Melphalan dose in myeloma patients ≥65 years of age undergoing high-dose therapy and autologous stem cell transplantation: a multicentric observational registry study

Abstract

The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65–77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70−180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264–2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.

Introduction

Multiple myeloma (MM) is a plasma cell malignancy that primarily affects older individuals, and two-thirds of MM patients are over 65 years of age at the time of diagnosis. Dose intensification with autologous stem cell transplantation (ASCT) is considered a standard therapy for MM patients younger than 65 years since randomized clinical trials demonstrated superiority over conventional chemotherapy even in the era of novel agents [1,2,3,4]. Different conditioning regimens have been studied, but high-dose melphalan 200 mg/m2 (MEL200) is the most widely used conditioning regimen in MM. MEL200 has been shown to be less toxic and noninferior to melphalan 140 mg/m2 (MEL140) plus 8 Gy total body irradiation (TBI), and to be superior to melphalan 100 mg/m2 (MEL100) [5, 6].

In contrast to younger MM patients, elderly patients are often considered ineligible for ASCT, and the use of high-dose melphalan and ASCT in MM patients over the age of 65 years has long been controversial, mostly due to an anticipated increase in treatment-related morbidity and mortality [7,8,9]. However, data from single centers suggest that the outcome and toxicity of ASCT in older MM patients is comparable to younger patients if the patients are thoroughly selected [10, 11].

Two randomized trials addressed the topic of intermediate-dose melphalan (MEL100) and ASCT in elderly MM patients, and showed contrasting data; the Italian Multiple Myeloma Study Group M97G Trial reported on the benefit in event-free and overall survival (OS) in elderly patients (age 55–75) given two cycles of MEL100 followed by ASCT as compared to six cycles of oral melphalan plus prednisone [12]. While the Intergroupe Francophone du Myélome trial IFM 99-06 found the combination treatment of melphalan, prednisone, and thalidomide (MPT) to be superior to one cycle of MEL100 followed by ASCT, for previously untreated patients aged 65–75 years with MM [13].

Despite the lack of prospective trials that clearly define the benefit of ASCT and the optimal melphalan dosing for conditioning in MM patients >65 years, numbers of ASCTs performed in this age group have increased significantly in the past decade [14,15,16]. Some centers routinely reduce the melphalan dose in patients over 65 years, based on the results of early publications with treatment-related mortality (TRM) rates between 8 and 18% for MEL200, and 2−3% for reduced melphalan doses [9, 17,18,19,20]. Other centers use MEL200 without an apparent increase in toxicity or TRM [11, 21, 22]. Our present study addresses the impact of the melphalan dose on early mortality (day +100 after ASCT), disease control and long-term outcome in MM patients aged 65 years and older by analyzing the prospectively collected dataset of the Swiss Blood Stem Cell Transplantation Registry.

Methods

Study design and data source

In this observational, national multicenter research project involving all Swiss adult Autologous Stem Cell Transplant Centers in Aarau, Basel, Bellinzona, Bern, Lausanne, St. Gallen, and Zürich, patients ≥65 years with symptomatic MM requiring single or double ASCT according the institutional standard were enrolled between 1999 and 2016. Data are provided by the Swiss Blood Stem Cell Transplantation Registry, which is a prospective, longitudinal collection of data from all patients with MM receiving high-dose therapy followed by ASCT in Switzerland. The prospective design of the study allows for minimizing selection bias, and for capturing all events required for the endpoint assessment. The prespecified follow-up schedule of the registry guarantees data quality and provides a homogeneous dataset.

All patients provided written consent prior to inclusion in the Swiss Blood Stem Cell Transplantation Registry, and the study was approved by the Ethical Committee Ticino, Switzerland (2017-00903 RIF.CE 3229).

Patients and treatment

Data were extracted from the Swiss Blood Stem Cell Transplantation Registry. Staging is based on the International Staging System (ISS), and high-risk cytogenetics are defined as the presence of del17p, t(4;14), t(14;16) or combinations of these [4, 23]. Two Melphalan dose groups were defined: MEL200 for patients receiving melphalan at a dose of 200 mg/m2, and MELlow for patients receiving less than 200 mg/m2 melphalan prior to ASCT.

Outcome

The primary endpoint of the study was the all-cause mortality during the 100 days after the first ASCT. Secondary endpoints were remission status at day +100, time to neutrophil recovery, and time to platelet recovery after the first ASCT. Progression-free survival (PFS) and OS were analyzed separately for patients given a single ASCT, and for those undergoing double ASCT.

