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Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983–93 (all with bone marrow) and 356 during 1994–98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with bone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 was the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.
Patients and methods
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- Patients and methods
Three-hundred and thirty-four patients with multiple myeloma who received a bone marrow graft from human leucocyte antigen (HLA)-matched sibling donors between 1983 and 1993 (group 1) were compared with 223 similar bone marrow transplants from the beginning of 1994 to the end of 1998 (group 2). These 223 bone marrow transplants were in turn compared with 133 peripheral blood stem cell transplants performed during the same time period (group 3). All patients were reported to the EBMT registry on so-called MED-A (limited data set) or MED-B (more extensive data set) forms. All 690 patients who had received an allogeneic transplant from a fully matched sibling donor were included in the study, disregarding the lack of complete data information on those patients who were only reported on MED-A or had missing data on MED-A or MED-B. The proportion of patients that could be evaluated is indicated for each parameter listed in Tables I and II and the numbers of evaluable patients are indicated in the results.
Table I. Patient characteristics before transplantation.
| ||Bone marrow 1983–93||Bone marrow 1994–98||PBSC 1994–98||P-values|
| ||Group 1 (n = 334)||Group 2 (n = 223)||Group 3 (n = 133)||Group 1/||Group 2/|
|Variable||% evaluated||% of evaluated||% evaluated||% of evaluated||% evaluated||% of evaluated||Group 2|
|Sex||100|| ||100|| ||100|| ||0·9|
| Female|| ||40|| ||39|| ||36|| |
| Male|| ||60|| ||61|| ||64|| |
|Ig subclass||88|| ||88|| ||81|| ||0·3|
| IgG|| ||52|| ||58|| ||64|| |
| IgA|| ||21|| ||20|| ||18|| |
| Light chain|| ||18|| ||12|| ||12|| |
| IgD|| ||2|| ||3|| ||3|| |
| Non-secr. + non-produc.|| ||3|| ||4|| ||1|| |
| Plasma cell leukaemia|| ||2|| ||2|| ||2|| |
| Other|| ||1|| ||2|| ||0|| |
|Stage at diagnosis||72|| ||52|| ||43|| ||0·5|
| I|| ||16|| ||12|| ||9|| |
| II|| ||20|| ||24|| ||21|| |
| III|| ||65|| ||64|| ||70|| |
|Treatment regimens (lines) before t(x)||70|| ||49|| ||43|| ||0·04|
| 1|| ||45|| ||56|| ||68|| |
| 2|| ||30|| ||30|| ||19|| |
| 3|| ||25|| ||14|| ||12|| |
|Response before t(x)||90|| ||91|| ||90|| ||0·1|
| CR|| ||14|| ||20|| ||13|| |
| PR|| ||59|| ||55|| ||61|| |
| NR|| ||14|| ||16|| ||18|| |
| Progression|| ||13|| ||8|| ||8|| |
Table II. Times to engraftment.
| ||Bone marrow 1983–93||Bone marrow 1994–98||PBSC 1994–98||P-values|| |
| ||Group 1 (n = 334)||Group 2 (n = 223)||Group 3 (n = 133)||Group 1/||Group 2/|
|Variable||% evaluated||Days (CI)||% evaluated||Days (CI)||% evaluated||Days (CI)||Group 2||Group 3|
|Neutrophils > 0·5 × 109/l||59||20 (19–21)||67||19(17–20)||65||14(13–16)||0·07||0·0001|
|Platelets > 50 × 109/l||47||27 (25–31)||55||27(25–32)||47||18(15–22)||0·6||< 0·001|
The median age at transplantation of patients in group 1 was 43 years (range 21–62), in group 2, 44 years (range 18–57) and in group 3, 46 years (range 25–60). Although there was only 1 year difference in the median age of patients in group 1 and 2, respectively, and 2 years difference between group 2 and 3, both differences were statistically significant (P = 0·003 and 0·007 respectively). The median time from diagnosis to transplantation was significantly longer in group 1 (median 14 months, range 2–168) compared with group 2 (median 10 months, range 3–155); whereas the median times for group 2 and group 3 were similar, i.e. 10 months in both (range for group 3, 2–136). For obvious reasons the follow-up time was longer for group 1 (median 73 months, CI 67–83) than for group 2 (median 22 months CI 16–27), and still shorter for group 3 (median 10 months CI 7–14).
