Long-term results (12 years) of high-dose therapy in 127 patients with de novo multiple myeloma

Abstract

This report describes the long-term outcome of a cohort of 127 de novo multiple myeloma patients treated with at least one course of high-dose therapy (HDT) in a single institution between June 1985 and December 1995, for whom the minimum follow-up duration for survivors is 6 years. The 12-year overall survival (OS) and event-free survival (EFS) rates are 24.9% and 3.1%, respectively, and the median survival and EFS are 49 and 17 months, respectively. Only four patients are alive and disease-free 79, 90, 132 and 153 after the first HDT, respectively. Three of them received a subsequent allogeneic bone marrow transplantation. Three factors significantly influence OS in this series: B2M at diagnosis, age, and the completion of a second HDT. The 10-year survival is 18.9% for the group of patients with B2M level >3 mg/l at diagnosis as compared with 41% for patients with B2M 3, with a median survival of 31 months vs 73 (P = 0.01). The 10-year survival is 23.4% for the group of patients aged >55 years as compared with 36.5% for patients aged <55 years, with a median survival of 34.5 months vs 70.5 (P = 0.04). The 10-year survival is 20.4% for the group of patients who did not receive a second HDT as compared with 35.2% for patients who completed a second HDT, with a median survival of 29 months vs 70 (P = 0.02). In this study we show that some patients treated with HDT experience durable remission and prolonged survival. This survival is significantly influenced by age (55 years), B2M at diagnosis (3 mg/l) and by the completion of two cycles of HDT.

Introduction

High-dose therapy (HDT) has been used in patients with multiple myeloma (MM) since 1983.1 During the last decade, it has been shown that the outcome of autografted patients for newly diagnosed MM was superior to those receiving conventional chemotherapy.2,3,4 Although HDT is of benefit, it is not considered curative. The effect of this strategy on survival can only be assessed in studies with long-term follow-up, but those data are rather limited. To our knowledge, less than five groups have reported survival data analysis 10 years or more after HDT in de novo MM patients.5,6,7,8,9 In the current report, we describe the long-term outcome of a cohort of 127 de novo MM patients treated with HDT in a single institution between June 1985 and December 1995, for whom the minimum follow-up duration for survivors is 6 years. We have specifically analyzed those factors that might predict for long-term survival.

Patients and methods

Patients

From June 1985 to December 1995, 127 patients with de novo MM received at least one course of HDT in our institution. Patient characteristics at diagnosis are listed in Table 1. Before December 1995, cytogenetic analysis was not performed on bone marrow samples.

Table 1 Patient characteristics at diagnosis

Before HDT, all patients were given debulking therapy which consisted of cycles of VAD,10 MP11 or alternating VMCP/VBAP11 (Table 2). Thirty-four of 127 patients (26.8%) received two lines of conventional chemotherapy before HDT (Table 2). Disease status at the time of the first HDT is summarized in Table 2.

Table 2 Induction chemotherapy and disease status at the time of the first HDT

The first HDT consisted of high-dose melphalan (HDM) alone in 76% of the cases (96 patients) or 140 mg/m2 melphalan (HDM140) plus total body irradiation (TBI) in 24% of the cases (31 patients, Table 3). Stem cell support was infused in 48% of the cases (61 patients), either bone marrow (23 patients) or peripheral blood stem cells (38 patients), while 52% of the cases (66 patients) did not receive stem cells after HDM140 (31 did not receive any growth factors, and 35 received either G- or GM-CSF12 after HDM) (Table 3).

Table 3 Conditioning regimens and hematopoietic support for the first HDT

Eighty patients (63%) received a second HDT either for consolidation in 30 responding cases (six patients less than 50 years received an allogeneic geno-identical bone marrow transplantation and 24 patients received an autologous stem cell transplantation ASCT) or for relapse or refractory disease in 50 cases treated with ASCT (Table 4).

Table 4 Disease status and stem cell support at the time of the second HDT

Sixteen patients received a third course of HDT supported by ASCT for a subsequent relapse (Table 5).

Table 5 Third HDT

Supportive therapy

It has been described previously.13

Criteria for a response

They have been defined previously.2

Survival and statistical analysis

The data were analyzed as of 1 September 2001. Actuarial overall and event-free survival curves were estimated using the method of Kaplan and Meier,14 and were compared by the log-rank test.15 Overall survival (OS) was calculated from the time of the first HDT until the occurrence of death from any cause or last follow-up if alive. Event-free survival (EFS) was calculated from the day of the first HDT until the time of progression, relapse or death. For the purpose of EFS, patients who had active disease at the time of the first HDT which never responded were plotted as failures from the time of HDT.

