Autografting

Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: a single-centre experience in 211 patients

Abstract

High-dose therapy with autologous stem cell therapy (ASCT) has become the treatment of choice for eligible patients with myeloma. We analysed retrospectively the prognostic influence of pre-transplant characteristics and transplant modalities on response and survival in 211 myeloma patients who were transplanted in our centre between 1994 and 2004. All patients received peripheral blood stem cell support after conditioning with melphalan alone (183 patients), or melphalan and total blood irradiation (28 patients). We evaluated the influence of age, type of multiple myeloma, status prior and post ASCT, previous treatment regimens, time of ASCT from diagnosis, year of autograft, dose of re-infused CD34+ cells, plasma cell infiltration and β2-microglobulin at diagnosis on overall survival (OS) and event-free survival (EFS) to define patients with better prognosis. Median OS and EFS from transplantation were 50.9 and 20.1 months, respectively. Median OS from diagnosis was 68.8 months. Transplant-related mortality was 1.4%. Lower β2-microglobulin levels, achievement of complete remission (CR) post transplant and lower plasma cell infiltration at diagnosis and transplant correlated with longer EFS and OS, whereas CR at transplant and low international prognostic index at transplant correlated with better EFS. Higher CD34+ cell dose correlated with improved OS. We conclude that ASCT is safe and effective and the outcome is independent of age, time from diagnosis, previous treatment and conditioning regimen.

Introduction

Multiple myeloma (MM) is a B-cell malignancy with a median age at presentation of 60–65 years.1 The outcome for MM patients after chemotherapy has not changed dramatically since the introduction of melphalan and prednisolone, although a large number of different chemotherapy combinations have been used.2 Advanced age is a poor prognostic factor in several trials using conventional chemotherapy even if the biological and clinical features in elderly MM patients are identical to those of younger patients.3 In the absence of any significant improvement after various conventional chemotherapy regimens, high-dose therapy with autologous stem cell transplantation (ASCT) has been extensively used in the last decade leading to higher complete remission (CR) rate with longer event-free (EFS) and overall survivals (OS).4, 5 Although the benefit from ASCT is mainly seen in a subgroup of patients with favourable initial characteristics who achieve CR post-ASCT, it is also of value in patients with resistant disease.6 This procedure is safe even in selected patients over the age of 65, mainly because of the use of peripheral blood stem cells (PBSC), which has shortened the period of haematopoietic recovery leading to a significant decrease in mortality, and also because of improvement in general supportive measures.7 However, several issues have to be clarified, such as defining the patient subsets that will benefit most from this procedure, the best timing of ASCT in the course of disease, the optimal conditioning regimen, the role of induction treatment in post-ASCT outcome and finally the management of patients with unfavourable characteristics.

In order to assess the clinical results of ASCT, we present here the data from 211 patients with MM who were autografted in our centre since 1994. We have evaluated the prognostic influence of pre-transplant characteristics and transplant modalities on disease response and survival.

Patients and methods

Patients

Between July 1994 and October 2004, 211 patients with MM underwent ASCT at the Department of Haematology, Hammersmith Hospital. Their clinical characteristics are shown in Table 1. All patients had adequate stem cell collection and met all the eligibility criteria of our ASCT protocol including acceptable cardiac (ejection fraction >40%), pulmonary (diffusion capacity for carbon monoxide >50% of normal) and hepatic (bilirubin and transaminases <2 × upper limit) functions. Patients with creatinine clearance between 30 and 50 ml/min were included but received a reduced dose of melphalan; patients with creatinine clearance below 30 ml/min were excluded.

Table 1 Patient characteristics

Poor performance status due to MM was not an exclusion criterion. All patients were informed about the benefits and risks associated with stem cell collection and ASCT. The majority of patients had only one line of prior chemotherapy (range: 1–5) pre-ASCT and, VAD was most commonly used.

At the time of transplant, only 5% of patients were in CR. The majority (82%) had achieved a partial remission (PR) with previous chemotherapy regimens, whereas 28 of them (13%) had refractory or progressive disease. The median time interval between diagnosis and transplant was 9.85 months (range: 3.3–93.9 months). Thirteen patients (6%) had a planned second transplant (seven had tandem autografts and six had reduced-intensity conditioned allografts) and all were censored for EFS at the time of the second transplant. No patient showed evidence of disease progression before the second planned transplant. Twenty-six patients (12%) had a second autograft after disease progression and three patients have had a third autologous procedure. Four patients have been transplanted with a reduced-intensity allograft after progression of disease.