Pretransplant patient data are shown in Table I. Gender, Ig-subclass, stage at diagnosis and response status at the time of transplantation did not differ significantly among the groups in evaluable patients. Values for beta2 microglobulin at diagnosis (not shown in Table I) were only available for 23%, 35% and 28% of the patients in groups 1, 2 and 3, respectively, but there was no significant difference between the group values (median value 3·2, 2·7, and 2·9 mg/l respectively) for evaluable patients.
The fraction of patients that had received only one treatment regimen before transplantation was significantly higher in group 2 (56%) than in group 1 (45%) and conversely the proportion of patients that had received more than three regimens (14%) was significantly lower in group 2 than in group 1 (25%), with no significant difference between groups 2 and 3 (Table I).
The conditioning regimens varied among groups and within groups. Regimens including only total body irradiation (TBI) and cyclophosphamide tended to be more commonly used in group 1 (37%) and 2 (39%) than in group 3 (27%) and, conversely, melphalan-containing regimens tended to be more commonly used in group 3 (29%, 31%, and 38%, in groups 1, 2 and 3 respectively). Melphalan alone was rarely used (0%, 1% and 4% in groups 1, 2, and 3) and so the use of busulphan plus cyclophosphamide was also uncommon (9%, 12% and 4% in groups 1, 2, and 3 respectively).
Prevention of graft-versus-host disease (GVHD) was at the discretion of each centre. The regimen most commonly used was cyclosporin + methotrexate without T-cell depletion (with the addition of prednisone in a few cases) in 57%, 52% and 73% of evaluable patients in groups 1, 2, and 3 respectively. T-cell depletion with or without additional treatment was used in 24%, 34% and 18% of patients in the respective groups and for the remaining patients, other treatment combinations were used.
The use of cytokines to promote engraftment was more frequent in the later time period, particularly in recipients of peripheral blood stem cell transplants. Cytokines were used in only 8% of group 1 patients compared with 31% of group 2 patients and 41% of group 3 patients. However, data was only available for 46%, 37% and 38% of patients in groups 1, 2 and 3 respectively.
Complete remission after transplantation was defined, for the purpose of this study, as the disappearance of abnormal immunoglobulins from serum and/or light chain from the urine, using either conventional electrophoresis or immunofixation, as well as disappearance of apparent myeloma cells from the marrow as previously described (Gahrton et al, 1995).
Statistical analysis Comparison of frequencies were made with a χ2 test. Median values were compared using Wilcoxon's signed rank test. A P-value of 0·05 was regarded as significant. All confidence intervals (CI) are 95% confidence intervals. Survival curves were generated according to the Kaplan–Meier product-limit method and were tested with the log-rank test. The curves were truncated when less than five patients were at risk. Overall survival, progression-free survival and treatment-related mortality were calculated from the time of transplantation, whereas survival from complete remission, relpse-free survival and relapse rate were calculated from the time of complete remission. All analyses were made using the SAS System for Windows, release 6·12.
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The present report shows that over a recent 5-year period (1994–98), the overall survival after allogeneic bone marrow transplantation for multiple myeloma has improved dramatically compared with transplants performed during the previous 5 and 11 years. This is in contrast to earlier analyses made by the EBMT, which failed to show improvement in outcome with time (Gahrton et al, 1995). The present study confirms that there was no significant improvement in survival from the time period 1983–88 to 1989–93. Thus, the improvement has occurred during the later 5 years, from 1994 onwards.
