Autologous transplantation Autologous stem cell ... - Nature

Bone Marrow Transplantation (2003) 31, 163–170 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

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Autologous transplantation Autologous stem cell transplantation in multiple myeloma: improved survival in nonsecretory multiple myeloma but lack of influence of age, status at transplant, previous treatment and conditioning regimen. A single-centre experience in 127 patients E Terpos, JF Apperley, D Samson, C Giles, C Crawley, E Kanfer, E Olavarria, JM Goldman and A Rahemtulla Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK

Summary: High-dose therapy with autologous stem cell transplantation (ASCT) has become the treatment of choice for symptomatic eligible patients with multiple myeloma (MM). We report our centre experience and analyse retrospectively the prognostic influence of pretransplant characteristics and transplant modalities on response and survival. A total of 127 MM patients (median age: 55.2 years) were transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients were in complete remission (CR), 73% in partial remission (PR), 12% showed minor response to previous treatment and 9% had stable or refractory disease. Prior to autograft, 79% of cases had received only one line of chemotherapy and 21% two or more lines. All patients received PBSC support after conditioning with 200 mg/m2 melphalan alone (100 patients) or melphalan and TBI (27 patients). We evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65 years), type of MM, status pre- and post-ASCT, number of lines of previous regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+ cells, plasma cell infiltration and b2-microglobulin at diagnosis on overall (OS) and progression-free survivals (PFS) to define patients with better prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only two patients progressed. Median OS and PFS from transplantation were 50.4 and 23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant-related mortality was 2.3%. Low levels of b2microglobulin and the achievement of CR post-transplant correlated with longer PFS (Po0.03 and o0.01, respectively). The median PFS was 36.1, 23.9, 21.1 and

Correspondence: Dr A Rahemtulla, Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, W12 0NN London, UK Received 03 May 2002; accepted 05 September 2002

16.4 months for nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an important prognostic factor at a cutoff value of 55 or 60 years. We conclude that ASCT is a safe and effective procedure even in resistant cases. The outcome was independent of age, time from diagnosis, previous treatment and conditioning regimen, but there was a tendency for better survival in the nonsecretory patients. Bone Marrow Transplantation (2003) 31, 163–170. doi:10.1038/sj.bmt.1703818 Keywords: multiple myeloma; autologous transplantation; nonsecretory multiple myeloma; age; melphalan; total body irradiation

Multiple myeloma (MM) is a malignancy of the elderly with a median age at presentation of 65 years.1 The outcome for MM patients after chemotherapy has not changed dramatically since the introduction of melphalan and prednisone, although a large number of different chemotherapy combinations have been used.2–4 Advanced age is a poor prognostic factor in several trials using conventional chemotherapy5–7 even if the biological and clinical features in elderly MM patients are identical to those of younger patients.8,9 In the absence of any significant improvement after various conventional chemotherapies, 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 progression-free (PFS) and overall survivals (OS).10–13 Although the benefit from ASCT is mainly seen in a subgroup of patients with favourable initial characteristics, it is also of value in patients with resistant disease.14 This procedure is safe even in patients over the age of 65,15,16 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,17 and also because of improvement in general supportive measures. However, several issues have to be clarified such as defining the patient subsets who will benefit most from this procedure, the best timing of ASCT

ASCT in multiple myeloma E Terpos et al

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in the course of disease, the optimal conditioning regimen and finally the management of patients with unfavourable characteristics. In order to assess the clinical results of ASCT, we present the data from 127 patients with MM who have been autografted in our centre since 1994. We have evaluated the prognostic influence of pretransplant characteristics and transplant modalities on disease response and survival.