Engraftment and disease response

Time to neutrophil engraftment was defined by time from ASCT (day 0) to absolute neutrophil count (ANC) recovery >0.5 × 109/L following the ANC nadir. Time to platelet reconstitution was defined as time from ASCT to the time of platelets count recovery above 20 × 109/L from the date of ASCT. If the platelet count did not fall below 20 × 109/L, patients were excluded from this part of the analysis.

Response to treatment was determined according to the International Myeloma Working Group criteria [24].

Statistical analysis

Continuous variables are shown as medians and interquartile ranges (IQR) and categorical variables as percentages. Comparisons between the groups were performed with the Student’s t test for the continuous and ordinarily scaled variables and the chi-square test or Fisher’s exact test for categorical variables, as appropriate.

All-cause mortality was calculated as time from ASCT to death within 100 days (event). In single ASCT patients, the PFS was measured from ASCT to the date of progression (event), death (event), or last follow-up (censoring) and the OS was measured from the date of ASCT to the date of death from any cause (event) or to last follow-up (censoring). In double ASCT patients PFS and OS were calculated from the second ASCT.

Survival analysis was performed by the Kaplan–Meier estimation and compared using the log-rank test. Multivariate analysis of PFS and OS was estimated by Cox regression adjusting for age at ASCT, melphalan dose, ISS stage at diagnosis, presence of high-risk cytogenetics, Karnofsky performance status (KPS) at ASCT, renal function, disease status at ASCT, time from diagnosis to ASCT, and year of ASCT. All statistical tests were two-sided. Statistical significance was defined as p value < 0.05. The analysis was performed with the Statistical Package for the Social Sciences software v.22.0 (Chicago, IL, USA).

Results

Between 1999 and 2016 a total of 447 MM patients aged 65 years and older received high-dose melphalan followed by ASCT, and were registered in the Swiss Blood Stem Cell Transplantation Registry. Three hundred eighty-eight patients (86.8%) were included in the present analysis. Fifty-two (11.6%) patients were excluded because they had undergone a prior ASCT when they were <65 years old. Seven (1.6%) patients were excluded due to incomplete follow-up data.

Baseline characteristics

Median age at ASCT was 67.5 years (IQR 66.3–68.9 years), 148 (38.1%) patients were female. Median time from diagnosis to ASCT was <12 months in 326 (84.0%) patients. Ninety-six (24.7%) patients received ASCT between 1999 and 2008, and 292 (75.3%) patients received ASCT between 2009 and 2016 (Supplementary Figure S1). Single ASCT was performed in 344 (88.7%) patients, and double ASCT in 44 (11.3%) patients. Melphalan dose for the first ASCT was MEL200 in 288 (74.2%) patients, and MELlow in 100 (25.8%) patients. In the MELlow group 20 (20%) patients received MEL100-MEL130, 69 (69%) patients received MEL140, and 9 (9%) patients received MEL150-MEL190. Baseline risk stratification according to ISS was stage I in 125 (37.4%) patients, stage II in 136 (40.7%) patients, and stage III in 73 (21.9%) patients. Details on the cytogenetic risk were available for 200 (51.5%) patients with 39 (19.5%) patients having high-risk disease. Disease status prior to ASCT was CR, VGPR, PR, or <PR in 47 (11.3%), 97 (25.0%), 226 (58.2%), and 21 (5.4%) patients, respectively. Most patients had a KPS of ≥90% (n = 304, 81.7%). An eGFR of ≤60 ml/min according to the CKD-EPI equation was present in 69 (18.4%) of the patients, while an eGFR of ≤30 ml/min was present in 10 (2.7%) patients. The left ventricular ejection fraction (LVEF) was ≤50% in three patients. Fourteen (4.2%) patients had concomitant AL amyloidosis.

Table 1 displays the baseline characteristics of patients treated with MEL200 (n = 288) and MELlow (n = 100). MELlow patients were slightly older with a median age of 68.1 years (65–77) vs. 67.3 years (65–75) (p < 0.001), including a higher proportion of patients >70 years in the MELlow group (24.0 vs. 9.0%, p < 0.001). The proportion of patients with renal impairment (eGFR ≤ 60 ml/min) was higher in the MELlow group compared with the MEL200 group (39.7 vs. 11.1%, p < 0.001). Also, the MELlow group comprised a higher proportion of patients with AL amyloidosis (8.3 vs. 2.5%, p = < 0.001). Finally, the median number of reinfused CD34+ cells/kg bodyweight was lower in the MELlow groups compared to patients given MEL200 (3.21×106/kg vs. 3.80×106/kg, p = 0.030). No differences in ISS stage, cytogenetic risk, KPS, LVEF, year of ASCT, and disease status prior to ASCT were observed between the two MEL dose groups.