The following parameters were examined for their prognostic value on EFS and OS: age, Durie–Salmon stage, isotype of the M-component, bone marrow plasmocytosis at diagnosis, beta2-microglobulin (B2M), albumin, hemoglobin and C-reactive protein levels at diagnosis, disease status at the time and after the first HDT, completion of a second HDT, disease status at the time and after the second HDT, conditioning regimens for the first and second HDT. All the parameters reaching significance (ie a P value <0.05, or close) in the univariate analysis were then included in a multivariate analysis using the Cox model.

Results

Toxicity and outcome after the first HDT

Four toxic deaths were observed (3.1%). The CR rate was 22.8%, PR rate was 63.8%, and 10.2% of the patients did not respond to HDT (Table 6). The toxicity of the first HDT is depicted in Table 6.

Table 6 Clinical outcome after the first HDT

Toxicity and outcome after the second HDT

The median time between the first and the second HDT was 4 months (2 to 11) for the group of 30 patients who received the second HDT as consolidation while it was 22 months (5 to 104) for the group of 50 patients who received the second HDT at the time of relapse or for a refractory disease. The toxicity and the disease response after the second HDT are summarized in Table 7.

Table 7 Clinical outcome after the second HDT

Survival analysis

At the reference date of 1 September 2001, the 12-year OS and EFS rates were 24.9% (±6.1) and 3.1% (±1.6), respectively, and the median survival and EFS were 49 and 17 months, respectively (Figures 1 and 2). Only four patients are alive and disease-free 79, 90, 132 and 153 months after the first HDT, respectively. Three of them received an allo-BMT. These four patients have no long-term complications of either autologous or allogeneic transplantation, and both their performance status and quality of life are normal.

Figure 1
figure1

OS for the 127 patients.

Figure 2
figure2

EFS of the 127 patients.

In the univariate analysis, age, B2M, the completion of a second HDT and IgA isotype were shown to be significant predictor of OS, but not of EFS. These four factors were included in the multivariate analysis. The IgA isotype was not an independent adverse prognostic factor, and the study identified three parameters as good risk features for OS : age 55 years, B2M 3 mg/l, and the completion of a second HDT (Table 8).

Table 8 Statistical analysis

The 10-year survival is 18.9% (±6.5) for the group of patients with B2M level >3 mg/l at diagnosis as compared with 41% (±7.5) for patients with B2M 3, with a median survival of 31 months vs 73 (P = 0.016, Figure 3). The 10-year survival is 23.4% (±6.3) for the group of patients aged >55 years as compared with 36.5% (±6.8) for patients aged <55 years, with a median survival of 34.5 months vs 70.5 (P = 0.04, Figure 4). The 10-year survival is 20.4% (±7.3) for the group of patients who did not receive a second HDT as compared with 35.2% (±6.3) for patients who completed a second HDT, with a median survival of 29 months vs 70 (P = 0.02, Figure 5). The better survival observed among the 80 patients who received a second HDT is not influenced by the delay between the first and the second HDT. The survival is strictly identical for the 30 patients who received a second early HDT as consolidation as compared with the survival of the 50 patients who received the second HDT later in the course of the disease at the time of relapse. Nevertheless, only the four patients who are alive and disease-free in our series are identified among the 30 responding cases who received an early second HDT as consolidation therapy. Three of them received an allogeneic BMT (out of six alloBMT performed in this subgroup of patients) and one received an ASCT (out of 24 ASCT performed in this subgroup of patients). Thus, the completion of an alloBMT seems to offer a significant chance of cure as compared with ASCT in this setting (P = 0.02, chi square).

Figure 3
figure3

Survival according to B2M level.

Figure 4
figure4

Survival according to age.

Figure 5
figure5

Survival according to the number of HDT.

Patients with all three favorable variables are 32/127 (25.2%) and patients with two and less 95/127 (74.8%). For the first group (very good prognosis), the 10-year OS rate is 48% as compared with 23.4% for patients with two and less favorable variables (P = 0.01). The median survival is 98 months for the very good prognosis group as compared with 36 months for the remaining 95 patients (Figure 6). The median EFS is 27 months for the very good prognosis group as compared with 14 months for the remaining 95 patients (P = 0.07).

Figure 6
figure6

Survival according to prognostic variables.

