The significance of elevated C-reactive protein (CRP) prior to autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has not been studied. We analyzed 1111 MM patients who underwent ASCT at Mayo Clinic from 2007 to 2015. A total of 840 patients (76%) received early ASCT (⩽12 months from diagnosis) and 271 patients (24%) received delayed ASCT (>12 months from diagnosis). Elevated CRP (> upper normal limit (8 mg/L)) was seen in 14% and 22% of patients undergoing early and delayed ASCT, respectively (P=0.003). There was no correlation of CRP with pre-transplant response, bone marrow plasma cell percentage or labeling index. Patients with an elevated CRP had a higher likelihood of having circulating plasma cells prior to ASCT (33 vs 19%; P<0.001). In the early ASCT cohort, the median overall survival (OS) in patients with normal and elevated CRP was not reached and 91 months respectively (P=0.011). In the delayed ASCT cohort, the median OS in respective groups were 73 and 30 months respectively (P<0.001), with elevated CRP being an independent prognostic marker on multivariate analysis (hazard ratio 2.0; 95% confidence interval, 1.0–3.8; P=0.045). Elevated pre-transplant CRP identifies a high-risk population especially in patients undergoing delayed ASCT and should be incorporated in the pre-transplant evaluation.
Interleukin-6 (IL-6) is a pro-inflammatory cytokine secreted by monocytes and stromal cells in the bone marrow (BM) microenvironment in multiple myeloma (MM), which subsequently stimulates proliferation of MM cells.1 BM plasma cells (BMPCs) also produce interleukin-1β (IL-1β), which in turn stimulates production of IL-6 by stromal cells.2 C-reactive protein (CRP) is a polypeptide secreted by hepatocytes in response to IL-6; hence, it can be used as a surrogate marker for IL-6 in the serum.3 CRP also binds to the Fcγ receptors on the surface of BMPCs, leading to activation of oncogenic pathways and inhibition of apoptosis in response to melphalan and dexamethasone in mouse models. Furthermore, CRP can also stimulate BMPCs to secrete IL-6 under stressful conditions.4
Elevated CRP at diagnosis has a negative prognostic impact on overall survival (OS) in MM in the context of Arkansas total therapy protocols and in patients receiving anthracycline and thalidomide-based induction regimens.5, 6 Furthermore, in patients with smoldering MM, a decrease in CRP level after treatment with an IL-1 receptor antagonist is associated with a superior PFS and OS.7 However, the prognostic impact of elevated CRP immediately prior to ASCT is unclear. Since IL-6 and CRP have growth-stimulating effects on MM cells and CRP inhibits apoptosis of malignant PCs in response to melphalan in preclinical studies,4 we hypothesized that an elevated pre-transplant CRP is associated with an inferior survival from transplant in patients with newly diagnosed or relapsed/refractory MM. To test our hypothesis, we retrospectively reviewed all consecutive patients undergoing their first ASCT in Mayo Clinic in the era of novel agent-based induction and post-transplantation therapies.
This study was approved by the Mayo Clinic Institutional Review Board. Informed consent was obtained from all patients for reviewing their medical records. Testing for CRP in serum is performed routinely in all patients as a part of the pre-transplant workup in our institution. CRP is quantified by the particle enhanced immunoturbidimetric assay using a commercially available reagent (Roche diagnostics, Indianapolis, IN, USA). Patients with serum CRP greater than the upper normal limit, which is 8 mg/L in our institution, were classified as the ‘elevated CRP’ subgroup and those with serum CRP less than or equal to the upper normal limit were classified as the ‘normal CRP’ subgroup. The lowest limit of detection for CRP in this assay is 3 mg/L. Receiver operating characteristics analysis was also performed to establish the optimal cut-off of CRP predictive of 2-year post-transplant survival. We have included all consecutive patients who underwent ASCT at our institution from January 2007 to May 2015.
High-risk cytogenetics by interphase fluorescence in situ hybridization (FISH) on BMPCs was defined as at least one of the following abnormalities: t(4;14), del(17p), t(14;16) or t(14;20)8, 9, 10 detected at diagnosis or at first presentation to Mayo Clinic prior to ASCT. Bone marrow examination and six-color flow cytometry of peripheral blood for identification of circulating plasma cells (CPCs) was also performed in all patients as part of the pre-transplant evaluation. Testing for CPCs was done prior to stem cell mobilization. For estimation of BMPC percentage pre-transplant, the highest estimate from BM aspirate (by manual counting), core biopsy (estimation of pathologist) and slide-based immunofluorescence method (by manual counting) was used for analysis.11
Stem cell mobilization, conditioning and transplant management in Mayo Clinic has been described previously.12, 13 Stem cell collections were performed with granulocyte colony-stimulating factor subcutaneously (10 mcg/kg/day), which was administered either alone or after cyclophosphamide (1.5 g/m2 daily for 2 consecutive days) or with plerixafor, which was routinely available since 2009. Conditioning was done either with full-dose (200 mg/m2) or reduced-dose melphalan (140 mg/m2) at physicians’ discretion, depending on general fitness, renal function and other co-morbidities.
