. 

Great care is required in the design and implementation of meaningful studies. This discussion led to an assessment of the value of a “myeloma tissue bank” to make precious clinical samples of cells/DNA/RNA available for critical comparative studies. See further comments below. 

Additional facets of importance include pharmacogenetics whereby drug dosage and scheduling can be adjusted based upon individual variation in drug sensitivity and metabolism. Studies of normal host cell DNA/RNA, and protein expression are required to identify relevant polymorphisms. 

Recommendation: It is a top priority to pursue research in the areas of genomics and proteinomics. It is to be anticipated that many new facets of myeloma will be uncovered which will require several years to fully analyze. Although this research will undoubtedly lead to new therapies, development of such treatments will require several additional years of pre-clinical and clinical trials. 

B. Other Priorities: 

Although molecular genetic research was identified as a clear priority, several other topics were seen to be very important including:

  • Viruses: role in pathogenesis and disease manifestations. Potential for therapeutic interventions
  • Bone disease: underlying mechanisms and potential for new therapies.
  • MGUS: natural history and knowledge to be gained from comparisons with myeloma.
  • International prognostic index: establishment of new reliable methods for diagnosis, staging and prognostic classification of myeloma and related disorders. Inclusion of new molecular and immune marker technologies.
  • Renal disease: identification of underlying mechanisms (including amyloidosis) and development of appropriate therapies for patients with reversible and irreversible renal insufficiency.
  • High dose therapy and hematopietic stem cell transplantation: assessment of what has been accomplished thus far re: improved remission and/or survival plus development of more effective and better-tolerated cytoreductive and maintenance strategies.
  • Immunology: identification of specific immune defects in myeloma patients as a basis for selective immunotherapy including vaccines and mini allogeneic transplant or lymphocyte infusion strategies.
  • Infection: better recognition of infectious complications as a basis for prophylactic and/or therapeutic interventions.
  • Imaging: the ongoing need to better identify sites of disease using state of the art imaging techniques including MRI, helical CT and FDG/PET scanning.

PRIORITIES FOR NCI VERSUS NON-PROFIT VERSUS PHARMACEUTICAL RESEARCH

It was recognized that each of these three types of research support has a different role to play in the overall myeloma research environment. The National Cancer Institute (NCI) can provide the highest level, broad based long term funding, plus potentially support selected new initiatives. Non-profit funding has the greatest flexibility with priorities strongly influenced by the sources of donated funds (e.g., patient funding to support clinical or translational research or patient education and/or advocacy). Pharmaceutical research is highly focused upon new drug approvals and the potential for significant profits. 

Within this broad framework, the IMF can play a critical role in supporting and promoting new clinically relevant research to maximize the quality of life for patients with myeloma. Since myeloma is an orphan disease that is not necessarily attractive to large pharmaceutical companies from a profit standpoint, creative methods are required to bring new drugs to the market for myeloma patients in a timely fashion. 

SPECIFIC PROJECTS involving the IMF

There was considerable discussion concerning several possible new IMF initiatives. Two topics garnished the most attention.

A. Help with the rapid development and implementation of the International Prognostic Index: 
It was agreed to proceed with this and a meeting of appropriate investigators was planned for the earliest opportunity. 
Addendum: The IMF sponsored the first meeting of the Prognostic Index Working Group at ASH 2000 in San Francisco. A follow-up implementation meeting will be in Banff in May 2001.

B. Establish an International Myeloma Tissue Bank to include both malignant and normal tissues: 
It was recommended that this project be the basis of specific fund raising drives with creation and implementation of an International Tissue Banking Resource as soon as feasible. Since Dr. Gareth Morgan (UK) already obtains tissue for molecular testing, a pilot tissue bank under his auspices can be considered. This is being reviewed by the IMF (UK). Further discussions are underway for 2001 to develop detailed plans for an International Myeloma Tissue Bank.

Other issues were addressed including:

  • Translational Research: a focus for IMF funding in this area.
  • Multi-year funding: the provision of funds (with appropriate review) for 2 or 3 year funding rather than single year funding.
  • Oncology Nursing Research: an initiative to invite applications for oncology nursing research projects.
  • Travel Grants: to provide funds for investigators to present research at important meetings and/or learn new techniques in the laboratories of experts.
  • Clinical Trial Support: provide support to promote orphan drug clinical trials if limited funding is otherwise available.


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