Treatment

Peripheral blood stem cells were collected during 1–3 consecutive leukaphereses, following high-dose cyclophosphamide 2 g/m2, i.v. for 2 days (total dose: 4 g/m2) with subsequent G-CSF. Apheresis was initiated upon recovery of CD34+ cells to >107/l.8 For patients who failed to mobilise with cyclophosphamide, etoposide was given at a dose of 1.6 g/m2 with subsequent G-CSF. Each sample was investigated by flow cytometric analysis for the presence of cells expressing CD34. The target cell dose for collection was >2 × 106 CD34/kg for each planned autograft.

The conditioning regimen consisted of melphalan alone in 183 patients with the addition of total body irradiation (TBI) in the remaining 28 patients. Melphalan, as a single agent, was given at a dose of 200 mg/m2 in 135 patients and at reduced doses (100 or 140 mg/m2) in 48 patients. The dose of melphalan was decreased in patients with reduced creatinine clearance (30–50 ml/min) or with significant cardiac or lung function impairment. If the combination of melphalan plus TBI was used (up to March 1998), 140 mg/m2 melphalan was infused. Total body irradiation, at a dose of 200 cGy b.d., was given for 3 days (total dose of 1200 cGy). Intravenous immunoglobulin was given to all patients, at a dose of 400 mg/kg, on days −1, +2, +14 and +28.

Response criteria

The EBMT criteria were used for assessing disease response.9 Complete remission was defined as the absence of a detectable monoclonal component in serum or in urine by immunofixation analysis, associated with <5% plasma cells in the bone marrow trephine. Patients were considered to be in PR if there was at least a 50% reduction of the initial paraprotein levels and a reduction of Bence Jones (BJ) proteinuria by greater than 90% or to <0.2 g/24 h. Patients with reduction of initial paraprotein between 25 and 49% and a reduction in BJ proteinuria by 50–89% but exceeding 0.2 g/24 h were considered as showing minor response (MR). Patients with responses not satisfying the criteria for CR, PR or MR were classified as having no response (NR). Progressive disease (PD) was defined as an increase in serum or urinary monoclonal protein by 25%, or a 25% increase in bone marrow infiltration in non-secretory myeloma. Relapse was defined as recurrence of monoclonal protein or bone marrow plasmacytosis if relapse was from CR, or a 25% increase from minimal tumour mass if relapse was from PR.

Statistical analysis

Data were analysed as of June 2005. Differences in the distribution of variables between patient subsets were analysed using the t-test. The Kaplan-Meier method was used to estimate EFS and OS probabilities, with differences compared by the two-sided log-rank test. Confidence interval was 95% for all analyses and the level of significance was equal to 0.05. Event-free survival and OS were defined as the time from ASCT to progression or death. However, OS from the time of diagnosis was also evaluated. Overall survival analysis considered death from any cause as an event. Complete remission and EFS duration were censored at the time of last contact if patients did not experience a progression or relapse before that time. Overall survival was censored at last contact.

Results

Cells infused, engraftment and treatment-related toxicity analysis

The median number of CD34+ cells infused was 3.4 × 106/kg (range: 0.8–19.2 × 106/kg). Our target cell dose for collection was not achieved in a proportion of patients, and a clinical decision was made regarding the autograft and cell dose to be infused. One hundred and five patients received >3.5 × 106 CD34+ cells/kg, whereas 106 patients received a lower dose of CD34+ cells/kg. No relationship was found between the characteristics of the patients at diagnosis and the number of PBSC collected. However, the number of stem cells collected correlated well with status of CR at transplant. Those patients in CR collected a median of 15.8 × 106 CD34+ cells/kg versus those patients in PR who collected a median of 8.2 × 106 CD34+ cells/kg. There was a statistically significant difference in OS (P=0.03) between the group that received >3.5 × 106 CD34+ cells/kg (median survival 71.5 months) and the group that received a lower dose (median survival 39.7 months).

The median time to platelet recovery >50 × 109/l was 17 days (range: 11–48 days) (however, a number of patients (n=31; 15%) were discharged before reaching a platelet count of 50 × 109/l and were therefore excluded, therefore, from this analysis), whereas neutrophil engraftment (>0.5 × 109/l) was achieved at a median time of 15 days (range: 10–32 days). Neither the number of infused cells nor the number of previous chemotherapy regimens was predictive of the time to neutrophil and platelet engraftment. Patients treated with melphalan and TBI conditioning regimen had a shorter neutrophil recovery than patients who received melphalan alone, mainly because the former group received G-CSF.