Table 1 Patient baseline characteristics according to melphalan dose group

Safety

Mortality within 100 days after a first ASCT was 1.5% (n = 6) for the entire patient population; four (1.4%) patients in the MEL200 group, and two (2%) patients in the MELlow group (p = 0.670) died (Fig. 1). Causes of death were infections in five (1.3%) patients, and a cardiovascular event in one (0.3%) patient.

Fig. 1
figure1

Kaplan−Meier estimates of all-cause mortality at 100 days according to MEL dose. Mortality within 100 days after a first ASCT was 1.5% (n = 6) for the entire patient population (not shown); four (1.4%) patients in the MEL200 group (200 mg/m2 of melphalan, blue), and two (2%) patients in the MELlow group (red) died (p = 0.670)

Time until platelet recovery was longer in the MEL200 group with a mean time to platelet recovery of 14.0 days (MEL200, CI 95% 13.3–14.6 days), vs. 12.7 days (MELlow, CI 95% 12.0–13.3 days), p = 0.005. A similar difference was observed in time to neutrophil recovery, with a mean time to neutrophil recovery of 12.1 days (MEL200 CI 95% 11.6–12.6 days), and 10.9 (MELlow 95% CI 10.5–11.3 days), p < 0.001.

Efficacy

The depth of response increased from 36.4% ≥ VGPR prior to ASCT to 66.6% ≥ VGPR by day +100 after the first ASCT. The proportion of patients achieving at least a VGPR was significantly higher in the MEL200 group as compared to the MELlow group (70.3 vs. 56.6%; p = 0.010) (Fig. 2).

Fig. 2
figure2

Remission status prior to first ASCT and at day 100 after first ASCT in n = 288 patients given MEL200 and n = 100 patients given MELlow. a Disease status prior to ASCT with no difference in deep responses (≥VGPR) between the two treatment groups (p = 0.572). b Disease status 100 days after ASCT according to melphalan dose. The depth of response increased from 36.4% ≥ VGPR prior to ASCT to 66.6% ≥ VGPR 100 days after the first ASCT. The proportion of patients achieving at least a VGPR was significantly higher in MEL200 patients when compared to the MELlow patients (70.3 vs. 56.6%; p = 0.010). MEL200 Melphalan dose = 200 mg/m2, MELlow Melphalan dose < 200 mg/m2, CR complete remission, VGPR very good partial remission, PR partial remission,  <PR stable disease or progressive disease

Progression-free survival

In patients undergoing single ASCT (n = 344) (Supplementary Table 1), median PFS was 27.7 months (95%CI 22.5–32.8) in the MEL200, and 22.1 months (95%CI 20.2–23.9) in the MELlow group (p = 0.294) (Fig. 3). PFS did not significantly correlate with age (≤70 vs. >70 years; 27.2 months vs. 21.5 months; p = 0.680), KPS (≥90% vs. <90%; 27.7 months, vs. 23.1 months; p = 0.527), renal function (eGFR >60 ml/min vs. eGRF ≤60 ml/min; 26.2 months vs. 28.2 months; p = 0.977), and cytogenetics (non-high-risk vs. high-risk; 27.7 months vs. 23.3 months; p = 0.663). The only variable associated with longer PFS was the ASCT period (1999–2008 vs. ≥2009; 19.4 months vs. 28.9 months, p = 0.018) (Supplementary Figure S2).

Fig. 3
figure3

Kaplan−Meier estimates of progression-free survival and overall survival according to melphalan dose. a Progression-free survival (PFS) in patients undergoing single ASCT (n = 344) was 27.7 months (95%CI 22.5–32.8) in the MEL200, and 22.1 months (95%CI 20.2–23.9) in the MELlow group (p = 0.294). b Overall survival (OS) in patients undergoing single ASCT was 91.2 months (95% CI 69.9–110.6) in the MEL200 group (blue), and 62.8 months (95% CI 44.7–81.0) in the MELlow group (red) (p = 0.015)

Overall survival

In patients undergoing single ASCT the estimated median OS was 91.2 months (95% CI 69.9–110.6) in the MEL200 group, and 62.8 months (95% CI 44.7–81.0) in the MELlow group (p = 0.015) (Fig. 3). Other factors associated with longer OS in univariate analysis were age (≤70 vs. >70 years; 82.8 months vs. 56.2 months; p = 0.021), ISS stage (ISS I 92.4 months, ISS II 63.4 months, ISS III 61.9 months; p = 0.004), and ASCT period (1999–2008 vs. ≥2009; 61.9 months vs. 73.9 months, p = 0.019), while cytogenetic risk, KPS, and disease status before ASCT had no impact on OS. A trend to a longer OS was seen in patients with better renal function (eGFR >60 ml/min vs. eGFR ≤60 ml/min; 83.8 months vs. 61.9 months; p = 0.060) (Supplementary Figure S3).

