The following is a recap from the American Society of Hematology's 47th annual meeting held in Atlanta, Georgia on December 10–14, 2005. We have selected the major myeloma presentations for you to keep informed on the latest myeloma research that was presented.
Dr. Paul Richardson
Dana-Farber Cancer Institute, Boston, MA
Dr. Richardson presented updated, long-term data on the APEX trial to investigate the effects of Velcade in patients with relapsed myeloma who have had at least one prior treatment regimen. Patients in the trial were randomized to receive either Velcade or dexamethasone therapy. Dr. Richardson also presented early data on the Phase I Revlimid + Velcade trial for relapsed and refractory myeloma.
Dr. Rafael Fonseca
Mayo Clinic, Scottsdale, AZ
Dr. Fonseca is currently studying genetic changes in myeloma plasma cells. A precise diagnosis can be made when the doctor can identify different sub-types of myeloma and their unique features. Genetic information is used to estimate prognosis and to determine the type and sequencing of therapy. Dr. Fonseca's presentation on the genetic abnormalities of patients diagnosed with MGUS or smoldering disease identifies those aberrations that can be seen prior to a myeloma diagnosis. His group is studying these mutations to see if there is a different risk of progression from MGUS or smoldering myeloma to active disease in patients with poor-risk or good-risk mutations.
Dr. Antonio Palumbo
Ospedale San Giovanni Battista, Turin, Italy
Dr. Palumbo began studying the combination of melphalan/prednisone/thalidomide (MPT) more than four years ago in the population of patients who were ineligible for autologous stem cell transplant (those over 65 years if age). His randomized clinical trial comparing MPT with standard MP (melphalan/prednisone) demonstrated a significant increase in the rate of overall response, with an incidence of complete response at approximately 25% in the MPT group. The duration of response was almost twice as long with MPT than with MP. Longer follow-up is needed to determine if there is an overall survival advantage with MPT. Side effects included the significant 25% rate of deep vein thrombosis in the MPT group.
Dr. Sundar Jagannath
St. Vincent's Comprehensive Cancer Center, New York, NY
Dr. Jagannath's presentation concerned a multi-center trial for newly diagnosed myeloma patients receiving frontline therapy with Velcade. Patients received Velcade alone for two cycles, and if they did not demonstrate a response, dexamethasone was added. Ten percent of the patients receiving Velcade alone in the first two cycles achieved complete remission (CR). At the end of six cycles of therapy with Velcade alone or Velcade plus dexamethasone, 90% of the patients had at least a 50% reduction in their M-protein and 19% were in CR. Most of the patients went on to have autologous stem cell transplantation. These patients are being followed for relapse and survival rates.
Dr. Brian Van Ness
University of Minnesota, Institute of Human Genetics, Minneapolis, MN
Dr. Van Ness presented his current work with the IMF Bank On A Cure program's genetic data. His strategy has been to look at genetic variation and its relationship to therapeutic response. Dr. Van Ness is particularly interested in variations in response to drugs and in toxicities from drugs. He has identified 3500 genetic variations (single nucleotide polymorphisms (SNPs) that influence risk and therapeutic response. From a candidate list of some 30,000 genes, he is isolating those that are significant in myeloma patients' responses, finding genes that contribute not only to increased risk (a high-producer IL-6 gene, for example), but to survival (the GST gene that repairs DNA). Thus far work has been done on a number of other SNPs, including those that are responsible for drug metabolism and transport, for levels of tumor necrosis factor alpha (TNF alpha), and for tumor angiogenesis. A computer chip has been customized to examine more globally the 3500 SNPs and their association with myeloma.
Dr. Thierry Facon
Centre Hospitalier Regional Universitaire de Lille, Lille, France
Dr. Facon presented an interim analysis of the ongoing Intergroup Francais du Myelome (IFN) 99-06 clinical trial comparing melphalan–prednisone (MP), melphalan-prednisone-thalidomide (MPT), and stem cell transplant with reduced-dose-chemotherapy (melphalan 100 mg/m2) in 436 newly diagnosed myeloma patients, aged 65-75 years. MPT produced the best progression-free survival and overall survival. There were concerns with toxicity issues that required dose adjustment or discontinuation of therapy, but Dr. Facon concludes that MPT is currently the treatment of choice for the elderly newly diagnosed. He is also encouraged by early studies of MP+Velcade and MP+Revlimid that are also likely to be good combinations for treatment of elderly myeloma patients.
Dr. Pieter Sonneveld
Erasmus University, Rotterdam, The Netherlands
Dr. Sonneveld studied single nucleotide polymorphisms (SNPs) collected from patient tissue samples in a large, multi-center, randomized, single versus double autologous transplant clinical trial that concluded in 1999. Dr. Sonneveld's particular area of investigation is the SNPs of proteins involved in drug metabolism and drug resistance. The ultimate goal of his research, which is being done in conjunction with the IMF's Bank On A Cure DNA study, is to identify groups of patients according to their response to treatment, the treatment-related toxicities they manifest, and their overall survival. He has isolated the MDR (multi-drug resistance) and GCP‑1 genes as conferring poor risk, and the C3A5 genetic mutation as one that confers better event-free survival, time to progression, and overall survival. The study is ongoing and will require meta-analysis of the HOVON clinical trials group data.
Dr. Heinz Ludwig
Wilhelminenspital, Vienna, Austria
Dr. Ludwig's major presentations at ASH concerned two studies: the first was of clinical features and outcomes in 259 myeloma patients younger than 40 years versus 8,296 patients older than 40 years; the second was of thalidomide/dexamethasone (thal/dex) versus melphalan/prednisone (MP) as first-line therapy in elderly patients with myeloma. The first study employed the 10,611-patient database used to establish the International Staging System for myeloma. The second presentation was the interim analysis of an ongoing trial of thal/dex versus MP in 205 elderly (median age 72), newly diagnosed patients with myeloma.