Two-sided Fisher’s exact test was used to compare categorical variables and two-sided Wilcoxon rank sum test was used to compare continuous variables. The primary end-point of this study was OS from ASCT. The secondary endpoints included best post-transplant response, time to engraftment and PFS. Depth of response was determined according to the current consensus response criteria.8 Best post-transplant response was defined as the best response at any time after ASCT in the first plateau. PFS was defined as time from transplant to disease progression or death due to any cause. OS was defined as time from transplant to death due to any cause. Patients who were alive and free of disease at the last follow-up visit were censored. Survival analysis was done using the method described by Kaplan and Meier.14 Differences in survival between the groups were tested for statistical significance using two-sided log-rank test. Univariate analysis using the Cox proportional hazards model was performed with the following variables: age⩾65 years, high-risk cytogenetics by FISH (vs standard-risk cytogenetics), international staging system (ISS) stage 3 disease at diagnosis (vs ISS stage 1 or 2 disease), less than very good partial response at transplant (vs very good partial response or better), elevated CRP at transplant (vs normal CRP), one or more relapses pre-transplant (vs no relapse), post-transplant maintenance therapy (vs no maintenance), creatinine clearance<60 mL/min at transplant (vs creatinine clearance⩾60), Karnofsky Performance Status <80 at transplant (vs Karnofsky Performance Status ⩾80 and CPCs at transplant (vs no CPCs). Factors prognostic for OS with a P-value less than 0.1 in the univariate analysis were studied in a multivariate analysis. JMP 10.0.0 (SAS Institute Inc., Cary, NC, USA) statistical package was used for all statistical analysis.
A total of 1113 patients underwent ASCT during the time period, among which data on pre-transplant CRP level were available for 1111 patients, who were included in the final analysis. A total of 840 patients underwent early ASCT (<12 months from diagnosis; 76%) and 271 patients underwent delayed ASCT (>12 months from diagnosis; 24%). To test the prognostic impact of CRP on a well-defined and representative patient population at a similar time point in the course of their illness, we have analyzed the early and delayed ASCT subgroups separately. A flow chart showing patients included in the study is depicted in Figure 1.
Early ASCT cohort
The median age of patients undergoing early ASCT (n=840) was 61 years (range, 24–76). Baseline clinical and demographic characteristics are summarized in Table 1. The median follow-up of the early ASCT cohort was 44 months (95% confidence interval, 40–47). Elevated CRP was seen in 117 patients (14%), with the median being 14.2 mg/L (range, 8.2–176 mg/L). Patients with an elevated CRP had a slightly higher likelihood of having ISS stage 2 or 3 disease at diagnosis compared to those with normal pre-transplant CRP levels (69 vs 61% respectively; P=0.017). The median time from diagnosis to transplant was 6 months and was similar in the two CRP subgroups. There was no significant difference in the incidence of FISH-defined high-risk cytogenetic abnormalities in patients with elevated or normal CRP. The patients had received a median of one line of induction regimen (range, 1–4) prior to ASCT. Although the proportion of patients with one or more relapses prior to transplant was low in the early ASCT cohort (8%), patients with an elevated CRP had a significantly higher likelihood of having ⩾1 relapse before ASCT (14 vs 7%; P=0.014). Elevated CRP was not associated with the percentage of pre-transplant BMPCs, labeling index of BMPCs and depth of pre-transplant response. Notably, 43% of patients undergoing early ASCT had attained a response of very good partial response or better at transplant. The incidence of pre-transplant CPCs by six-color flow cytometry was almost twofold higher in patients with elevated CRP compared to those with normal CRP levels (31 vs 17% respectively; P=0.001). There was no significant difference in the use of proteasome inhibitor and/or immunomodulator-based induction regimens in the subgroups. Patients with an elevated CRP had a higher incidence of having a Karnofsky Performance Status <80 compared to those with normal CRP (27 vs 10% respectively; P<0.001).
The transplant outcomes of patients undergoing early ASCT stratified by pre-transplant CRP level are summarized in Table 2. There was no significant association of elevated CRP with time to engraftment or rate and duration of hospitalization. The incidence of post-transplant stringent complete response was lower in patients with elevated CRP (29 vs 35%; P=0.032).