The transplant-related mortality (TRM) was 1.4% (3/211 patients); one patient died because of parainfluenza viral infection and two patients died because of septicaemia. No patient developed grade III–IV cardiac, pulmonary, renal or liver toxicity (World Health Organization scale), whereas neutropenic fever was present in almost all patients and severe mucositis was observed in a third of the patients.

Clinical response, overall survival and progression-free survival

The median follow-up was 32 months (range: 6–123 months). Overall response rate was 95%. Thirty-three patients (16%) achieved a CR post-ASCT, 143 patients (68%) a PR, 28 patients (13%) an MR, whereas four patients had refractory disease. All 11 patients who were autografted in CR remained in CR; nine of these are alive with a median survival now of 81.7 months (range: 14.5–123.3 months). Of the patients who were in PR at the time of the autograft (n=150), 22 (15%) achieved a CR after transplant, whereas 112 (75%) remained in PR. Of these 112 patients, 60 (54%) patients had a further >50% reduction in their paraprotein or >90% reduction in their BJP post transplant. In 29 patients who were in PR post transplant, paraprotein was detected by immunofixation or electrophoresis only. Nineteen out of 29 were positive by immunofixation only with negative electrophoresis.

Sixteen out of 22 patients who had achieved an MR after initial chemotherapy, 5/11 with refractory disease and 10/17 with PD at the time of transplantation achieved a PR post-ASCT. Table 2 summarises clinical status pre- and post transplant.

Table 2 Status pre- and post transplant

The median OS was 50.9 months and the median EFS was 20.1 months, whereas the median survival from diagnosis was 68.8 months (Figure 1).

Figure 1
figure1

Event-free survivals and overall survivals for all patients.

The status of disease before autograft significantly affected EFS. As shown in Figure 2a, patients who had undergone ASCT in CR have an as yet undefined median EFS compared with patients who were in MR before transplant in whom EFS was 11.0 months. Status at transplant shows a significant trend towards statistical significance for OS.

Figure 2
figure2

Overall survivals and event-free survivals according to status at transplant.

Response to ASCT strongly correlated with both EFS and OS. Patients who achieved a CR post-ASCT had a longer EFS and OS than patients who achieved a PR or MR (median EFS was 59.0, 22.0 and 9.0 months, for CR, PR and MR patients, respectively (P<0.0001); median OS has not been reached yet for CR patients, whereas it was 47.1 and 34 months for PR and MR patients respectively (P=0.01)) (Figure 3).

Figure 3
figure3

Overall survivals and event-free survivals according to status post transplant.

β2-Microglobulin at diagnosis was a predictor for both EFS and OS. Patients with renal impairment (serum creatinine >150 μmol/l) were excluded from this analysis. Those with low β2-microglobulin levels (<3 mg/l) had a longer median EFS (P=0.08; 20.1 versus 15.6 months) and median OS (P=0.001; not reached yet 28.0 months) than patients with β2-microglobulin levels of >3 mg/l at diagnosis.

β2-Microglobulin at transplant was analysed, and showed a statistically significant EFS (P<0.02) for patients with a low β2-microglobulin (<3 mg/l) versus levels above that. Again patients with significant renal impairment were excluded here.

The International Prognostic Index (IPI) at transplant was assessed. An IPI of stage I was statistically significant for EFS (P<0.03) versus stage II or III. There was no significant difference seen with regard to OS. The IPI at diagnosis was not assessed, as serum albumin was not available for the majority of our patient cohort.

Age did not influence OS or EFS. The median OS for patients 60 and >60 years was 50.9 and 48.3 months, respectively (P=0.81). We looked at plasma cell infiltration on trephine bone biopsy at diagnosis and pre-transplant. A plasma cell infiltrate of <50% at diagnosis versus >50% showed statistical significance for improved EFS (P=0.002) and OS (P=0.006). The median survival with <50% plasma cells was 21.1 months versus 16.1 months for >50%. The median OS for those with a plasma cell infiltrate <50% is undefined, that is, has not yet been reached versus 46.0 months for the group of patients with >50% plasma cells in trephine biopsy at diagnosis (Figure 4).

