We are international

This was the first session dealing with the role of high dose therapy and transplantation. All of the major groups from around the world presented their data.  There was a consistent trend for longer survival with use of high dose therapy and autotransplant. There is an emerging consensus that autotransplant as part of "primary induction" is optimal for a majority of patients who are transplant candidates. Does every patient need and/or benefit from a transplant? This is still under debate since some data (e.g., MRC [UK] recently published in the New England Journal of Medicine) indicate particular benefit with high risk disease, reflected by high serm beta 2 microglobulin (β2m > 8 mg/dl). Conversely, other studies, including the Little Rock "Total Therapy" approach, indicate best outcome and very long survival for good risk patients with low β2m and absence of chromosome 13 deletion by cytogenetics (13q-). High dose melphalan is the "standard" high dose approach.  Total body irradiation is no longer recommended. Skeletal targeted irradiation ("STI") with the use of Holmium™ is under investigation.

Autotransplantation:  The French Experience: Dr. Jean-Luc Harousseau

Dr. Harousseau presented the results of the Intergroupe Francais du Myelome, the first randomized trial to show the superiority of high dose therapy (HDT) with autologous bone marrow transplatation as compared to conventional chemotherapy (N Engl J Med 1996;335:91-97)..

In this trial, at the time of diagnosis, 200 patients less than 65 years of age with Durie-Salmon Stage II or III were randomly assigned to receive either conventional chemotherapy or high dose therapy.

Conventional chemotherapy consisted of alternating cycles of VMCP/BVAP administered at 3-week intervals for 12 months for a total of 18 cycles. HDT was administered after four to six cycles of VMCP/BVAP to all patients with WHO performance status of 2 or less, a serum creatinine level less than 150 mo/L and more than 2 x 108 nucleated cells/kg in the marrow collected and unpurged. Patients were prepared with high dose melphalan (140cnd total body irradiation (TBI) (8 Gy). Interferon alpha (IFNα) was administered at a dose of 3 x 108 U/m2 3 times/week until relapse in both arms. Comparison of the two therapeutic modalities was made on an intention-to-treat basis, with all patients studied in their assigned treatment groups. None of the intial characteristics differed significantly between treatment groups. The response to initial chemotherapy and the compliance with interferon treatment were also comparable.

An updated analysis of this study confirms that, with a median follow-up of 7 years, HDT significantly improves event free survival (EFS) (median 28 months versus 18 months, 7 year EFS 16% vs.8%, p=.001) and overall survival (OS) (median 57 months versus 44 months, 7 year OS 43% versus 25%, p=0.03)

In this IFM 90 trial, HDT significantly improved the response rate since 38% of patients enrolled in the HDT arm achieved a complete remission or very good partial remission (>90% reduction of the M-component) verus 14% of patients enrolled in the conventional chemotherapy arm (P<.0.001).

Response was a predictor of overall survival;

Autotransplant did not have a statistically signiifcant impact on overall survival in patients with low beta 2 microglobulin (β2m <3) .

There was a significant OS survival advantage for autotransplaant in patients with highcbeta 2 microglobulin (β2m >3) .

Autotransplant provided an overall survival advantage in patients under 60 years of age. .

...but not in patients over 60 years of age.

Autotransplantation:  The British Experience: Dr. J. Anthony Child

Dr. Child The approaches introduced at the Royal Marsden Hospital in the early 1980s with escalation of melphalan to 140 mg/m2 without stem cell support and related studies under the aegis of the MRC were the basis for the introduction of high dose therapy (HDT) with supporting autologous bone marrow and, subsequently, peripheral blood stem cell transplantation in the UK. In previously untreated patients the complete response (CR) rate as assesed at that time approached 50%. The strategy which emerged was initial conventional dose antracycline-containing infustional chemotherapy followed by high dose melphalan (HDM) at 200 mg/m2 or HDM 140 mg/m2 with the addition of total body irrafiation (TBI).

Although the depth of remission was evidently greater than with purely conventional dose therapy the remissions were not enduring. The concept of maintaining longer remissions was introduced with the use of interferon-alpha (IFNα) in a maintenance role. At the time of the initation of MRC Myeloma VII in 1993, there was a clear need for outcome data on HDT in comparison with conventional dose chemotherapy in the large randomised trial setting. In the series of MRC trials leading up to Myeloma VII, the most effective conventional dose regimen was ABCM2 and this was chosen as the standard treatment: doxorubicin 30 mg/m2 i.v., carmustine 30 mg/m2 i.v. short infusion d1: cyclophoshamide 100 mg/m2 /d orally and melphalan 6 mg/m2 /d orally d22-25; cycle repeating every 6 weeks to maximal response (plateau) maximum 12 cycles. Patients could switch to cyclophosphamide 300 mg/m2 i.v. weekly in the event of undue myelosurpression.  Planned mainenance was IFNα (Roferon A) initially at 3 megaunits3x/week. The intensive regimen ws C-VAMP; doxorubicin 9 mg/m2 /d and vincristine 0.4 mg/d continuous infusion d1-4; methylprednisolone mg/m2 i.v. or orally(max 1.5g) d1-5; cyclophosphamide 500mg i.v. d1, 8 and 15; cycle repeating every 21 days to maximal response with minimum of 3 cycles before stem cell harvesting. Adustments for cytopenias/renal dysfunction were applied. Stem cells were mobilized using cyclophosphamide 2-4 mg/m2 and G-CSF d5-12. The HDT comprised HDM at 200 mg/m2 followed by the infusion of {BSCs at 24hrs. Bone marrow autograft and TBI + melphalan 140 mg/m2 were permissable options. Methylprednilsolone 1.5 g/d was given i.v. for the first 4 days following HDM. The melphalan dose was modified according to creatinine clearance.