Patients and methods Patients Between July 1994 and July 2001, 127 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 the ASCT protocol that included age up to 70 years, acceptable cardiac (ejection fraction 440%), pulmonary (diffusion capacity for carbon monoxide 450% of normal) and hepatic (bilirubin and transaminases o2 upper limit) functions. Poor performance status because of MM was

not an exclusion criterion. All patients were informed about the benefits and risks associated with stem cell collection and ASCT. In all, 49 patients were transplanted between 1994 and 1997 and 78 patients were autografted between 1998 and 2001. Prior to autograft, patients had received zero (only one patient) to five lines of treatment, while 78% of the cases had received only one regimen of chemotherapy. Most patients were treated with VAD (82 patients, 65%) or VAD-like regimen (ZDex (idarubicin and dexamethasone), C-VAMP (cycloposphamide, vincristine, doxorubicin and methylprednisolone)) (35 patients, 28%), while nine patients (7%) had received ABCM (adriamycin, BCNU, cyclophosphamide and melphalan) as first-line treatment. At the time of transplant, only 6% of patients were in CR. The vast majority had achieved a partial remission (PR) with previous chemotherapy regimens, while 12 of them (16%) had stable but refractory disease. The median time interval between diagnosis and transplant was 9.6 months (range: 3.3–80 months). Of the patients, 18 (14%) had a second transplant; five of these had a planned second ASCT and 13 were autografted after progression of their disease. These patients were censored for PFS analyses from the day of the second transplant.

Treatment Table 1

Patient characteristics No

Patients Age (median, range) >55 >60 >65

127 55 (27–70) 65 32 13

Percent 100 51.1 25.1 10.2

Gender Male Female

79 48

62.2 37.7

Type IgG IgA IgD BJ Nonsecretory

69 28 1 23 6

54.3 22.0 0.7 18.1 4.7

Lines of previous therapy o2 X2

100 27

78.7 21.2

Status at transplantation CR PR MR NR Refractory Progressive Prior untreated

7 93 15 6 4 1 1

5.5 73.2 11.8 4.7 3.1 0.7 0.7

100 27

78.7 21.2

22 59 71

17.3 46.4 55.9

Conditioning Melphalan alone Melphalan+TBI Time of ASCT from diagnosis p6 Months p9 Months p12 Months

Bone Marrow Transplantation

The conditioning regimen consisted of melphalan alone in 100 patients with the addition of total body irradiation (TBI) in the remaining 27 patients. Melphalan, as a single agent, was given i.v. at a dose of 200 mg/m2, over 30 min, on day 2, with the appropriate hydration. The dose of melphalan was decreased to 50% in patients with reduced creatinine clearance (30–50 ml/min). If the combination of melphalan plus TBI was used, 140 mg/m2 melphalan was infused over 30 min on day 4. TBI, at a dose of 200 cGy b.i.d., was given from day 3 until day 1 (total dose of 1200 cGy). Eight patients who received melphalan and TBI were given G-CSF from day 1 (EBMT Cellpro randomised study), and 12 out of 19 remaining patients, who had entered in the Cellpro pilot study,18 were given G-CSF from day 14 post-transplant, at a dose of 5 mg/kg/day, until neutrophil recovery. Blood cell count, electrolytes, renal and liver functions were monitored daily. Ciprofloxacin and fluconazole were administered prophylactically until neutrophil engraftment (40.5 109/l), while acyclovir was given for 35 days. Cotrimoxazole and penicillin were added after neutrophil engraftment for Pneumocystis carinii and bacterial prophylaxis. Pneumocystis prophylaxis was continued until 6 months post-transplant. Patients who developed neutropenic fever greater than 381C received intravenous broad-spectrum antibiotic treatment according to protocol. Intravenous immunoglobulin was given to all patients, at a dose of 400 mg/kg, on days 1, +2, +14 and +28. PBSC were collected during 1–3 consecutive leukaphereses, following high-dose cyclophosphamide 2 g/m2, i.v., for 2 days (day 1 and day 2) (total dose: 4 g/m2) with subsequent G-CSF at 5 mg/kg/day from day 5 to the last day of leukapheresis. Apheresis was initiated upon recovery of CD34+ cells to 4107/l. For patients who failed to


The EBMT criteria were used for assessing disease response.19 CR was defined as the absence of a detectable monoclonal component in serum or in urine by immunofixation analysis, associated with o5% 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 o0.2 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 had no response (NR). Progressive disease was defined as an increase in serum or urinary monoclonal protein by 25% or a 25% increase in bone marrow infiltration in nonsecretory 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 March 2002. Differences in the distribution of variables between patient subsets were analysed using the w2 test. The Kaplan–Meier method was used to estimate PFS 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. PFS and OS were defined as the time from ASCT to progression or death. However, OS from the time of diagnosis was also evaluated. OS analysis considered death from any cause as an event. CR and PFS duration were censored at the time of last contact if patients did not experience progression or relapse before that time. OS was censored at last contact.