Figure 4
figure4

Overall survivals and event-free survivals according to percentage of bone marrow plasma cells at diagnosis.

Plasma cell infiltration pre-transplant was also significant for EFS (P=0.008). The median EFS for those with plasma cells <50% was 21.6 months versus 11 months for patients with plasma cells >50%. Overall survival also reached statistical significance (P=0.05), the median OS for patients with plasma cells <50% pre-transplant is 60.7 months versus 33.6 months for >50% plasma cells in trephine biopsy.

The number and type of previous regimens, the time from diagnosis to transplant (9 versus >9 months) or the addition of TBI to melphalan in the conditioning regimen did not affect either OS or EFS.

Twenty-six out of 211 patients (12%) were transplanted >2 years from diagnosis; there was no difference in EFS or OS between those transplanted early or late.

Table 3 summarises the results from the univariate analysis in which β2-microglobulin levels at diagnosis, plasma cell infiltration at diagnosis and pre-transplant and status post transplant emerged as significant for both OS and EFS, whereas status β2-microglobulin and IPI at transplant predicted for EFS. We also looked at multivariate analysis on the above variables, for 72/211 (34%) of our cohort. Results, in particular for β2-microglobulin, were unavailable for the rest of the group, and it was found that status pre-transplant was significant for EFS and β2-microglobulin at diagnosis was statistically significant for OS. As the analysis was restricted, the other factors significant by univariate analysis did not emerge.

Table 3 Univariate analysis of the significant variables

Discussion

We present the results of a retrospective analysis of patients with MM who were autografted in our centre between 1994 and 2004. All patients received PBSC after high-dose therapy. The TRM in this study was very low (1.4%) and may be explained by the use of PBSC support rather than bone marrow stem cells after high-dose chemotherapy, and also treatment with melphalan (200 mg/m2) alone as the conditioning regimen rather than melphalan with TBI. The lower TRM in patients receiving melphalan alone at a dose of 200 mg/m2 compared with the combination of melphalan and TBI has also been described in a randomised trial where the TRM in the combination arm was 3.6 versus 0% in the melphalan arm.10

The median OS and EFS after transplant was 50.9 and 21.1 months, respectively; this finding is comparable with the registry data of the European Group for Blood and Marrow Transplantation and the data of other reported studies.11, 12 Although the median OS from diagnosis is almost 5 years, patients continued to progress and die several years after ASCT with OS and EFS curves failing to show a stable plateau. Even with a second planned ASCT, there are very few long-term survivors, suggesting that ASCT does not eradicate the disease.13

In a number of large trials, the status of the disease before the autograft was a prognostic factor for OS and EFS.11, 12 Refractory patients have had a better outcome after transplantation than after conventional chemotherapy.14 Vesole et al.15 have reported a median OS of 19 months in 72 refractory patients of which 22% achieved CR or PR. In our series, there was a significant trend towards improved OS in patients who had achieved a CR with the previous therapy and patients in CR pre-ASCT had longer EFS than the others. We have also shown that patients who have progressive or refractory disease or MR pre-transplant can benefit from high-dose therapy with 62% of them achieving a PR, and so poor response to induction therapy does not automatically predict poor long-term outcome. This was also shown by Alexanian et al.6 and Singhal et al.16

The status post transplant was strongly associated with both EFS and OS in this study. Patients who achieved a CR had a longer EFS and OS than other patients. Although Rajkumar et al.17 showed that achieving a CR after ASCT does not result in prolonged EFS and OS, our data confirm the results of other studies showing that achieving a CR post autologous transplant has an important influence on both EFS and OS and that this subset of patients may derive the greatest benefit from the procedure.4, 18 This finding is in accordance with the observation that post-transplantation tumour load in the bone marrow predicts for survival.19 Therefore, there have been attempts to identify pre-transplant predictors of CR. Twenty-two patients in PR pre-transplant subsequently converted to CR; all these patients had normal β2-microglobulin at diagnosis where the result was available. Eighteen out of 22 patients (82%) had a β2-microglobulin <2.5 mg/l at transplant, and also 15/22 patients were stage I IPI at transplant. Nadal et al.20 recently showed that the pre-transplant levels of paraprotein and the plasma cell infiltration of the bone marrow were strongly associated with the achievement of CR post-ASCT.

