We are international

By Brian G.M. Durie, M.D.

This year there were over 75 abstracts dealing with myeloma at the American Society of Clinical Oncology meeting, held in New Orleans June 4th-8th 2004. For discussion purposes, I have divided these into: frontline therapy, clearly a focus of attention, and miscellaneous but important, a review of other topics. Details of the frontline therapy are available in the IMF’s Special ASCO update Report, which includes interviews with the presenters, available online at http://asco.myeloma.org.

Frontline Therapy

Eleven presentations dealt with new interventions in the frontline setting. The anxiously awaited results of the randomized phase III trial of thalidomide plus dexamethasone versus dexamethasone alone, from the Eastern Cooperative Group (ECOG), were presented by Dr. Vincent Rajkumar from the Mayo Clinic. Considering best response within 4 cycles, the response with thalidomide plus dexamethasone was 68% (67/98 patients) versus 46% (46/98 patients) in the dexamethasone arm. This clearly superior initial efficacy had to be balanced against some increased risk of deep venous thrombosis (16% versus 3%). Perhaps more importantly, thalidomide/dexamethasone provided efficacy comparable to historical results with VAD and similar complex regimens, but with less overall impact upon quality of life. However, deep venous thrombosis (DVT) prophylaxis with an anticoagulant needs to be considered to eliminate the up-front DVT risk for patients receiving thalidomide plus dexamethasone.

This new “gold standard” for frontline induction was available for immediate comparison with two other frontline therapies evaluated in phase II trials: bortezomib (VELCADE®) alone (dexamethasone given after first 2 cycles) and bortezomib (VELCADE®) combined with Adriamycin and dexamethasone (the “PAD” regimen [P = PS-341 or VELCADE®]). Both of these early trials show remarkable benefit. Dr. Sundar Jagannath from St. Vincent’s, New York (Abstract # 6551), representing the Salick Research Network, showed the 79% response rate (CR plus PR: i.e. all patients with > 50% reduction in myeloma protein level) with VELCADE® plus dexamethasone frontline. Dr. Jamie Cavanagh from St. Bartholomew’s Hospital, London (Abstract # 6550), reported a remarkable 94% CR plus PR rate with the three-drug PAD regimen after 4 cycles of therapy. Stem cell harvesting and transplantation has been feasible in the usual fashion in both these trials, as was the case in the thalidomide/dexamethasone study.

The preliminary VELCADE® results combined with the more mature thalidomide data raise the expectation of > 80% response rates in the upfront setting. Considering combination or sequential therapies and other strategies, the new goal becomes one of trying to achieve response for all patients as a basis for stem cell harvesting and transplant. It’s suddenly not crazy to think that this can be achieved soon. This is further emphasized by the results presented by Dr. Antonio Palumbo from Torino, Italy (Abstract #6549), in patients who are not transplant candidates. The combination of thalidomide plus melphalan/prednisone produced a 94% CR + PR rate, very comparable to the PAD results, but without the option for future transplant.

With these high response rates, the issue and priorities become:

  • What are the side effects?
  • Is stem cell transplant planned?
  • How quickly is response achieved?
  • Is stem cell harvesting compromised?
  • Which approach gives the longest response duration (remission) and survival?

We are just starting to form ideas about these and other questions. Interestingly, deep venous thrombosis, which is a concern (16% likelihood) with thalidomide/dexamethasone, has not occurred with the frontline VELCADE® trials (0%). In the thalidomide/melphalan/prednisone study, the DVT percentage was 19%. Neuropathy of different types is an issue with all these new protocols. Of note, the neuropathy that occurred in the upfront VELCADE® trials appears to be partially or completely reversible. Further studies and follow-up are required. Stem cell transplant is feasible, except after thalidomide/melphalan/prednisone. Response is achievable rather quickly with both the thalidomide and VELCADE® combinations. Within 2 or 3 cycles of therapy, most of the achievable response has occurred. This abbreviates the upfront induction period versus VAD, for example. The major outstanding questions relate to response duration and survival with and without stem cell consolidation. These questions are now the basis for several planned trials.

This is obviously very good news. The ASCO meeting included additional abstracts that further extend these notions. Firstly, two abstracts focused on the role of Doxil® (Abstracts # 6548 and 6509). In one abstract (Abstract # 6548) presented by Dr. Mohamad Hussein from the Cleveland Clinic, the combination of Doxil® plus vincristine and dexamethasone was shown to be equally effective versus traditional VAD and much less expensive: about half the cost. In a related abstract (Abstract # 6709) Dr. Antonio Vendette and colleagues evaluated the cost of 4 days of pulse Adriamycin versus the traditional 4-day VAD infusional approach. The 4-day bolus approach was < 30% of the cost, with apparent equivalent efficacy. This may prove to have relevance related to the “PAD” protocol discussed above.