The median follow-up was 24 months (range: 6–83). Overall response rate (CR+PR) was 96%. Of the seven patients autografted in CR, five remained in CR, one progressed and one died because of septicaemia. Of the patients who were in PR at the time of the autograft, 14 (15%) achieved a CR after transplant, while 78 (84%) remained in PR. All six patients who had not responded to previous chemotherapy regimens, 14 out of the 15 patients with MR and three out of the five patients with refractory or progressive disease at the time of transplantation achieved a PR post-ASCT. The median OS was 50.4 months and the median PFS was 23.5 months, while the median survival from diagnosis was 79.7 months (Figure 1). Patients who achieved a CR post-ASCT had a longer PFS than patients who achieved a PR (median PFS: 31 vs 16.3 months, Po0.01), but there

100 90 80 70 60 50 40 30 20 10 0

100 90 80 70 60 50 40 30 20 10 0

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). A total of 80 patients received 44 106 CD34+ cells/kg, while 47 patients received a lower dose of CD34+ cells/kg. No relationship was found between the main characteristics of the patients at diagnosis and the number of PBSC collected. The median time to platelet recovery (450 109/l) was 17 days (range: 12–never achieved), while the neutrophil engraftment (40.5 109/l) was achieved at a median time of 16

165

Clinical response, OS, PFS

% survival probability

Response criteria

days (range: 10–35). Neither the number of infused cells nor the number of previous chemotherapy regimens was predictive of the time to neutrophil and platelet engraftment; however, 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 2.3% (3/127 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), while neutropenic fever was present in almost all patients, and severe mucositis was observed in one-third of the patients.


mobilise with cyclophosphamide, etoposide was given at a dose of 1.6 g/m2 on day 1 with subsequent G-CSF at 5 mg/ kg/day from day 3 to the last day of apheresis. Each sample was investigated by flow cytometric analysis for the presence of cells expressing CD34 and a minimum of 2 106 CD34+ cells/kg were collected.

PFS and OS

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Figure 1 OS and PFS for 127 autografted patients; the median OS from diagnosis was 79.7 months. Bone Marrow Transplantation


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We present here the results of a retrospective analysis of a cohort of patients with MM who were autografted in our



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OS and PFS by age at ASCT.


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median survival < 65 = 50 months, > 65 = 38 months Figure 2

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progressive disease) or between patients with CR/PR and patients with no response to treatment (NR, refractory or progressive disease). The number of previous regimens, time from diagnosis to transplant (p6 vs 46 months, p9 vs 49 months, and p12 vs 412 months), the dose of CD34+ cells that was reinfused (p4 vs 44 106/l, and p3 vs 43 106/l) or the addition of TBI to melphalan in the conditioning regimen did not affect either OS or PFS. However, the level of b2-microglobulin at diagnosis had a significant effect on PFS. Despite the small number of patients with available data (39 patients), PFS was longer in patients with b2-microglobulin levels of below 3 mg/l (Po0.03) although there was no difference in OS (Po0.1) (Figure 5). Table 2 summarises the results from a univariate analysis in which only b2-microglobulin levels at diagnosis and status post-transplant emerged as significant for PFS.


