The American Society of Hematology (ASH) meeting this past December was the largest ever, with over 17,000 attendees. There were also an impressive number of abstracts on myeloma and related topics with over 250 abstracts out of the 5,452 total submitted abstracts.
Molecular and cellular genetics were popular topics particularly looking toward the application of the new gene array technology and information coming from the human genome project. Multiple genetic abnormalities occur in myeloma cells for reasons that remain unknown. From an observational standpoint, loss of all or part of chromosome 13 (- 13 or 13q-) is associated with more aggressive disease and poorer patient outcome. Conversely, gains of whole chromosomes (known as hyperdiploidy), without chromosome 13 loss, are associated with particularly good prognosis (Shaughnessy et. al., Little Rock Group: Abstract #645). Deletion or loss of chromosome 22q (11.2) is a new recurrent chromosomal abnormality noted by the group of J. Drach et. al. from Vienna, Austria (Abstract #647) associated with a poor prognosis. Of interest, we have recently noted plasma RNA derived from the chromosome 22q 11.2 region in the blood of patients with active myeloma (Acta Oncologica, 39: 789, 2000). Along the same lines, several investigators presented data related to the expression of two genes deregulated as part of a chromosome t (4:14) translocation. The fibroblast growth factor receptor 3 (FGFR3) is over-expressed (Abstract #403), but this does not correlate with an overall different prognosis (see Abstract #656 from the group of Douglas Joshua in Australia), although it may correlate with a higher likelihood of response to thalidomide treatment (Abstract #721). With the advent of the gene array technology, the screening of the whole batteries of genes is now possible. Initial results (see Abstracts #3483-3488) indicated great complexity in gene expression, particularly related to the impact of new treatments such as thalidomide and ImiDs (new thalidomide analogs). By the time of ASH 2001, there will probably be enough information for a whole session on gene expression related to disease status and treatment.
Four abstracts dealt with bone disease in myeloma ( #1561, 1562, 1565 and 1569). Abstract #1561 from Gregory R. Mundy’s group in San Antonio showed evidence of the role of a new factor, macrophage inflammatory protein (MIP) – 1 alpha, in stimulating osteoclast formation in different animal models. The concept that MIP – 1 alpha plays an important role in causing myeloma bone destruction provides a new target for treatment intervention.
Several studies evaluated the impact of high dose chemotherapy with transplant.
Perhaps the most interesting was the long-term follow-up for patients transplanted at the Royal Marsden Hospital in Surrey, U.K. (Abstract #2215). Continuous first complete remission for over 10 years was noted in 14 patients (4.3%) of 327 living patients diagnosed since April 1979. Details of these patients were presented and discussed with a view to better characterizing and potentially increasing upon this small, but very important group of myeloma patients. In a separate abstract (Abstract #3282), it was noted that very young patients (age < 35 years) are likely to do particularly well with transplants. Several abstracts dealt with follow-up of high dose therapy treatment using different doses and schedules either up front or later in the disease course. Of interest, one report from Italy (Abstract #1804) showed comparable outcome with high dose melphalan used at a dose of 200mg/m2 versus 100mg/m2 suggesting that the higher dose may not be required.
Overall, the largest number of abstracts dealt with new treatment approaches –
a very positive and encouraging trend. Several groups presented their results with thalidomide (Abstracts #718-726). Thalidomide is clearly an important new active agent for the treatment of myeloma. Questions now revolve around the most appropriate dose and schedule; up-front versus relapse uses; use alone or in combination with Dexamethasone or Dexamethasone and Biaxin; as well as in combination with different chemotherapy regimens (e.g., DT-PACE regimen). The results from the Mayo Clinic presented by Dr. Rajkumar (Abstract #722) were particularly impressive showing a 77% response rate in previously untreated patients using a combination of Thalidomide 200mg/day (with dose escalation) combined with pulses of dexamethasone 40mg daily for 4 days repeated with 4 day rest periods. Severe skin rash was a problem with the dose escalation, which has subsequently been stopped after the first 7 patients were treated with 400mg thalidomide. The ongoing study uses a 200mg/day flat dose and will require further follow-up and analysis. The very high percentage responses (e.g., 83% of 24 patients) noted by Dr. Coleman’s group from New York using the BLT-D protocol, adding Biaxin to the combination (Abstract #720) were also impressive, but will need further follow-up and confirmation re: both efficacy and potential toxicities particularly in patients with cardio-pulmonary disease. The long-term follow-up of 169 patients treated with Thalidomide in Little Rock (Abstract #2213: Barlogie et al) was also presented. The efficacy of Thalidomide (alone) in patients with advanced and/or high-risk refractory myeloma was confirmed with a 30% overall response rate (> 50% regression). 26% of the responders achieve durable remissions with nearly 50% of patients with at least 1 favorable characteristic being projected to be alive at 2 years. The results with the new (less toxic) ImiD (thalidomide analog) are now awaited with great expectation. Preliminary laboratory results were presented.
Other treatment results of interest included use of antigen loaded dendritic cell immunotherapy (e.g., Mylovenge: Abstract #713), Rituxan in myeloma (Abstract #704), Waldenstrom’s (Abstract #727), and the protesome inhibitor PS-341 (Abstract #2219). Two additional abstracts showed efficacy of Arsenic Trioxide (ATO: Trisenox), especially combined with ascorbic acid (Abstract #687) or alpha interferon (Abstract #412).
Although several groups reported possible early benefit with dendritic cell immuno-therapy, it should be noted that one group reported that dendritic cells from myeloma patients are defective and maybe do not have full immunotherapeutic potential (Joshua et. al., Abstract #695). Initial data with a new monoclonal antibody specific for myeloma (HM 1.24) were presented indicating synergistic efficacy combined with alpha interferon when tested in vitro against myeloma cell lines (Ozaki et. al., Japan, Abstract #3239). Phase I-II patient studies with this antibody are currently under way in the United Kingdom. Likewise, Phase II studies are now underway with ImiD, PS-341 and Arsenic Trioxide. In the next issue of Myeloma Today, there will be a more comprehensive review of ongoing clinical trials in myeloma.
ASH 2000 was a great opportunity to hear the latest in myeloma and realize how much progress is being made including the translation of promising research findings into new clinical trials.
Editor’s Note: The annual meeting of the American Society of Hematology (ASH) was held in San Francisco, California on December 1st - December 5th, 2000. Full abstracts were reported in Blood; Volume 96: 11, November 16, 2000.