Validation of prognostic factors and survival of patients with multiple myeloma in a real-life autologous stem cell transplantation setting: a Swiss single centre experience

DOI: https://doi.org/10.4414/smw.2011.13203

Introduction

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been widely established as consolidation or salvage treatment for patients with multiple myeloma (MM) [1–4]. In general the response after first ASCT is being used to direct the subsequent patient treatment; application of two consecutive ASCTs within 2–6 months (so-called double or tandem ASCT) is usually reserved for patients not achieving at least a very good partial remission (VGPR) after the first ASCT, according to results from two randomised prospective trials [5–6]. The indication and timing of high-dose chemotherapy with subsequent ASCT have been matter of debate recently in light of new active drugs, e.g., proteasome inhibitors and immunomodulatory derivatives (IMIDs), which are increasingly incorporated into various first line treatment regimens before ASCT [7–12]; the question whether high-dose chemotherapy can be safely replaced by a non-high dose consolidation treatment will be answered by a recently activated international trial [13]. Furthermore, the impact and composition of maintenance treatment after ASCT and even allogeneic transplantation concepts are currently under discussion and various prospective trials will further define future treatment strategies for younger MM patients [14–17]. Until these data are available and also implemented in daily practice, retrospective analyses – especially of patients who are treated in transplantation centres outside the clinical trials setting – are helpful in demonstrating the current options for patients desirous of knowing their specific risks and benefits at a given institution. We started our autologous stem cell programme in Zürich in 1988 and have performed more than 1000 transplantations since that time, with MM the most frequent indication for ASCT [18]. In terms of quality control we continuously evaluate our programme’s clinical data. We have therefore analysed the clinical course and outcome of our MM patients receiving ASCT between 2002 and 2007 and identified possible risk factors for survival.

Additionally, we have assessed the morbidity of our treatment regimens with regard to length of hospital stay, need for antibiotics and blood product transfusions.

Patients and methods

Patient data assessment

Records from patients with MM who received at least one ASCT at our transplantation centre were analysed retrospectively on the basis of a prospective database. This analysis was approved by our local ethics committee.

The Zürich transplantation centre comprises two hospitals, Zürich University Hospital and Triemli City Hospital, Zürich. Data regarding myeloma stage according to the international staging system (ISS), response to treatment before and after ASCT, event free survival (EFS) and overall survival (OS) were collected. Also, various parameters such as age, gender, body mass index, time from initial diagnosis to ASCT and number of ASCTs per patient were documented if available. As quality control for our transplantation programme we also collected data on the haematological toxicity of the treatment and the supportive care measures performed during the post-transplant period.

Treatment

Individual eligibility for ASCT was discussed in our multidisciplinary autologous transplantation board and determined in accordance with international recommendations. Patients received either one or two ASCTs. The second ASCT was usually performed sequentially 2–6 months after the first ASCT (so-called double or tandem ASCT), or, in a few patients who had initially received single ASCT, later in their disease course in the event of progression. All patients received primary induction chemotherapy as chosen by the attending oncologists. For stem cell mobilisation, either cyclophosphamide on day –12 or vinorelbine on day –8 was given, followed by collection of the stem cells on day 0. Additionally, patients received filgrastim at a dose of 10 μg/kg body weight per day from day –4 on. Aphereses were performed at our transplantation centre until at least 4 x 10⁶ CD34-positive cells per kilogram body weight were collected. Subsequently stem cells were cryopreserved and thawed immediately before retransfusion.

Conditioning chemotherapy consisted of melphalan at a dose of 200 mg/m², given in two doses at days –3 and –2 or as single dose at day –2 before stem cell transplantation. Patients with reduced performance score, organ dysfunctions, e.g. renal insufficiency or age over 65 years received a reduced dose in the range of 100–140 mg/m² melphalan. Patients received filgrastim from day +5 on or pegfilgrastim once on day +1 after ASCT to shorten time to engraftment.

Response criteria

Assessment of disease response was chiefly based on serological testing because bone marrow biopsy after transplantation was omitted in most of our patients. Thus, our response assessment varied from the International Myeloma Working Group uniform criteria, which are currently proposed as a new standard for response assessment [19].