was no difference in OS (the probability of 3 years survival was 77% in patients in CR and 69% in partial responders, P ¼ 0.6). Age was found to influence neither OS nor PFS. We compared three age- groups (p55 vs 455, p60 vs 460 and p65 vs 465 years), but found no significant differences in OS and PFS (Figure 2). The median OS for patients p55 and 455 years was 53.2 and 39.6 months, respectively (P ¼ 0.29); for patients p60 and 460 years it was 50.4 and 37.6, respectively (P ¼ 0.57); and for patients p65 and 465 years it was 50 and 38 months, respectively (P ¼ 0.52). Patients with non secretory MM tended to have better OS and PFS (P ¼ 0.1), having a median PFS of 36.1 months, while patients with IgG, IgA and BJ subtypes had a median PFS of 23.9, 21.1 and 16.4 months, respectively (Figure 3). The status of disease prior to autograft did not significantly affect either OS or PFS. There was no significant difference in those patients with chemoresistant disease and those in PR or CR. Median PFS and OS for patients with CR+PR prior to autograft was 24 and 50.2 months, respectively, while in patients with MR+NR+refractory disease was 18.4 and 58.9 months, respectively (Figure 4). There was also no difference between patients with MR and true nonresponders (NR, refractory or


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non-secretory light chain IgA

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167 PFS By diagnosis

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light chain

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Figure 4 PFS and OS by status at transplantation.

PFS and OS by β2-microglobulin levels _ vs. >3 mg/l) at diagnosis (55 years) (p60 vs >60 years) (p65 vs >65 years) Ig type (IgG vs others) (nonsecretory vs others) Lines of previous treatment (o2 vs X2) Status at transplant (CR+PR vs others) (CR+PR vs NR+refr./progr. disease) (MR vs NR+refr./progr. disease) Status post-transplant (CR vs PR) Time from diagnosis to autograft (p6 vs >6 months) (p9 vs >9 months) (p12 vs >12 months) TBI (no vs yes) b2-microglobulin at diagnosis (p3 vs >3 mg/l) Cell reinfusion dose (p3 vs >3 106 CD34+/kg) (p4 vs >4 106 CD34+/kg) Plasma cell infiltration at diagnosis (p30% vs >30%)

OS

PFS

0.38 0.29 0.57 0.52 0.23 0.10 0.39 0.98 0.46 0.91 0.65

0.71 0.18 0.66 0.54 0.35 0.10 0.53 0.41 0.28 0.71 0.009

0.87 0.34 0.27 0.39 0.10 0.70 0.34 0.58

0.67 0.65 0.61 0.55 0.03 0.90 0.24 0.27

centre between 1994 and 2001. All patients received PBSC after high-dose therapy. The overall response rate after autograft was 96%, similar to that reported from other large trials. The TRM in this study was lower compared to that described in other trials in which TRM ranged from 3 to 20%.20–23 This low TRM 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 Bone Marrow Transplantation


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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 recent randomised trial where the TRM in the combination arm was 3.6 vs 0% in the melphalan arm.24 The median OS and PFS after transplant was 50.4 and 23.5 months, respectively; this finding is comparable to the registry data of the European Group for Blood and Marrow Transplantation and the data of other reported studies.10,25–27 Although the median OS from diagnosis is over 6.5 years, patients continued to progress and die several years after ASCT with OS and PFS curves failing to show a stable plateau. Even with a second ASCT there are very few long-term survivors, suggesting that ASCT does not eradicate the disease.28 In a number of large trials, disease status disease prior to the autograft was a prognostic factor for OS and PFS.26,27,29 Refractory patients have had a better outcome after transplantation than after chemotherapy,21 although patients with prolonged (41 year) primary resistant disease gained only minimal advantage from high-dose therapy with ASC support.30,31 Vesole et al have reported a median OS of 19 months in 72 refractory patients who were transplanted between 1991 and 1996, of whom 22% achieved CR or PR.32 In our series, there was no significant advantage in OS and PFS in patients who had achieved a CR or a PR with the previous therapy compared to patients with MR, NR or refractory disease, not even compared with NR or refractory patients. This result, although the number of patients with refractory disease is low, suggests that patients with chemoresistant disease can benefit from ASCT as much as those with chemosensitive disease. The status post-transplant was strongly associated with PFS. Patients who achieved CR had a longer PFS than patients in PR after ASCT. There has been some evidence that achieving CR after ASCT does not result in prolonged PFS,33 particularly in patients relapsing after, or who are refractory to standard chemotherapy.34 However, our data confirm the results of several other studies showing that achieving CR has an important influence on PFS and that this subset of patients may derive the greatest benefit from the procedure.10,35 Advanced age has been shown to be a poor prognostic factor in several trials using conventional chemotherapy5–7 or ASCT.26,27 An Italian study of 290 patients showed that age emerged as an important prognostic factor at a cutoff value of 55 years,26 while other studies using a cutoff value of 65 years or even 70 years have suggested that age is not an exclusion criterion for ASCT programmes.15,36 We evaluated OS and PFS using different cutoff values (55, 60 and 65 years) and found no difference in survival between the resultant groups. Although the number of patients 465 years was small, these results suggest that age may not be a barrier for ASCT in MM patients and that selected patients over the age of 70 years can benefit from the procedure. 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 PFS and OS was not significantly different between the two conditioning strategies (PFS: 23.6 and 21.1