Single vs. double ASCT

Baseline characteristics of single ASCT patients (n = 344, 88.7%) and double ASCT patients (n = 44, 11.3%) are shown in Supplementary Table 2. Double ASCT was more commonly applied in the earlier treatment period (1999–2008 vs. ≥2009; 61.4 vs. 20.1%, p < 0.001). No differences in ISS stage, cytogenetic risk, KPS, and renal function were observed. However, the remission status prior to ASCT was deeper in the single when compared to double ASCT group (p = 0.001). In the double ASCT group 29 of 44 (69%) patients received MEL200 during the first ASCT. In five (11.4%) patients the melphalan dose was reduced, and in three (6.8%) patients the melphalan dose was increased for the second ASCT. The median time between the two ASCT was 3.31 months (IQR 2.75–4.15 months).

Median PFS was 26.1 months (95% CI 22.5–29.7 months) in the single ASCT group, which was not significantly different from the 24.5 months (95% CI 17.7–31.3 months) in the double ASCT group (p = 0.586). Likewise, median OS was not different in the double and the single ASCT group with 76.3 months (95% CI 64.4–88.2 months), and 88.9 months (95% CI 46.6–131.2 months), respectively (p = 0.469).

Multivariate analysis

In a multivariate Cox regression analysis adjusted for melphalan dose, age, KPS, renal function, and the year of ASCT the melphalan dose had no impact on PFS and OS. The initial risk stratification showed a significant association of advanced ISS stage and reduced OS with an HR of 2.961 (1.187–7.385; p = 0.020) for ISS stage II, and an HR of 4.573 (1.561–13.392; p = 0.006) for ISS stage III. The association of the cytogenetic risk group with OS was borderline with an HR of 2.423 (0.880–6.676; p = 0.087) for high-risk cytogenetics (Table 2).

Table 2 Single ASCT: multivariate analysis of PFS and OS

Discussion

This national multicenter analysis is the largest data collection to address the impact of the melphalan dose on the outcome in myeloma patients ≥65 years of age. The main finding of the study is the low all-cause mortality before day +100 with no differences between patients treated with MEL200 and patients treated with lower doses (MELlow) (1.4 vs. 2%, p = 0.670). Hematological toxicity was only minimally higher in the MEL200 group when compared to the MELlow group.

The relatively low day +100 overall mortality rate in our study compares favorably with the mortality rate of 8−17.6% reported in MEL200-treated patients in earlier studies [19, 20]. This might reflect a careful patient selection process and the allocation of comparably fit elderly patients to ASCT, a hypothesis that is supported by the low comorbidity profile in our patient population. Similar mortality rates of 0–4% in MEL200-treated patients were also observed in data collections from various single centers published in recent years [11, 21, 22]. In contrast to prior studies we did not observe an impact of different melphalan doses on day +100 mortality in our patient cohort. In a prior retrospective single center analysis, a significant improvement of the TRM was reported in elderly patients (n = 77) when reducing the melphalan dose from MEL200 to MEL140 [9]. However, the TRM in MEL200-treated patients (n = 25) in this study was rather high (16%). Our lower day +100 mortality rate may be because only newly diagnosed, and no relapsed/refractory myeloma patients were included in our analysis. Moreover, differences in induction therapy may have influenced outcomes.

Deeper responses were observed for the higher melphalan dose group after one cycle of ASCT, with 70.3% of the MEL200 patients achieving a VGPR or better, compared to 56.6% of the MELlow patients (p = 0.010). However, the improved response rate did not translate into a longer PFS, which is somewhat surprising as the depth of response is known to be a good surrogate for PFS, and presumably for OS in myeloma patients [25]. We cannot exclude that a difference between different melphalan dose groups might be observed in larger series. Although the MEL200 group had a significantly longer OS (91.2 months vs. 62.8 months, p = 0.015), the melphalan dose did not emerge as an independent variable for OS in a multivariate analysis, when corrected for age, ISS stage, cytogenetic risk, KPS, renal function, disease status at ASCT and the treatment period. Younger age (<70 years) was associated with better OS (82.8 vs. 56.2 months, p = 0.021). Likewise, a better eGFR (>60 ml/min/1.73 m2) according to CKD-EPI equation also showed a statistically nonsignificant trend to better OS (83.8 vs. 61.9 months, p = 0.060). In our study MEL200 patients were slightly younger and had a better renal function when compared to MELlow patients. We therefore conclude that differences in baseline characteristics rather than the MEL dose have an impact on OS in the elderly patient population. A borderline association of the cytogenetic risk group with OS was observed, with data on the cytogenetic risk available for half of the patients. However, the only variable independently associated with OS in our study was the ISS stage at diagnosis.