Complete Remission (CR) was defined as negative immunofixation and disappearance of monoclonal protein in serum and urine. Near Complete Remission (nCR) was defined as disappearance of monoclonal protein in serum and/or urine but persistence of positive immunofixation. Very Good Partial Remission (VGPR) was defined as reduction of monoclonal protein >90% in serum. Partial Remission (PR) was defined as reduction of paraprotein ≥50% in serum. Patients with Minor Response (MR) showed a paraprotein reduction of between 25–49% respectively. Stable Disease (SD) was defined as every response between minor response and progressive disease (PD). The latter was documented in patients who had an increase in monoclonal protein ≥25% or clinical progression after transplantation. Patients with no data available regarding their response were regarded and coded as non-responders (i.e. SD).

Event free survival (EFS) was defined as time from ASCT to the time of first recurrence after achievement of CR or nCR, to the time of progression in non-CR patients, as verified by serological assessment, bone marrow biopsy or imaging, or to the time of death by any cause. Overall survival (OS) was defined as time from ASCT to the time of death by any cause, as documented in the patient charts.

Statistics

Descriptive statistics (median and range, or counts) were calculated for all variables. Event free and overall survival was calculated from the date of ASCT and censored at the date of last follow-up. Survival curves were computed using the method of Kaplan and Meier, and compared using the logrank test [20]. Univariate regression analysis was performed using Cox proportional hazards regression [21]. P-values <0.05 were considered statistically significant. All analyses were performed in the R programming language [22].

Results

Patient demographics

Between January 2002 and December 2007 a total of 182 ASCTs were performed in 120 MM patients. Sixty-three (53%) patients received single ASCT, and 57 (47%) patients tandem ASCTs during this period. Five (8%) of the single-transplanted patients received a second ASCT later in the disease course after disease progression. The median time from diagnosis to the first ASCT was 6.24 months (range 3.55–283.04 months). Patients predominantly received split dose melphalan for conditioning. Only in six cases (3%) was melphalan given as a single dose at day –2 before ASCT. Three patients (2%) underwent haemodialysis at the time of ASCT, in two patients (2%) underlying amyloidosis of the kidneys had been diagnosed. Cytogenetics were not done routinely at our institution during that time period, pathological findings are reported only in five patients (4%) (three patients with del(13q), one patient with del(13q) and t(4;14), one patient with complex aberrations). Patient characteristics are shown in table 1.

Figure 1

Kaplan–Meier analysis of the event free survival and the overall survival of all patients. Median EFS was 23.1 months (95% CI: 19.4–28.4) and median OS was 49.8 months (95% CI: 43.7 – not reached). ASCT, autologous stem cell transplantation.

Figure 2

Impact of the response to ASCT treatment on patients’ outcome. (A) Event free survival, and (B) Overall survival. ASCT, autologous stem cell transplantation; CR, complete remission; nCR, near complete remission; VGPR, very good partial remission; PR, partial remission.

Figure 3

Impact of ISS myeloma stage (A, B), patient age (C, D), and melphalan dose (E, F) on patients’ outcome. (A, C, E) Event free survival, and (B, D, F) Overall survival. ISS, international staging system; Mel, melphalan.

Pre- and post-transplant period

The patients’ peri-transplant outcome is shown in table 2. The conditioning regimens used were standard dosed melphalan (200 mg/m²) (n = 149; 82%), reduced dosed melphalan (100–140 mg/m²) (n = 32; 17%), and a combination of bortezomib, thalidomide, dexamethasone and BEAM (VT-Dexa-BEAM) (n = 1; 1%). Patients subsequently received a minimum of 2 x 10⁶ CD34+ cells per kilogram body weight (median 3.96 x 10⁶ CD34+ cells/ kg; range, 2.01 x 10⁶ – 42.4 x 10⁶). The median duration of grade 4 neutropenia was 6 days (range 3–10 days) and the median time to engraftment was 10 days (range 6–13 days). The median duration of grade 4 thrombocytopenia was 3 days (range 0–15 days). Filgrastim was administered for a median of 7 days (range 1–16). The median length of hospital stay from the day of ASCT was 15 days (range 1–66 days). Patients received a median of 1 (range 0–8) platelet transfusions and a median of 0 (range 0–9) red blood cell transfusions. Fever developed in 108 cases (59%) after ASCT, and antibiotics for therapeutic purposes were given in 147 cases (81%) during the post-transplant period. Bacterial pathogens were isolated in 58 cases (32%). Bacteria isolated were Escherichia coli (n = 20; 11%), coagulase-negative Staphylococcus sp. (n = 14; 8%), non-haemolytic Streptococcus sp. (n = 8; 4%), Clostridium difficile (n = 8; 4%), Pseudomonas aeruginosa (n = 3; 2%), Staphylococcus aureus(n = 2; 1%), Moraxella catarrhalis (n = 2; 1%), and others (n = 12, 6%).