months, respectively; OS: 53.2 and 39.6 months, respectively). Some studies have shown that melphalan alone as a conditioning agent is less toxic, with respect to mucositis and duration of neutropenia and thrombocytopenia, number of red blood cell transfusions and duration of hospitalisation, compared to the combination of melphalan with TBI.11,24,37 There is also some evidence that patients treated with melphalan 200 mg/m2 conditioning may have a longer OS.24 On the other hand, there are data showing no difference in engraftment and toxicities using different conditioning regimens with TBI.38 In our study, although melphalan alone was as effective as melphalan and TBI, patients treated with melphalan and TBI had a shorter duration of neutropenia because of the use of G-CSF in the immediate post-transplant period in a subset of these patients. In this study, there was a tendency towards a better outcome in patients with nonsecretory MM after ASCT. Nonsecretory MM, which accounts for 1–5% of all myelomas, has the same presenting features as those in patients with other MM types, and also has similar response rates to conventional chemotherapy.39 However, there are some data describing better outcome in this type of MM.40 The earlier presentation owing to the formation of symptomatic local lesions or the greater sensitivity to high-dose therapy owing to the stage of maturation of plasma cells may be responsible for a possible better outcome in these patients. However, because of the low number of patients with nonsecretory MM in our series, a larger study would be required to confirm these data. We found no differences in OS and PFS among patients with other types of MM. Recently, Sirohi et al reported that patients with BJ type of MM have a significantly shorter OS (median: 2.8 years) than IgG and IgA patients.41 In this study, the median OS in the different types of MM was 32.2, 50.2 and 35.5 months, and the PFS was 16.4, 23.9 and 21.1 months, for BJ, IgG and IgA MM, respectively, suggesting that these MM subtypes may not influence outcome post-ASCT. The optimal timing of high-dose therapy and ASCT remains uncertain. A large randomised trial has shown that there is no difference in OS among patients who were treated with early or late ASCT, although early ASCT was associated with a shorter period of chemotherapy leading to a better quality of life.42 In patients treated with planned tandem autografts, the timing of ASCT had a strong correlation with prolonged PFS. Patients who were autografted within a year from initial chemotherapy had a longer PFS.33 In this study, we compared patients who were treated with late ASCT (over 12 months from diagnosis) with patients who were autografted within 12 months from diagnosis. There was no difference in OS and PFS, confirming the data of Fermand et al 42. A low number of previous chemotherapy courses prior to ASCT has also been associated with longer survival in a number of studies.26,27,29 In our series there was no difference in OS and PFS between patients with one compared with two or more previous chemotherapy courses (OS: 45.5 and 53.2 months, and PFS: 24.7 and 21.1 months, respectively).


We conclude from this 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, disease status prior to ASCT, interval from diagnosis to ASCT and number of previous regimens, while patients with a low b2-microglobulin level at diagnosis have a better outcome after transplantation. The beneficial influence of the nonsecretory subtype on outcome remains to be confirmed in a larger series of patients.

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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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