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IXth International Myeloma Workshop - Monday, May 26th, 2003 - Tandem Autologous Transplantation.
05.31.03

 

This session focused on Tandem Transplatation in multiple myeloma. The role of double transplants remain controversial. Strong advocates such as Barlogie (Little Rock) and Harousseau (IFM: France) show evidence of improved or extended survival. The ramdomized data from France show statistically significant benefit for patients with significant residual disease after the first transplant and before the second transplant. Based upon the discussions, further studies are required to reach true consensus.


Tandem Transplants: Dr. Michelle Attal

Dr. Attal presented the results of the French intergroup trial (IFM 94). High dose therapy supported with autologous stem cell transplantation has been introduced in the management of aggressive myeloma and promising survivals from single institutions, case controlled and randomized studies have been reported. However, after a single tranplant (ST), almost all patients ultimately relapse.

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In order to improve these results, the role of double transplantation (DT) has been evaluated in uncontrolled studies. However, direct comparison of these results with those observed after ST is unsatisfactory as patients, undergoing high dose therapy are subject to considerable selection bias (including young age, good performance status and normal renal function.)

Thus, multicentric and prospective randomized trials designed to avoid these sources of bias are required to compare ST and DT. The "Intergroupe Francophone du Myelomé" (IFM) initiated such a trial.

From October 1994 to to March 1997, 399 untreated myeloma patietns under the age of 60 years were randomized at diagnosis to receive ST prepared with melphalan (140 mg/m2) and the second one prepared with melphalan (140 mg/m2) and TBI (8 Gy). Patients were initially treated with 3-4 cycles of the VAD regimen

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Patients included in the trial were all symptomatic, aged under 60 years with not prior myeloma treatment.

The trial involved 36 centers, enrolling 399 patients with median follow-up of 75 months.

The bulk of the patients participating were able to complete at least one transplant.

.Overall, there was a 5% rate of toxic deaths.

More patients had a >90% remission after tandem transplant (50% versus 42%), as well as a >50% remission (50+39=89% versus 42+42=84%).

There was a stitstically significant advantage in event-free survival for the tandem transplant arm (30 months versus 25 months).

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The difference in 7 year overall survival was also statitstically significant (42% versus 21%).  Adcantages were also seen in the death rate and median overall survival.

Prognostic factors for overall survival were LDH, treatment arm, serum beta 2 microglobulin (β2m) and age.

.Patients with less than a 50% response to the induction therapy who then received tandem transplats (arm B) had longer overall survival.

...whereas the OS benefit was not statistically significant for those with >50% response. Similarly, those with at least a 90% response to the first transplant did not show a statistically significant OS advantage whereas those with lesser responses did seem to benefit.

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Dr. Attal summarized his conclusions as follows:


Tandem Transplants: Dr. Jean-Paul Fermand

Dr. Fermand presented the results of the group "Myélome-Autogreffe" multicenter prospective trial. In 1996, the group initiated a multicenter prospective trial where patients afed under 56 with newly diagnosed symptomatic multiple myeloma were randomly assigned up-front to receive either a single HDT (HDT1) or two sequential HFT (HDT2). In addition, all patients were independently randomized to be transplanted with unselected ABSC (unselected arm) or CD34-enriched ABSC (CD34 arm).

In all cases, patients first received one or two courses of high dose steroid containing regimens and ABSC were therafter mobilized by cytoxan (CTX)  (4 g/m2) and lenograstim (10mg/kg/d). When appropriate (CD34 arm), part of the collected ABSC were selected using the Isolex®300i system. The selection procedure resulted in a median purity of 95% (65--100) and in a more than two log tumor cell depletion. In the HDT1 arm, HDT was preceded by 3 monthly courses of a VAD-like regimen and combined in a multi-drug regimen (carmustine, etoposide, melphalan 140 mg/m2 (MLP 140) and CTX 60 mg/kg with a TBI (12 grays in 6 fractions).. Patients treated in the HDT2 arm received M:LP 140 alone (alwaus supported by unselected ABSC) followed 2 to 3 months later by a second MLP 140 combined with etoposide (30 mg/kg) and 12-gray TBI. In both arms, TBI including HDT were supported with unselected or CD34 enriched ABSC.