Discussion

Few data are available in the literature regarding the long-term follow-up of patients treated with HDT for MM. In 1994, Cunningham et al5 presented the results of a series of 63 previously untreated patients with MM who had received HDM140 without autologous stem cell support. The overall response rate was 82%, with 32% patients entering CR. The median duration of response was 18 months and six patients (9.5%) remained alive and free from disease progression at 60 to 84 months. The median survival was 47 months, and 35% of patients were expected to be alive at 9 years. The same group has updated these results in an abstract form.8 Among 327 living myeloma patients included in the data of the Myeloma Unit of the Royal Marsden Hospital and treated with HDT, 14 of these patients (4.3%) had a first CR that lasted 10 years or longer. Barlogie and coworkers6 reported a series of 133 patients with advanced MM (74% resistance, 41% resistant relapse) treated with five HDT regimens including unsupported or hematopoietic growth factor-supported HDM and bone marrow autograft supported HDM ± TBI between 1985 and 1990. The median follow-up of living patients was 9 years. Only four patients (3%) were alive in CR at 10 years. The OS and EFS were both significantly longer for patients less than 50 years of age, with a B2M level at diagnosis 2.5 mg/l, and absence of resistant relapse at the time of HDT. No plateau was observed in this series. Reece and coworkers7 recently showed long-term results of HDT followed by ABMT using marrow purged with either 4-hydroperoxycyclophosphamide or mafosphamide in a series of 29 patients responding to VAD regimen. The HDT consisted of an aggressive three-drug conditioning regimen: busulfan, melphalan and cyclophosphamide. With a median follow-up of 7.5 years, seven patients remained in continuous CR (five) or PR (two). The actuarial OS rate was 28% at 9 years. A registry study from the EBMT group was reported in 1999.9 In this retrospective trial, actuarial OS and PFS at 8 years after ASCT was 25 and 20%, respectively, but the survival curves showed no signs of plateau. In the analysis of newly diagnosed responsive patients, there was a trend for improved OS in the double transplant patients (n = 278) as compared with patients who had received a single autograft (n = 1252). Finally, the group from Little Rock has reported another paper summarizing the results of HDT for 1000 consecutive patients receiving melphalan-based tandem HDT.16 In this series, all patients received HDM200 as the first HDT cycle, and 76% received a second HDT cycle (10% of the second HDT cycles were allotransplants). Although the median follow-up was not mentioned in this report, the survival curves were plotted for 9 years. Plateaus of EFS, OS and CR duration were noted at 5 years (52% continuous CR at 5 years) in a subgroup of 112 patients presenting with four favorable factors, ie low B2M (2.5 mg/l), C-reactive protein 4 mg/l, pre-HDT standard chemotherapy 12 months, and absence of chromosome 13 abnormalities.

Our results are similar to those already reported. We found a low toxic death rate (<4%) after the first and the second cycle of HDT. Of note, we reported a high incidence of invasive pulmonary aspergillosis after the first cycle of HDT especially in the cohort of patients who received HDM140 without stem cell or hematopoietic growth factor support.17 The EFS rate indicates the low probability for cure, but some factors are associated with a prolonged survival. A young age (less than 55 years in our series) and low B2M (3 mg/l in our experience) have been reported previously16 by Barlogie et al. Interestingly, we found that OS was significantly longer in patients receiving two cycles of HDT as compared with one. This finding was mentioned in the EBMT retrospective trial.9 Preliminary results of the IFM94 trial comparing in de novo MM patients one to two cycles of HDT followed by autologous PBSC transplantation seem to confirm the superiority of the double transplant arm.18 In our series, the timing of the second cycle of HDT (upfront as consolidation or delayed at the time of relapse) does not influence OS, but the number of patients in each group was too small to draw definite conclusions regarding this issue.

Only six patients in our series received allotransplants as consolidation after a first cycle of HDT. Three of them are alive and free from disease, and these results seem to be better than those of autografts. Due to the small number of patients, it is not possible to draw definite conclusion regarding our attitude. We try to allograft all patients <50 years with an HLA-identical sibling early in the course of their disease. A case-matched study comparing allogeneic and autologous transplantation in patients treated up to 1994 has shown that although allotransplants had a lower relapse rate the OS was superior for autologous transplants owing to the high transplant-related mortality with allogeneic transplantation.19 Nevertheless, a more recent paper from the same group showed a dramatic improvement in outcome of allotransplants performed between 1994 and 1998.20 The improvement was the result of a significant reduction in transplant-related mortality due to fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, and earlier transplantation and less prior chemotherapy. Since 1995, we have performed 10 additional allotransplants for de novo myeloma patients, and the EFS of our series of 16 patients is now 50% at 10 years (personal communication). Allogeneic transplantation probably remains the only way to obtain a cure in patients with MM.

Throughout our results, it is important to stress that disease progression or relapse post transplantation is no reason to discontinue all further treatment. As clearly shown in this study, the median time from first transplant to relapse is shorter than relapse from death.

In this study we show that some patients treated with HDT experience durable remission and prolonged survival. This survival is significantly influenced by age (55 years), B2M at diagnosis (3 mg/l) and by the completion of two cycles of HDT.

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Moreau, P., Misbahi, R., Milpied, N. et al. Long-term results (12 years) of high-dose therapy in 127 patients with de novo multiple myeloma. Leukemia 16, 1838–1843 (2002). https://doi.org/10.1038/sj.leu.2402613

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Keywords

  • multiple myeloma
  • high-dose therapy
  • long-term outcome

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