Our data show clearly that a lower infiltrate of plasma cells at diagnosis and at transplant predicts for both improved EFS and OS and could be associated with the development of CR post transplant. To increase the CR rates, more intensive conditioning regimens have been used, including TBI, busulphan and cyclophosphamide. The CR rate with this conditioning regimen is near 45% and exceeded considerably the 13% of CR in our study, having tolerable toxicity and long EFS and OS.21

The majority of our patients received melphalan 200 mg/m2 as a conditioning regimen. Only 28 patients had received the combination of melphalan plus TBI. The median duration of EFS and OS was not significantly different between the two conditioning strategies (EFS: 23.6 and 21.1 months, respectively; OS: 53.2 and 39.6 months, respectively).

The role of induction therapy on outcomes of ASCT in MM has not been systematically studied. In our study, we found no differences in survival between patients who received VAD as initial chemotherapy compared with patients who received another regimen. A low number of previous chemotherapy regimens before ASCT has been associated with longer survival in a number of studies.11, 12, 14 In our series, there was no difference in OS and EFS between patients with one and those with two or more previous chemotherapy regimens.

Advanced age has been shown to be a poor prognostic factor in several trials using conventional chemotherapy or ASCT. An Italian study of 290 patients showed that age emerged as an important prognostic factor at a cutoff value of 55 years,12 and a Czech study showed in the multivariate analysis that age at a cut-off value of 60 years predicts independently for survival.22 However, other studies using a cutoff value of 65 years or even 70 years have suggested that age is not an exclusion criterion for ASCT.22, 23 We evaluated OS and EFS using 65 years as a cutoff point and found no difference in survival between the resultant groups. Reece et al.24 also found that EFS and OS are similar for myeloma patients aged below or above 60 years who underwent an ASCT. These results show that age may not be a barrier for ASCT in MM patients and that patients over the age of 65 years can benefit from the procedure.

The optimal timing of high-dose therapy and ASCT remains uncertain. In patients treated with planned tandem autografts, studies have shown that the timing of ASCT had a strong correlation with prolonged EFS and patients who were autografted within a year from initial chemotherapy had a longer EFS.25 In this study, we compared patients who were treated with late ASCT (over 9 months from diagnosis) with patients who were autografted within 9 months from diagnosis. There was no difference in OS and EFS, confirming the data of Fermand et al.26 In our series, only 12% of patients were transplanted after 2 years from diagnosis; there was no difference in EFS or OS between those transplanted early or late.

There was a significant difference in OS between patients who received a higher dose of stem cells (>3.5 × 106 CD34/kg) and those who received a lower dose of cells (Table 2). We found no relationship between the characteristics of patients at diagnosis and the number of stem cells collected. As OS is prolonged but not EFS, and the OS curve diverges late, there is no evidence that it is explained by early TRM. Also if the increased stem cell dose improved OS by preventing relapse possibly owing to better immune reconstitution, EFS should also show benefit. We postulate then that the improved OS is due to better tolerance to further treatment after relapse.

Our study confirmed the predictive value of β2-microglobulin for EFS and OS even when patients with renal impairment were excluded. In our cohort, low β2-microglobulin at transplant showed improved EFS. Stage I IPI at transplant was significant for improved EFS and this group may predict those patients at transplant who will have a superior outcome. We were unable to comment on the IPI score at diagnosis, as serum albumin was not available for the majority of our patients.

We conclude from this large single-centre study that high-dose therapy with ASCT is an effective and safe treatment in patients with MM, and that the outcome is independent of age, gender, interval from diagnosis to ASCT, the number and type of previous regimens and conditioning regimen. Response to ASCT, β2-microglobulin level and plasma cell infiltration at diagnosis and transplant predict for both EFS and OS, whereas CR status, β2-microglobulin level and IPI stage pre-transplant predict for EFS. Finally, the number of re-infused CD34+ cells was highly significant with regard to OS.

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Acknowledgements

We thank the staff of the Bone Marrow Transplant wards of the Hammersmith Hospital and the referring physicians for their contribution and valuable discussion.

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Correspondence to A Rahemtulla.

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O'Shea, D., Giles, C., Terpos, E. et al. Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: a single-centre experience in 211 patients. Bone Marrow Transplant 37, 731–737 (2006). https://doi.org/10.1038/sj.bmt.1705307

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Keywords

  • multiple myeloma
  • autologous transplantation
  • survival
  • age
  • melphalan

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