The study also shows that the improvement is entirely a result of a lower transplant-related mortality during the latest 5-year period. The reports to the EBMT registry indicate that acute GVHD has not changed during this period; the incidence of both overall and severe GVHD was about the same. Also, an analysis of causes of death indicates that acute GVHD as a cause of death was about the same, i.e. 12% of deceased patients during the first time period and 11% during the second one. On the other hand, there was a significant difference in deaths caused by interstitial pneumonitis and bacterial and fungal infections. There was no significant difference in other causes of death, although there was, for example, a tendency for more organ failures during the first time period (14%) compared with the later one (8%). There are several possible reasons for the reduction in interstitial pneumonitis, including better treatment of cytomegalovirus infection and, perhaps, changes in dosage and fractionation of cytotoxic drugs and TBI respectively: factors that cannot be adequately analysed from the present report forms.
The improvement in transplant-related mortality was not caused by selection of more female patients, which has previously been shown to be an important favourable prognostic factor (Gahrton et al, 1995). However, it is probable that earlier transplantation (10 months from diagnosis during the latest time period and 14 months during the earlier one) has played an important role. This in turn results in a lower number of treatment regimens before the transplantation. Previous studies have shown that fewer treatment lines before transplantation is the second most important favourable prognostic parameter for survival in multivariate analysis (Gahrton et al, 1995). Fifty-six percent of the evaluable patients received only one treatment regimen and 14% had more than two during the later time period compared with 45% and 25% during the earlier one.
The use of peripheral blood stem cells (PBSCs) instead of bone marrow did not per se change the overall outcome. The transplant-related mortality was similar to that of transplantation with bone marrow cells during the same time period and, although the engraftment rate was more rapid using PBSCs, there was a tendency for a higher incidence of chronic GVHD. Also the use of PBSCs did not translate into reduced transplant-related mortality or a significantly lower death rate caused by bacterial and fungal infections.
Cytokines were used more frequently during the later time period. Although engraftment rate was only shortened when PBSCs were used (which did not per se improve transplant-related mortality), the possibiliy that cytokines played a role in the reduced death rate cannot be excluded.
Unfortunately, the relapse rate does not appear to have improved, either with bone marrow cells or with PBSCs. Most patients were conditioned with TBI plus cyclophosphamide during the two time periods, although a slight shift towards more frequent use of TBI plus melphalan during the later period could be seen. However, TBI plus melphalan has not previously been shown to be superior to TBI plus cyclophosphamide in EBMT studies, although variations in dose regimens, fractionations, etc. have not been considered in these studies. In one small study (17 patients), conditioning with fractionated TBI (total dose 12 Gy) and melphalan 70–110 mg/m2 resulted in a comparatively low relapse rate and a low transplant-related mortality (Russell et al, 1997), but in another one the conventional TBI plus cyclophosphamide regimen gave similar favourable results (Volin et al, 1999). However, the present study and the previous reports do not give a clear indication as to how the conditioning could be changed to reduce the relapse rate without increasing the transplant-related mortality.
Allogeneic transplantation appears to be the most probable way to obtain a cure in patients with multiple myeloma. Although occasional molecular remissions can be obtained with autologous transplantation (Bjorkstrand et al, 1995; Corradini et al, 1999), these are usually transient, and the frequency and durability of molecular remissions is higher using allogeneic transplantation (Corradini et al, 1999). Also, there is now the possibility of using donor lymphocyte transfusions to treat patients with persistent disease, indicated by persistent immunoglobulins in the serum or light chains in the urine. Donor lymphocyte transfusion may also induce remissions in relapses after previous complete remissions (Aschan et al, 1996; Tricot et al, 1996;Lokhorst et al, 1997; van der Griend et al, 1999). Thus, allogeneic transplantation should be considered for the treatment of younger patients with multiple myeloma who have a matched-sibling donor. Prognostic factors at diagnosis that are unfavourable for autologous transplantation may strengthen the indication. Early transplantation, intensive anti-viral, anti-bacterial and anti-fungal treatment are important factors in obtaining a favourable outcome. Recently, non-myeloablative conditioning followed by allogeneic transplantation has proven to be feasible, and associated with low transplant-related mortality (Slavin et al, 1998; Giralt et al, 1999; Molina et al, 1999). However, the relapse risk is still unknown. Results may be improved if performed as a second transplant after autologous transplantation and followed by donor lymphocyte infusions at early signs of relapse. Such a study is now being planned within the EBMT.