The planned maintenance in this treatment arm was also IFNα. The EMBT.IBMTR response criteria were used whereby CR required paraprotein negative by immunofixation.

A total of 407 previously untreated patients under 65 years of age were randomised to receive "Standard" or "Intensive" treatments. Only 30 (15 percent) patients in the Standard group went on to recieve an autograft and 4 (2 percent) an allograft, outside protocol.

In the 401 evaluable patients, response rates for the Intensive Group were higher than in the Standard Group: CR 44.3% vs. 8.5% (P<0.001);  PR 42.3% vs. 4-.5%.

In an intention to treat (ITT) analysis better overall survival and progression-free survival was seen in the Intensive group than the Standard group, (log rang p=0.04 and p < .001 respectively) Overall, there was an improvement in median survival of approximately one year in the intensive group: 54.1 (95% confidence interval 33.1 to 51.6) in the Standard group. Other analyses showed a trend to improved survival frp,minimal response (MR) 25.6 months through partial response (PR) 39.8 months to CR, 88.6 months. A significant interaction between treatment group and pretreatment serum beta 2 mucroglobulin (β2m) level was seen (p=0.003, Cox Model).

Stratified log rank analysis was carried with the β2m strata <4.0, 4-8/0 and >8.0 mg/l (as defined in previous MRC studies). Within each stratum, the Intensive group had a longer median survival than the Standard group but this difference was greatest in those with baseline serum β2m > 8 mg/l - median survival 41.9 months in the Intensive group compared with 13.1 months in the Standard group. In cohort studies to further investigate the impact of attaining minimal residual disease (MRD) after HDT, immunophenotypic characterisation of plasma cells by flow cytometry suggested that patient who were a normal phenotype post-HDT had an improved survival compared to patients who were immunofixation negative but with plasma cells of malignant phenotype.

Although the worldwide data on the straight non-selected randomised comparison of conventional-dose treatment versus treatment incorporating HDT are limited, an overview including published data from the comparable IFM and MAG studies suggest that there is a significant survival benefit from HDT. It is unlikely that further trials of this nature will be pursued. In the forthcoming MRC Myeloma IX Trial, all younger/fitter patients (not defined strictly by age) will receive HDT as a compnent of their first line treatment.

Autotransplantation:  The Spanish Experience: Dr. Joan Bladé

Dr. Bladé presented the results of autotransplant clinical trials conducted in Spain. The key trial compared conventional chemotherapy (VBMCP/VBAD) to high dose therapy with stem cell transplantation (HDT/SCT)

Patients in each of the arms of the trial were comparable along many key dimensions, with the conventional arm having more patients with Hemoglobins below 10 g/dl.

Each arm had similar response rates to the initial chemotherapy,

Not surprisingly, the high dose arm had a significantly higher rate of complete remissions (CR), 30% versus 11%.

...The HDT arm also had a higher progression-free survival (43 months versus 34 months), although the difference was not statistically significant.

Autotransplantation:  US Experience: Dr. Bart Barlogie

Dr. Barlogie presented the results of the US intergroup trial (S9321) and the extensive Little Rock experience.

The intergroup trial was conducted by the Southwest Oncology Group (SWOG) with participation from other cooperative groups in the US.

The trial compared allogeneic and autologous transplant to conventional chemotherapy (VBMCP). The allogeneic arm was closed early in the study because it proved to be inferior to both the auto and conventional arms in both overall survival and event free survival.

Platelet counts and LDH were significant prognostic factors.

The TT I (Total Therapy I) program in Little Rock used VAD, High Dose Cytoxan and EDAP as induction followed by a double transplant using MEL  200, followed by interferon maintenance.

...And showed superior Overall Survival and Event Free Survival in a retrospective comparison to conventional chemothreapy protocols used in Southwest Oncology Group (SWOG) trials.

The retrospective analysis shows a better outcome for TT I vs. the SWOG regimens, with age being the other most significant factor impacting survival.

The panel (below) fielded questions at the end of the session.

Please note that the Unknown Patient is a patient, not a doctor and not a scientist. This summary represents a layman's view of what was said at the conference and should form a basis for raising awareness of issues that could be discussed with a qualified professional. In no way should anything contained in this report be taken as medical advice or form the basis for action without first consulting a qualified medical professional who is familiar with your specific medical situation.