Dr. Jamie Cavenagh
St. Bartholomew's Hospital, London, England
Dr. Cavenagh continued to report on his ongoing trial combining Velcade, Adriamycin, and dexamethasone (PAD) in previously untreated myeloma. Among this group of younger (median age 61 years) patients, there was a 95% response rate (³50% reduction in monoclonal protein) before stem cell transplant, and an 81% very good partial response rate (>50% but £90% reduction in monoclonal protein) following transplant with (PAD) as frontline therapy. A second presentation of Dr. Cavenagh's involved combining Velcade with melphalan in patients with relapsed/refractory disease. The Phase I/II multi-center study was done to establish the maximum tolerated dose, safety, and effectiveness of this combination. Velcade appears to be effective in combination with chemotherapy in both the up front and relapse situations.
Dr. Joseph McGuirk
Kansas City Blood and Marrow Transplant Program, Kansas City, MO
Dr. McGuirk reported on the first 70 patients enrolled in the AMD-3100 compassionate use program for poor stem cell mobilizers in need of stem cell harvest prior to autologous stem cell transplantation (SCT). The patients had non-Hodgkins lymphoma, leukemia, myeloma, or solid tumors. They were given a combination of GCSF (granulocyte colony stimulating factor) and AMD-3100 to promote generation of stem cells for harvesting. 60% of the enrolled patients, all of whom had been previously unable to mobilize stem cells, were successfully harvested and moved on to SCT. According to Dr. McGuirk, this is a potentially live-saving combination that produces minimal toxicity.
Dr. Shaji Kumar
Mayo Clinic, Rochester, MN
Dr. Kumar presented the results of two studies at Mayo. The first was a gene expression study conducted on 50 patients who were randomized to receive either thalidomide and dexamethasone (30 patients) or dexamethasone alone (20 patients). Dr. Kumar's second presentation concerned the use of the free light chain (FLC) assay to assess disease and response to therapy, particularly in oligosecretory and non-secretory patients.
Dr. Jesus San Miguel
University Hospital of Salamanca, Salamanca, Spain
Dr. San Miguel presented interim data on the ongoing PETHEMA study of melphalan, prednisone, and Velcade in elderly, previously untreated myeloma patients. A second presentation by Dr. San Miguel concerned the rate of peripheral neuropathy in the APEX Velcade trial. Dr. San Miguel also presented preliminary data from a Phase I/II study in patients with relapsed/refractory myeloma of the novel therapy Aplidin, which is a marine-derived molecule with a novel mechanism of action.
Dr. Michael Wang
MD Anderson Cancer Center—Houston, TX
Dr. Wang presented data on a Phase I dose escalation multi-center clinical trial with the new drug Atiprimod for patients with relapsed/refractory myeloma. Atiprimod is a small molecule that inhibits angiogenesis (blood vessel formation at the site of the cancer cells) and promotes apoptosis (programmed cell death). Thus far side effects have been tolerable and none have been severe. No maximum tolerated dose has been achieved. Results have been encouraging as researchers continue to define a dose that will be effective in producing significant responses and will be safe and well tolerated.
Dr. Ravi Vij
Washington University Hospital, St. Louis, MO
Dr. Vij presented four posters based on a clinical trial using Velcade as both induction and consolidation therapy before and after transplant (peri-transplant). The first presentation concerned the use of GCSF alone in successful mobilization of stem cells—Dr. Vij and colleagues were the first to document this procedure in patients who went on to successfully harvest stem cells and undergo transplant. The second presentation dealt with markers of immune function and immune modulation after the use of Velcade in the peri-transplant setting. Dr. Vij et al. noted substantial decreases in CD8 cells and in the CD8 to CD4 ration, indicating Velcade's pronounced immunomodulatory activity. His third poster concerned the increased incidence of herpes zoster (shingles) with Velcade in the peri-transplant setting. Dr. Vij's final presentation concerned the effect of Velcade on markers of bone resorption.
Dr. Angela Dispenzieri
Mayo Clinic, Rochester, MN
Dr. Dispenzieri presented data on a pre-clinical mouse study with the combination of Velcade and the radiopharmaceutical Quadramet (153 samarium EDTMP). A previous Mayo study in which Dr. Dispenzieri was involved examined the use of Quadramet along with zoledronic acid to reduce bone pain in myeloma patients. Fourteen months out, the patients continue to have long-term improvement in pain. Even more significantly, of the 8 patients involved in that study, 4 achieved at least a 25% reduction in their M-protein. This led Dr. Dispenzieri to go further with Quadramet by combining it with an effective anti-myeloma agent and assess the results. In vitro studies of Velcade and Quadramet demonstrated synergy between the two drugs. In Dr. Dispenzieri's mouse study, survival more than doubled in the mice who received both drugs. Two new clinical trials have thus been proposed: one with Quadramet alone, to determine both myeloma response and pain response, and one with Quadramet and Velcade in combination.
NOTE: Webcasts from ASH 2005 are available on the IMF website www.myeloma.org. They include interviews with myeloma researchers, ASH 2005 presentations and posters, and a CME-accredited program, New Agents and New Opportunities for Multiple Myeloma—Today and Tomorrow, which brought together leading experts to discuss changing clinical practice in the context of new agents and new discoveries. We hope you will find this material informative and useful.