Receiver operating characteristics analysis in the early transplant cohort could not identify a significant cut-off predictive of 2-year post-transplant survival. A total of 536 events (including 223 deaths) had occurred at the time of last follow-up. A trend towards shorter PFS was noted in the subgroup with elevated CRP compared to those with normal CRP level (median, 23 vs 26 months respectively; P=0.088). The median OS was inferior in patients with elevated CRP (91 months vs not reached respectively; P=0.011), with the 5-year OS rates being 53% vs 67% respectively. The Kaplan–Meier curves for PFS and OS is shown in Figures 2a and b. On a multivariable analysis (MVA) (Table 3), elevated CRP retained its independent negative prognostic impact on OS (hazard ratio 1.5, 95% confidence interval, 1.0–2.3; P=0.045).
The cause of death for patients in the early and delayed ASCT cohorts stratified by the pre-transplant CRP level is shown in Supplementary Appendix I. In the early ASCT cohort, data on cause of death were available for 218 out of 223 patients. There was no significant difference in the incidence of myeloma-related and non-myeloma-related deaths in the two CRP subgroups (P=0.139).
Delayed ASCT cohort
The median age of patients in this cohort was 62 years (range, 38–76). Baseline clinical and demographic characteristics are listed in Table 1. The median follow-up of the delayed ASCT cohort was 53 months (95% confidence interval, 45–58). A total of 59 patients (22%) had elevated CRP pre-transplant, with the median being 14.8 mg/L (range, 8.1–172 mg/L). Patients with an elevated CRP had a higher proportion of ISS stage 2 and 3 disease at diagnosis compared to those with normal CRP (41 vs 34%; P=0.042). There was no significant difference in the incidence of FISH-defined high-risk cytogenetics, percentage of pre-transplant BMPCs, labeling index and pre-transplant depth of response between the two CRP subgroups. The median time from diagnosis to transplant was 27 months, with no statistically significant difference in the two groups. The patients had received a median of two prior lines of therapy (range, 1–6), with no significant difference in the incidence of proteasome inhibitor and/or immunomodulator-based therapy between the two subgroups. In the delayed ASCT cohort, 77% of patients had ⩾1 relapse prior to ASCT. However, there was no significant difference in the incidence of relapsed patients in those with elevated or normal CRP (P=0.124). Patients with an elevated CRP had a trend towards an increased incidence of clonal CPCs detected by six-color flow cytometry (37 vs 25%; P=0.068) and an increased incidence of having a Karnofsky Performance Status <80 prior to transplant (19 vs 10% respectively; P=0.069).
The outcomes of the delayed ASCT cohort are listed in Table 2. There was no clinically significant difference in the time to engraftment among patients with elevated or normal CRP. However, patients with an elevated CRP had a significantly higher rate of hospitalization during transplant (66 vs 48%; P=0.014). There was no significant difference in the depth of post-transplant response in patients with elevated or normal pre-transplant CRP level.
Receiver operating characteristics analysis in the delayed transplant cohort identified a cut-off of 6.7 mg/L for predicting 2-year post-transplant survival; hence, we chose to retain the upper normal limit of 8 mg/L for analysis. There were a total of 207 events of progression or death (including 116 deaths) at the time of last follow up. The median PFS in subgroups with elevated and normal CRP was 14 and 21 months respectively (P=0.035). The median OS in the respective groups was 30 and 73 months respectively (P<0.001), with the 5-year OS rates being 24% and 58% respectively. The 6-month OS rate in the two respective groups was 92% and 96% respectively, which indicates that the large difference in median OS is not due to an increased early mortality after ASCT in patients with elevated CRP. The Kaplan–Meier curves for PFS and OS are shown in Figure 2c and d. On MVA (Table 3), elevated CRP had an independent negative prognostic impact on OS (hazard ratio 2.0, 95% confidence interval, 1.0–3.8; P=0.045). Other factors retaining an independent negative prognostic impact on OS included CPCs at transplant and one or more relapses prior to transplant.
The cause of death was available for 115 out of 116 patients. There was no significant difference in the incidence of myeloma-related or non-myeloma-related deaths in the two CRP subgroups (P=0.165) (Supplementary Appendix I).