In the second Doxil® abstract (Abstract # 6509), Dr. Robert Rifkin, on behalf of U.S. Oncolocy, again showed that the Doxil® combination was equivalent in efficacy to VAD, but had several clinical advantages, including less neutropenia, alopecia, and hospital/clinic visits. In view of recent observations that Doxil® is highly synergistic with VELCADE®, there is considerable interest in Doxil® as part of frontline strategies.

A randomized trial dealing with maintenance therapy following frontline treatment was also presented. Dr. Chaim Shustik from Montreal, Canada, on behalf of the NCI Canada (Abstract #6510) analyzed 307 patients who reached maintenance and received treatment with either nothing or dexamethasone, following either melphalan plus prednisone or dexamethasone induction. In this trial, dexamethasone as a monthly pulse (40mg daily for 4 days) extended the initial remission duration by a median of approximately 7 months, but unfortunately did not extend overall survival. Interestingly, this is virtually identical to what has been reported for alpha interferon used in the maintenance setting.

Two additional abstracts evaluated the impact of zoledronic acid (Zometa®) used frontline for symptomatic or untreated smoldering myeloma (Abstracts # 6702 and # 6680). For symptomatic myeloma, Zometa® combined with thalidomide and dexamethasone was safe and effective (response rate 68%: same as randomized trial above). For smoldering myeloma, the Zometa® (unlike Aredia, which has not shown prophylactic value) showed a trend towards lesser bone events. More data are required.

In the final frontline abstract, results of autologous stem cell transplants from Austria were presented by Dr. Heinz Ludwig (Abstract # 6657). The transplant protocol, including alpha interferon maintenance, showed a favorable outcome versus historical experience with non-transplant approaches in Austria, including high CR plus PR rate (90%) and median overall survival of 66.5 months.

Miscellaneous But Important

The most important additional presentation was by Dr. Paul Richardson (Abstract # 6511) who summarized the results of the randomized phase II trial for relapsed myeloma, which compared bortezomib (VELCADE®) with dexamethasone. This study involved 669 patients recruited internationally and showed that, at the mandated early interim analysis, bortezomib (VELCADE®) was significantly more effective than dexamethasone. There was a 58% improvement in the median time to progression for the 327 patients receiving bortezomib versus the 330 patients receiving high-dose dexamethasone (p < .0001 for difference). Overall, there was an approximately 30% improvement in survival during the first year with VELCADE®. This is obviously very helpful information in establishing the role for VELCADE® and in future integration of VELCADE® into “standard of care” therapies.

Follow-up information was presented on the two radiotherapeutic agents 166holmium DOTMP skeletal targeted radiotherapy (Abstract #6656) and samarium153 Sm-EDTMP (Tetramethylene-phosphonate [Abstract # 6737]). Follow-up from the phase II holmium dosimetry trial confirmed favorable efficacy and safety combined with high-dose melphalan and autologous stem cell support. This dose-finding study serves as a basis for the full-scale trial now beginning to evaluate complete remission rates and outcome. The samarium study showed that combined with Zometa, there was significant palliation of bone pain and skeletal events in elderly myeloma patients.

Three studies showed promising results with early testing. A phase I/II trial with “Xcellerated T cell” therapy (Abstract #2540) showed rapid recovery of T lymphocytes in patients after autologous stem cell transplantation. Whether this will impact outcome is not yet known. A new antibody drug immunoconjugate (IMMU-110) showed promise in the laboratory in preclinical studies targeted against myeloma cells (Abstract #6535). A study of immune testing (Abstract #6554) showed that an antigen found on the testis, called cancer testis antigen number 7 (CT7 [MAGE-C1]), is for some reason expressed quite strongly on the surface of myeloma cells from patients with stage III disease. This may be the basis for new immune therapy.

A final abstract (Abstract #8088) drew attention to a new complication associated with bisphosphonate therapy, called osteonecrosis of the jaw. This is the third research group to draw attention to this association. The true frequency of osteonecrosis in myeloma patients is unclear. The background details are discussed in the alert published in the Myeloma Minute. Different degrees of bone damage in the jaws underneath the teeth can occur, ranging from exposed bone, bone spurs, poor healing at the site of tooth extraction or dental implants, or infection/inflammation at sites of gingivitis or dental caries. It seems that osteonecrosis-related problems can mostly be managed conservatively, with removal of areas of dead bone plus use of antibiotics and rinses, etc., avoiding major intervention. Patients on bisphosphonate therapy need to be very alert about potential poor healing in the dental region. Tooth extraction should be undertaken with due caution. Full consultation is recommended for any major procedures. Please consult the Myeloma Minute for further details, or call the hotline at 800-452-CURE.

The ASCO meeting therefore provided a wealth of new information and was truly a watershed in terms of new options for frontline therapy. The coming months will be exciting, as further details become available about the outcome with these new treatment strategies.