Two patients (1%) died within the first 100 days after ASCT. The first patient died at day +100 after ASCT due to disease progression, the second patient died at day +61 after ASCT due to severe neutropenic enterocolitis and superinfection with cytomegalovirus.

Response and survival

Of the 63 patients who received single ASCT, 57 (90%) had responded (≥PR) to induction chemotherapy. Eighteen (28%) of these patients had either VGPR or nCR, and 6 patients (10%) had already achieved CR status at the time before ASCT. Of the 57 patients who received a true double ASCT, 42 (74%) had at least PR after induction chemotherapy, with 5 (9%) having achieved VGPR or nCR and 2 (4%) having achieved CR before the first ASCT. After high-dose chemotherapy and subsequent ASCT, the 63 single autografted patients had an overall response rate of 82.5%, with 15 patients (24%) having achieved VGPR or nCR and 26 (41%) CR after ASCT. The 57 patients who received double ASCT had an overall response rate of 82.5%. Sixteen patients (28%) had achieved either VGPR or nCR, and 21 (37%) CR after the second ASCT (table 3).

The entire patient population had a median EFS of 23.1 months (95% confidence interval (CI): 19.4–28.4) and the median OS was 49.8 months (95% CI: 43.7 – not reached), respectively (fig. 1). The median EFS in patients who received single ASCT was 21.3 months (95% CI: 16.9–31.5), and 27.2 months (95% CI: 19.9–31.9) in patients who received double ASCT. The corresponding median OS were 46.4 months (95% CI: 35.2 – not reached) and 63.7 months (95% CI: 48.9 – not reached), respectively.

EFS and OS correlated with the response to ASCT. Patients achieving a CR had a significantly prolonged EFS compared to patients with less than PR (HR: 2.38; 95% CI: 1.19–4.75; p = 0.014), and patients achieving a CR also had a significantly prolonged OS compared to patients with PR (HR: 2.5; 95% CI: 1.12–5.61; p = 0.026) or less than PR (HR: 3.77; 95% CI: 1.4–10.19; p = 0.009) (fig. 2a and 2b). The achievement of CR was not significantly better than achieving nCR or VGPR regarding EFS (HR: 1.67; 95% CI: 0.96–2.9; p = 0.07) and OS (HR: 1.72; 95% CI: 0.76–3.89; p = 0.2).

Patients with disease stage I or II according to the International Staging System (ISS) at diagnosis had a better outcome than patients with MM stage III. The median EFS in the former was 28.4 months (95% CI: 22.8–40.2) and 13.7 months (95% CI: 10.1–25.0) in the latter patients (HR: 1.57; 95% CI: 1.2–2.04; p = 0.0006). The corresponding median OS was 61.1 months (95% CI: 49.8 – not reached) for patients with ISS I or II and 33.1 months (95% CI: 27.6–46.4) for patients with ISS III (HR: 2.31; 95% CI: 1.6–3.35; p <0.0001) respectively (fig. 3a and 3b).

Age was not associated with EFS (HR: 0.86; 95% CI: 0.48−1.55; p = 0.62) or OS (HR: 0.65; 95% CI: 0.23−1.83; p = 0.41) (fig. 3c and 3d).

Patients who received standard dose melphalan showed a trend towards improved EFS (HR: 1.63; 95% CI: 0.96−2.75; p = 0.07) and OS (HR: 1.99; 95% CI: 0.94−4.22; p = 0.07) compared to patients who received reduced dose melphalan (fig. 3e and 3f).

Risk factor analysis

By univariate analysis, achievement of a CR before ASCT correlated with better EFS compared with any other response (p = 0.016), without impacting on OS (p = 0.21). Also, CR after ASCT was associated with improved EFS (p = 0.006) and OS (p = 0.0024) compared with any other response. In the subgroup analysis, the achievement of CR after ASCT was associated with better OS especially compared to PR (p = 0.026) and responses less than PR (p = 0.009).

Other parameters significantly associated with a better EFS were paraprotein levels of less than 5 g/dL at diagnosis (p = 0.007), a time of 6–12 months from diagnosis to ASCT compared with earlier transplantation (p = 0.042), and MM stage of less than III according to ISS (p = 0.0006). The latter parameter was also significantly linked with better OS (p <0.0001) (table 4).