There are no data from randomized controlled trials clarifying the relevance and impact of different levels of dose intensification with melphalan prior to ASCT in elderly patients. A small prospective observational trial in patients aged 65 years and older comparing MEL140 (n = 18) vs. MEL200 (n = 32) showed a slightly better OS and PFS in the higher melphalan dose group, without excess toxicity [26]. In contrast, a recently published report from the EBMT registry that included younger patients (<65 years) with MM showed no significant differences in OS and PFS between patients treated with MEL140 and MEL200 [27]. However, similar to our analysis this EBMT analysis revealed that patients given MEL140 were significantly older than those receiving MEL200 (64 vs. 59 years), had a lower KPS, and a lower eGFR. In addition, patients in the MEL140 group had a more advanced ISS stage and a worse remission status prior to ASCT, as compared to MEL200 patients. The key finding of this EBMT analysis was that patients who achieved less than a PR after induction therapy appeared to benefit most from MEL200 over MEL140 in terms of OS, PFS, and relapse risk. The authors concluded that the remission status after induction therapy and prior to ASCT should guide decision making with respect to MEL dose. Our study was not powered to assess differences in MEL dose efficacy with respect to the remission status prior to ASCT. Nevertheless, we observed differences in the depth of remission between single and double ASCT patients with double ASCT patients having significantly inferior disease control prior to ASCT (≥VGPR, 11.6 vs. 39.8%, p < 0.001). This finding most likely reflects the practice to double transplant patients who achieve insufficient responses (<VGPR) after a first ASCT [28, 29].

There is no standardized recommendation on MEL dose reduction in elderly patients. Results of the study presented here suggest that age, renal function, and the presence of amyloidosis may have led physicians to modify melphalan doses in clinical practice. The day +100 mortality rate in our MELlow patients indicates that the actual clinical decision-making approach is safe. However, strategic trials are warranted to identify elderly patients ≥65 years that are fit to receive ASCT, and those in whom a melphalan dose reduction is advisable. These trials should ideally use objective and standardized tools to define patients’ individual “fitness”, including evaluation of comorbidities, combined with a detailed geriatric assessment [30,31,32]. Prospective randomized controlled trials such as the ongoing DSMM XIII study (NCT01090089) are warranted to clarify whether in elderly patients ASCT is really superior to conventional therapy in the era of modern induction and salvage therapies.

Our analysis is derived from nonrandomized prospective data of the Swiss Blood Stem Cell Transplantation Registry that collects data from all patients undergoing high-dose therapy with ASCT at the seven Swiss Adult Transplant Centers. Therefore, the strength of this study is to reflect not only a highly selected study population of elderly patients, but also a real-life scenario including all consecutive elderly myeloma patients judged to be fit to receive dose intensification and ASCT.

Although the dataset is complete, the interpretation is somewhat limited by the fact that melphalan dose allocation was not randomized, but based on the treating physicians discretion and local practice guidelines. Another limitation of the study is the lack of information concerning post-transplant treatment such as consolidation and maintenance therapy, which might preclude firm conclusion with respect to PFS and OS.

In conclusion, the data of our large real-life transplant cohort demonstrate that ASCT with doses up to MEL200 is safe in thoroughly selected elderly MM patients aged 65 years or older. Melphalan dose was reduced in one-fourth of the patients, and even though the higher dose group showed a better response, the dose reduction was not associated with inferior PFS in a multivariate analysis. These data need to be confirmed in prospective randomized controlled trials.

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Acknowledgements

This work was supported by a grant from ABREOC 2016 to BG.

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BG, GG and MK designed the study, analyzed the data, and wrote the first draft of the manuscript; GG and GS performed statistical analyses; all authors collected patient data, and critically read, discussed and corrected the manuscript.

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Correspondence to Bernhard Gerber.

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The authors declare that they have no conflict of interest.

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This work has been presented at the 59th Annual Meeting of the American Society of Hematology, 2017.

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Ghilardi, G., Pabst, T., Jeker, B. et al. Melphalan dose in myeloma patients ≥65 years of age undergoing high-dose therapy and autologous stem cell transplantation: a multicentric observational registry study. Bone Marrow Transplant 54, 1029–1037 (2019). https://doi.org/10.1038/s41409-018-0379-y

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