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This work was supported by grants from the Swedish Medical Research Council, the Swedish Cancer Fund and Funds from the EBMT.
The following centres have reported myeloma transplants to the EBMT registry: Hospital San Orsola, Bologna (S. Tura, M. Cavo); University Hospital, Utrecht (L. F. Verdonck, A. W. Dekker); Huddinge University Hospital, Huddinge (J. Aschan, P. Ljungman); University Hospital St. Radboud, Nijmegen (A. Schattenberg, T. de Witte); Helsinki University Central Hospital, Helsinki (L. Volin); Hospital Clinic, IDIBAPS, Barcelona (E. Montserrat, J. Bladé); Dr Daniel Den Hoed Cancer Centre, Rotterdam (J. J. Cornelissen, A. Hagenbeek); Ospedale San Martino, Genova (A. Bacigalupo); Hôpital Claude Huriez, Lille (F. Bauters, T. Facon); S. Camillo Hôspital, Rome (A. De Laurenzi, N. Petti); Leiden University Medical Centre, Leiden (F. v.d. Loo, R. Willemze); Hopital E. Herriot, Lyon (M. Michallet); Nottingham City Hospital, Nottingham (N. H. Russell); Hammersmith Hospital, London (J. M. Goldman, J. Apperley); Royal Marsden Hospital, Surrey (R. Powles); University Hospital, Essen (U. W. Schaefer, D. W. Beelen); Hopital du Haut Leveque, Pessac (J. Reiffers); Cliniques Universitaires St. Luc, Brussels (A. Ferrant); Ospedale Civile, Pescara (G. Torlanto, P. di Bartolomeo); Hôpital Henri Mondor, Creteil (J. P. Vernant); Ospedale versus Cervello – USL 60, Palermo (I. Majolino); Universita Tor Vergata, Rome (S. Amadori, L. Cudillo); Turku University Central Hospital, Turku
(K. Remes, A. Rajamäki); Hôpital A. Michallon, Grenoble (L. Molina, J.-J. Sotto); Rigshospitalet, Copenhagen (N. Jacobsen, L. Vindelov); Royal Free Hospital, London (H. G. Prentice, M. Lowdell, M. Potter); Hotel Dieu, Nantes (J. L. Harrouseau, N. Milpied); Pesaro Hospital, Pesaro (G. Lucarelli, M. Galimberti); University College London Hospital, London (A. H. Goldstone, D. H. Linch); Hôpital La Miletrie, Poitiers (F. Guilhot, V. Delwail, F. Millot); Ospedale di Careggi, Firenze (A. Bosi, S. Guidi); UCT Medical School, Cape Town (N. Novitzky, E. Holland); Addenbrookes Hospital, Cambridge (R. Marcus, P. Mahendra, G. Bass, C. Howlett); Universitätskrankenhaus Eppendorf, Hamburg (A. R. Zander, R. Erttman); Kantonspital, Basel (A. Gratwohl); Universität Ulm, Ulm (F. Hermann, D. Bunjes, W. Friedrich); Hôpital Cantonal Universitaire, Geneva (B. Chapuis, C. Helg, M. Storbinski); University Hospital Maastricht, Maastrict (H. Schouten, A. Ten Haaft); Udine University Hospital, Udine (M. Baccarani, R. Fanin); CHU Sart-Tilman, Liege (Y. Beguin, G. Fillet, B. Sautois); Cordoba Hospital, Cordoba (A. Torres Gomez, P. Gomez Garcia); Ospedale Niguarda Ca'Granda, Milano (E. Morra, R. Cairoli, P. Morenco); Diagnostic & Therapeutic Centre of Athens, Athens