Our study shows that elevated pre-transplant CRP has an independent negative prognostic impact on post-transplant survival in patients with MM, especially in the cohort undergoing delayed ASCT, where it identifies a high-risk subgroup with a 5-year OS rate of 24%. There was no association of elevated CRP with pre-transplant response. In the phase 2 randomized trial of anti-IL-6 monoclonal antibody siltuximab with bortezomib vs bortezomib alone in relapsed/refractory MM, no significant correlation was noted between CRP suppression and clinical response,15 similar to the findings in our study. CRP was not associated with the percentage of BMPCs and labeling index pre-transplant. However, elevated CRP could be an indication of more active disease due to its association with the presence of CPCs prior to transplant.
Despite the widespread use of ASCT in MM after novel agent-based induction therapy, there is limited literature on pre-transplant prognostic factors for survival after transplant. Pre-transplant variables shown to have a negative impact on survival in the era of proteasome inhibitor s and immunomodulators include less than a very good partial response after induction therapy,16, 17 pre-transplant BMPCs⩾5%,18, 19 minimal residual disease after induction therapy,20 presence of clonal CPCs21 and 1p31.32 deletion in BMPCs.22 Pre-transplant CRP was shown to be correlated with an increased incidence of clonal CPCs by six-color flow cytometry in our study. Since clonal CPCs are known to secrete IL-6 and express IL-6 receptor for autocrine and paracrine growth stimulation,23 correlation with an elevated CRP could be a reflection of increased circulating IL-6 in these patients. Earlier studies have also shown an independent correlation of CRP with disease activity at diagnosis and after treatment, as detected by technetium 99 m-sestamibi scintigraphy.24, 25 Elevated CRP at diagnosis is also strongly associated with the presence of greater than seven focal lesions on magnetic resonance imaging, greater than five focal lesions on metastatic bone survey (P<0.001 for both)26 and more than three FDG-avid lesions on positron emission tomography.27 Owing to a strong correlation of elevated CRP with focal lesions in the medullary and extramedullary compartments, the lack of association between CRP and pre-transplant response is plausible as focal involvement in the marrow could be missed by a single BM examination. Furthermore, clonal CPCs have been shown to be oligosecretory or non-secretory.28
Patients with an elevated CRP in the delayed ASCT cohort had a significantly higher rate of hospitalization during ASCT. A pilot study on the use of anti-IL-6 antibody during ASCT has shown effective suppression of CRP in the peri-transplant period, along with decreased transplant-related toxicities, including mucositis, nausea/vomiting and duration of fever, compared to historical control.29 However, it is unclear whether it confers any survival advantage in patients with an elevated pre-transplant CRP. Presence of high-risk cytogenetic abnormalities was not prognostic for PFS or OS from transplant in the delayed ASCT cohort in our study. A prior study has shown that the prognostic impact of baseline high-risk cytogenetic abnormalities by FISH on OS attenuates over time.30 The median time from diagnosis to ASCT in the delayed ASCT cohort in our study was 2.3 years, which could partly explain the lack of impact of high-risk cytogenetics on OS in this subgroup.
In patients undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, elevated CRP (defined as >10 mg/L) was shown to be associated with a higher transplant-related mortality, with the optimal threshold affecting transplant-related mortality being 3.67 mg/L.31 In our study, the cause of death was related to relapsed myeloma in a majority of patients (78%) in both CRP subgroups. Furthermore, there was no statistically significant difference in the incidence of non-relapse mortality in both early and delayed transplant cohorts among patients with normal or elevated CRP levels. Death within 100 days of transplant was only seen in 11 out of 1111 patients (0.99%), with only 6 of the 11 deaths not related to early relapsing myeloma.
This study has limitations. It is a retrospective study and the findings need to be validated prospectively and by other groups. However, given the lack of reliable prognostic markers in relapsed/refractory MM other than response to prior therapy,32 the magnitude of impact of elevated CRP prior to ASCT in this population can be helpful in risk stratification.
In summary, we have demonstrated that elevation of pre-transplant CRP is seen in 14% of patients undergoing early ASCT and in 22% undergoing delayed ASCT. Although the negative prognostic impact of elevated CRP in the early ASCT cohort is modest, it clearly identifies a high-risk subgroup in patients undergoing delayed ASCT, in whom the 2-year PFS is only 25% and 5-year OS is only 24%. Prospective studies on ASCT in MM should evaluate the prognostic implication of serum CRP levels on survival both at diagnosis and at transplant.
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RC designed the study, analyzed the data, wrote the first draft and approved the final version of the manuscript. MAG designed the study, analyzed the data, wrote the first draft and approved the final version of the manuscript. EM designed the study, analyzed the data, revised the manuscript critically and approved the final version of the manuscript. MAG, SKK, FKB, DD, AD, SRH, WJH, PK, MQL and NL performed patient management, revised the manuscript critically, participated in final data analysis and approved the final version of the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website