Discussion

In the present analysis we observed that ASCTs performed for MM at our centre results in high response rates of over 80% in single and in double transplanted patients. Compared to available data in the literature, the procedure-related mortality during the years 2002 and 2007 was very low with 0.5% [23]. A CR after ASCT and ISS stage of less than III were the best predictors for prolonged survival. Age was not associated with a worse outcome in selected patients eligible for ASCT.

We were able to document a median survival of 49.8 months from the first ASCT in our patients. Separately analysed by the number of ASCTs, the median survival was 46.4 months for single-transplanted patients, and 63.7 months for double-transplanted patients respectively. These results are in accordance with other published outcome analyses [5, 24–26]. In general, only patients who do not achieve at least a VGPR after the first ASCT might benefit from a double ASCT [5–6]. Following this assumption, chiefly patients with an insufficient response proceeded to a second ASCT at our centre.

We showed that patient survival correlates with the response achieved after ASCT. Patients who achieved only a PR or less than PR had a significantly shorter OS compared to patients achieving a CR. On the other hand, CR did not result in a significantly longer OS compared to the patient subgroup achieving nCR or VGPR. This result is remarkable considering that our patient number was rather small and usually only studies with large patient numbers were able to link survival with response status achieved after treatment. A similar association of patient survival with CR after ASCT was reported recently in a subgroup analysis of more than 750 patients treated within the GEM2000 protocol, where the quality of response to induction therapy had indeed a positive impact on the quality of the response to ASCT, but without impacting on survival as impressively as the post-transplant response status [27]. The superiority of VGPR compared with PR after ASCT was demonstrated by an analysis of the IFM-99 trials [28]. We also found a significant impact of CR on patient survival, but we cannot confirm this observation for patients with nCR or VGPR after ASCT, most probably because of small patient numbers. However, CR was not superior to nCR or VGPR in our patient cohort, and in our view this finding supports the general recommendation to omit a second ASCT in patients who achieve at least a VGPR after first ASCT.

We transplanted a very heterogeneous patient cohort with MM at our transplantation centre. Notably, a few selected high-risk patients with co-morbidities such as renal insufficiency or light chain amyloidosis were also treated and a substantial subset of patients (16%) were aged over 65 years. Patients were considered transplantable if they were biologically fit and judged able to tolerate high dose therapy by the attending physician and our regular stem cell transplantation board. The dose of melphalan was individually adjusted according to physical status and organ function. This heterogeneity of the patient collective is reflected in the trend to prolonged EFS and OS in patients receiving standard dose melphalan for conditioning compared to patients with presence of risk factors, whose melphalan dose was reduced. One interesting finding of this analysis is that elderly patients did not have, in general, a worse outcome than younger patients. The fact that EFS was positively influenced by a higher melphalan dose may be partially explained by a simple dose-efficacy correlation, as higher drug doses may achieve a better treatment result [29]. Furthermore, we observed the well known association of initial ISS stage with patient survival. Our findings are in accordance with other reports showing similar data [3, 30–33]. In contrast, the number of previous chemotherapy regimens before ASCT did not affect patient outcome. This finding may be explained by the fact that the majority of the patients received only one regimen for induction, mainly VAD, and that most patients with insufficient response could be “rescued” by a second regimen, either by using combination chemotherapy (M2 protocol) initially or bortezomib and IMIDs during the last years of the observation period. Finally, we did not find a statistically significant impact of time between diagnosis and first ASCT on overall survival.

The main limitation of this analysis is the limited patient number. Additionally, patients were treated outside the framework of a controlled clinical trial and differed considerably regarding number and duration of preceding treatment regimens, induction treatment, and risk factor profile. The data presented here represent a “real-life” transplantation experience, a scenario that is applicable to the majority of patients. These results are free from possible selection bias created by entrance criteria of clinical studies, and the conclusions reached by an analysis such as ours have their impact on daily practice and on communication with patients. The main goal of our efforts remains the continuous improvement in patient care we aim to achieve by monitoring and analysing treatment outcome.

In conclusion, ASCT is a very safe and effective treatment option for eligible patients with MM. Treatment-related mortality is very low. Older patients with good performance status also benefit from an ASCT. Achievement of a CR before ASCT is a predictor for better EFS, and CR status after ASCT remains the best predictor for a prolonged OS and may spare the patients multiple ASCTs.

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