Two hundred and thirty patients were included in the study. At the reference date of 01/12/2002, median follow-up ws 52 months since randomization. Baseline characteristics of HDT1 (n=94) and HDT2 (n=99) groups were close. Similarly, there was no significant difference between the unselected (n=94) and CD34 (n=99) arms.

All analyses were performed on an intent to treat basis. There was no ecidence ofor benefit of CD34 selection as compared to the use of unselected ABSC. Post transplant hematological recovery was similar but immunological recovery was delayed in the CD34 selected group in which the incidence of serious infections was increased. However, relpase and death rates were not significantly different between the 2 groups (45 and 51 deaths in the unselected group and in the CD34 group, respectively, p=0.3 by the log-rank test.

In HDT groups, treatment completion rates were satisfactory, with 6/114 transplants not performed in HDT1 group (allogeneic transplant n=1, refusal n=1, mobilisation failure n=1, early death due to disease progression n=3). Median intervals between randomization and TBI- including transplant were similar (5 months in the HDT2 arm).

Present analysis did not show any significant difference in terms of early mortality, disease response and outcome of patients included in HDT groups. Early death rates (within 9 months post randomization, including toxic death and fatal progressive disease) were 12% and 7% in the HDT1 and the HDT2 arms, respectively. Response (complete response + minimal residual disease) rates were 39% and 37%, respectively. During follow-up, there were 53 deaths in each arm and the 2 overall survival curves were not statistically different (p=0.14 by the log rank test). The event free survival curves were nearly identical (p=0.55).

In conclusion, present analysis of the study did not show any significant benefit of single HDT versus tandem HDT and of CD34+ selectionof autografts which appeared to increase the incidence of serious infections.


Tandem Transplants: Dr. Peter Sonneveld

Dr. Sonneveld presented the results of the Hovon 24 MM trial.

The Hovon 24 trial compared double-intensified therapy (Melphalan 70 mg/m2 x 2) followed by either maintenance or myeloablative therapy and PBSCT and maintenance.

The results showed statistically significant benefit in event free survial, progression free survival and time to progression but not in overall survival.

The Hovon 24 trial compared double-intensified therapy (Melphalan 70 mg/m2 x 2) followed by either maintenance or myeloablative therapy and PBSCT and maintenance.


Tandem Transplants: Dr. Michele Cavo

Dr. Cavo presented the results of the Italian experience with tandem tranplants for multiple myeloma

The Bologna 96 clinical tiral randomized 386 patients between single and double transplant regimens.

The Bologna 96 clinical tiral randomized 386 patients between single and double transplant regimens.

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Response rates were relatively high, with the second transplant adding a small increment to an already high response rate.

The trial showed an increase in event free survival for the double transplant arm.

Overall survival showed no significant improvement but there was improvment for time to progression.


Tandem Transplants: Dr. H. Goldschmidt

Dr. Goldschmidt presented the results of the German experience with tandem tranplants for multiple myeloma

The GMMG-HD2 clinical tiral randomized 266 patients between single and double transplant regimens.

216 of these patients from 45 centers were evaluable.

The first results do not show a statistically-significant advantage for tandem transplants for event-free survival.

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Tandem Transplants: German Experience: Upgrade In Response Rate Is A Determinant Factor For The Favorable Outcome Effect Of A Seconf Transplant On MM. Update Of  A Tandem Transplant Phase II: Dr. Carlos Grande

16 of 48 patients in PR after the first transplant achieve CR after the second..

Comparison of 42 tandem transplant patients who attained final CR with 53 in the control group who attained CR with single ASCT shows no significant differences in either EFS or OS.  For tandem patients in final PR, the differences were again not significant.

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Dr. Grande concluded that the value of tandem transplant is likely there only if patients do not achieve CR after the first transplant.


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

The discussion reflected the ongoing controversy and ambiguity of the evidence on this issue of single versus tandem transplants. One of the questioners finally asked if the panel would vote as to whether they would recommend tandem transplants to their patients over a single transplant. Five of the eight panel members indicated their preference for tandem transplants (see below).

 

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.

 

 


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