(G. Karianakis, A.G. Papayannis); University Hospital Gent, Gent (L. A. Noens, F. Offner, Y. Benoit); Centre Rouen Becquerel, Rouen (Tilly); Med. University of Klinik, Tubingen (L. Kanz, C. A. Muller, H. Einsele); University Hospital of Turin, Torino (M. Agliette); Hospital Universitaria, ′Marquès de Valdecilla', Santander (A. Iriondo, C. Richard, E. Conde); Glasgow Royal Infirmary, Glasgow (P. Tansey); Hôpital Cochin, Paris (F. Dreyfus, Belanger); University Hospital, Lund (A. Bekassy, P. G. Nilsson, S. Lenhoff, B. Falk); Heinrich Heine Universität, Dusseldorf (R. Haas, A. Heyll); University of Verona, Verona (G. Perona, A. Ambrosetti); Institut Gustave Roussy, Villejuif
(J. L. Pico, J.-H. Bourhis); K. Marcinkowski University of Medical Science, Poznan (J. Hansz, P. Gcrski, J. Gozdzik); Istanbul Medical School, Istanbul (Y. Tangun, D. Sargin); University of Perugia, Perugia (M. Martelli, F. Aversa); University Hospital Gasthuisberg, Leuven (M. A. Boogaerts); Hôpital Jean Minjoz, Besancon (J.-Y. Cahn); Academisch Zienkenhuis bij de Universiteitvan, Amsterdam (H. Van den Berg, H. Behrendt); Christian-Albrechts-University, Kiel (N. Schmitz, P. Dreger); Hospital Santa Creu i Sant Pau, Barcelone (I. Badell Serra, J. Sierra, J. J. Lopez, C. Sola); University of Milano, Milano (G. Lambertenghi Deliliers); Hospital Clinico Universitario, Valencia (J. Garcia-Conde, I. Benet); Policlinico San Matteo, Pavia (E. P. Alessandrino); Klinikum Groáhadern, Munich (H.-J. Kolb, W. Wilmanns, M. Schleuning); R G Vall Hebron, Barcelona (A. Juli, J. Zuasu, J. Bueno); U.L.B. – Hôpital Erasme, Brussels (W. Feremans, A. Kentos); Royal Infirmary, Manchester (J. A. L. Yin); Service des Maladies du Sang, Angers
(M. Boasson, N. Ifrah); Hospital Universitario La Fe, Valencia (M. A. Sanz, G. F. Sanz); Wynberg Hospital, Wynberg (P. Jacobs, J. M. G. Du Toit); Hôpital Necker, Paris (A. Fischer, S. Blanche); Institut Jules Bordet, Brussels (P. Stryckmans, D. Bron); University of Vienna, Vienna (H. Greinix, P. Halhs, K. Lechner); University of degli Studi La Sapienza, Rome (F. Mandelli, W. Arcese, G. Meloni); University Hospital, Uppsala (B. Simonsson); University Hospital, Innsbruck (D. Nachbaur); R. Dr Antonio Bernardino de Almeida, Porto (P. Pimentel, F. Campilho, A. Campos); Royal Liverpool University Hospital, Liverpool (R. E. Clark, J. K. M. Duguid); The George Papanicolaou General Hospital, Exokhi (A. Fassas); Hospital Regional de Malaga, Malaga (J. Maldonado Eloy-Garcia); Hôpital de Purpan, Toulouse
(M. Attal, F. Huguet); Hôpital Pontchaillou, Rennes (Bergeron, Le Gall, Leprise); Clinical Puerta de Hierro, Madrid (M.-N. Fernández, J. R. Cabrera-Marin); St. Bartholomew's Hospital, London (S. Kelsey, A. Lister, A. Rohatiner, A. Newland); Charite, Berlin (R. Arnold, G. Gaedecke, G. Massenkiel); Universitätsklinikum Dresden, Dresden (G. Ehninger, U. Schuler); University of Erlangen, Erlangen (M. Gramatzki, W. Rösler); University of Freiburg, Freiburg (J. Finke, W. Lange, H. Bertz); Istituto Di Clinica Medica, Cagliari (L. Contu, G. La Nasa); Hôpital St. Louis, Paris (E. Gluckman); Hôpital Saint Antoine, Paris (N. C. Gorin, L. Fouillard); Royal Infirmary, Edinburgh (A. C. Parker, I. O. Jenny); Hôpital de Nancy, Nancy (Witz); The Oxford Radcliffe Hospital, Oxford (T. Littlewood); Pitie-Salpetriere, Paris (V. Leblond, L. Sutton); The London Clinic, London (D. Guéret-Wardle, F. H. David, P. Gravett); Centre Jean Perrin, Clermont-Ferra (R. Plagne, J. O. Bay, B. Choufi, H. Cure); Birmingham Heartlands Hospital, Birmingham (D. W. Milligan, C. D. Fegan); East Hospital, Gothenburg
(A. Fasth, L. Mellander); Medical School of Hannover, Hannover (B. Hertenstein, A. Ganser, A. Schrauder); R. Prof. Lima Basto, Lisboa (M. Abecasis); Universita Cattolica S. Cuore, Rome (G. Leone, A. Di Mario); Gata Military Medical Academy, Etlik Ankara (A. Yalgin, F. Arpaci, A. Ozet); Hôpital CIMIEZ, Nice (N. Gratecos, J. G. Fuzibet); St George's Hospital Medical School, London (J. C. W. Marsh, E. C. Gordon-Smith); Hospital Nuestra Senora Aranzazu, San Sebastian (R. Lasa Isasti); Ibni Sina Hospital, Ankara (H. Koc, M. Beksac, O. Ilhan); Evangelismos Hospital, Athens (N. Harhalakis); University Medical Centre, Ljubljana (J. Pretnar, P. Cerneic); Universitá degli Studi di Bari, Bari (V. Pavone, V. Liso); Institute of Haematology and Blood Transfusion, Praha (A. Vitek, P. Kolbylka); Hôpital de Percy, Clamart (T. de Revel, Auzanneau); CHU de Dijon, Dijon (D. Caillot); CHR-CHU-Hôpital de Hautepierre, Strasbourg
(F. Oberling, B. Lioure); Charles University Hospital, Pilsen (V. Koza, P. Cetkovsky, K. Cerna); Charles University, Hradec Krávolé (S. Filip); Norrland University Hospital, Umeå (E. Löfvenberg, P. Hörnsten); Antartida Hospital Privado, Buenos Aires (L. Feldman, V. Milovic); King's Healthcare NHS Trust, London (G. J. Mufti, A. Pagliuca); The Roald Dahl Paediatric Haematology Centre, Sheffield (E. Vandenberghe, R. Hinchliffe); Johannes-Gutenberg-University, Mainz (C. Huber, K. Kolbe, G. Derigs, E. Alten); Hospital no. 9, Minsk (A. Uss, P. Mitskevitch); Istituto Scientifico H.S. Raffaele, Milano (C. Bordignon); University of de Palermo, Palermo
(G. Mariani, M. Musso, R. Perricone); Silvestrini Hospital, Perugia (A. Amici, P. Zucchetti); Hospital G. U. ‘G. Maranon', Madrid (T. Pintado Cros); C.A.C. Francois Baclesse, Caen (A. M. Peny).