ABSTRACT
Objectives
Multiple myeloma (MM) is a class of malignant plasma cell diseases. An increasing application of autologous stem cell transplantation (ASCT) and anti-myeloma agents represented by proteasome inhibitors (PIs) has improved the response rates and survival of MM patients. Patients progressing within 12 months were recently categorized with functional high-risk (FHR), which could not be clarified by existing genetic risk factors, with poor outcomes. Our study aimed to investigate clinical indices related to FHR and seek prognostic roles in transplant-eligible MM patients.
Methods
Demographic and individual baseline clinical characteristics were compared by using the Pearson's chi-square and Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were described by Kaplan-Meier estimates and compared using the log-rank test. Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with FHR status.
Results
From 18th January 2010 to 1st December 2022, 216 patients were included and divided into two groups according to the FHR status. There was no difference in baseline data between the two groups. Renal impairment (RI, Scr > 2 mg/dL) was common in MM patients and made sense in FHR status. AST levels were validated as independent predictors for FHR status (p = 0.019).
Discussion
Patients with RI or higher AST levels (AST > 40 U/L) tended to have worse outcomes. However, transplants had apparently improved prognoses.
Conclusion
Therefore, in the PIs era, transplantations are still effective therapies for transplant-eligible MM patients.
Introduction
Multiple myeloma (MM) is the second most common hematological malignancy, representing approximately 1% of all cancers [Citation1,Citation2]. This plasma cell disorder primarily involves elderly individuals, with a median age of 69 years [Citation3,Citation4]. The treatment approach for MM commonly entails a regimen consisting of a combination of three or four drugs, followed by an autologous hematopoietic stem cell transplant (ASCT) for patients who are eligible for the procedure [Citation5]. Although ASCT is not curative, it continues to be an integral part of the standard-of-care treatment for MM, despite advancements in drug therapies, characterized by the clinical application of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), etc. [Citation6]. The introduction of chimeric antigen receptor (CAR) T cells and bispecific antibodies revolutionized MM treatment in recent years. Through these strategies, PIs, represented by bortezomib (Btz), carfilzomib (Cfz) and ixazomib (Ixz), have been recognized as a class of key agents in MM therapy [Citation7]. MM cells exhibit a higher proteasome activity than normal cells, leading to a strong sensitivity to PIs [Citation8]. Although the initial response rates of treatment regimens containing PI combinations approach 90%, patients eventually relapse leading to cancer progression [Citation9]. To date, high-dose chemotherapy followed by ASCT is still the standard of care for transplant-eligible MM patients although there is controversy over transplant-related risks, including massive non-relapse mortality (NRM) [Citation10].
Despite significant advances in the treatment of MM, relapses remain a major obstacle. It is not uncommon for patients with MM to relapse within 18 months, even without any high-risk feature at baseline [Citation11]. Multiple studies have confirmed that clinical indicators, including serum free light chain (FLC) and lactate dehydrogenase (LDH), played key roles in early relapse (ER). The concept of functional high-risk (FHR) has recently been proposed, for those progressing within 12 months since therapy initiation [Citation12]. Andrew and colleagues further investigated that FHR patients had a median OS of only 20.2 months. FHR patients even without any known genetic high-risk hereditary factors showed very poor prognosis [Citation13]. More importantly, these FHR patients could not be separated through well-known gene expression patterns of high-risk diseases.
As a result of the hyperproduction of monoclonal heavy and light chain paraproteins (M-proteins) in serum and urine, diffuse organ damage, especially renal impairment (RI), occurs, which is defined as a serum creatinine (Scr) level > 2 mg/dL [Citation14,Citation15]. RI is regarded to be correlated with early mortality [Citation16,Citation17]. Several anti-myeloma agents (e.g. PIs) have been applied to multiple clinical trials, which, at the time of the prolonged survival, increased rates of renal recovery [Citation18,Citation19]. Btz is effective and well tolerated in MM patients with RI, including those requiring dialysis [Citation20]. Because the pharmacokinetics of Btz are not affected by the extent of deterioration in renal function [Citation21]. MM patients resistant to PIs have a poor prognosis, particularly in those in concert with renal insufficiency [Citation22]. In fact, despite the availability of novel drugs, scientists have shown that survival in patients with kidney injury in the first few weeks after diagnosis was not improved [Citation23,Citation24].
Evidence from the real world demonstrates that in transplant-eligible patients, PI remains the most widely used first-line drug for the treatment of MM. In this study, we aimed to discuss the effects of RI on FHR status in MM patients and seek the determining factors among biochemical parameters. Herein, we performed a comprehensive analysis in transplant-eligible patients receiving PI-based chemotherapy explored the clinical signatures between patients with FHR and functional standard risk (FSR) and further discussed the determining factors for FHR status.
Methods
Study design and population
In this single-center retrospective observational study, we reviewed the medical records of adult patients with newly diagnosed MM at Shandong Provincial Hospital from 18th January 2010 to 1st December 2022, as defined by the International Myeloma Working Group (IMWG) criteria [Citation25]. Staging and risk assessments were performed per the international staging system for MM. Patients aged < 65 years, without end-stage liver or cardiac diseases, along with measurable diseases and active MM [Citation26] were considered eligible for high-dose chemotherapy and ASCT. Cases undertaking PI-based first-line therapy were further concluded in our study. We retrospectively collected clinical and demographic information at diagnosis from electronic medical records, including demographic and baseline information, laboratory results, image examinations, bone marrow tests and treatment outcomes. Cytogenetic abnormalities (CA) include hypodiploid genotype, amp (1q21), del (17p13), del (13q14) and translocations involving the immunoglobulin heavy chain gene (IgH) located in chromosome 14q32 [Citation14,Citation27,Citation28]. All the patients were on regular follow-up schedules. All patients signed informed consent at the first visit and the study was approved by the Medical Ethical Committee of the Shandong Provincial Hospital. This study was conducted in accordance with the principles of the Declaration of Helsinki.
Treatments and outcomes
Patients included in this study received a doublet or triplet chemotherapy regimen, containing PI and dexamethasone. The choice of induction therapy was at the physician’s discretion and the patient as per insurance coverage/out-of-pocket expenses. Patients undertook maintenance therapy either with Btz or other drugs after ASCT. Disease response was assessed according to IMWG criteria, including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) [Citation29]. The primary endpoint was overall survival (OS), measured from the diagnosis date to the date of death/censorship. The secondary endpoint was progression-free survival (PFS), which was assessed from the diagnosis date to disease progression or the time of death or censoring was recorded.
Statistical analysis
Using frequencies and percentages, categorical variables were summarized, while continuous variables were presented as median and interquartile ranges (IQRs). Demographic and individual baseline clinical characteristics were compared by using Pearson’s chi-square test for categorical variables and the Mann–Whitney U test for continuous variables. PFS and OS were described by Kaplan-Meier (K-M) estimates and compared using the log-rank tests. Logistic regression analysis was used to assess the association between baseline characteristics at MM diagnosis and FHR status. The collinearity between variables and FHR was calculated by the collinearity diagnosis. A two-sided P < .05 was considered statistically significant. All statistical analyses were carried out using SPSS 22.0 software and the R software (R project).
Results
Population characteristics
A total of 760 newly diagnosed MM patients were included in this study. The median age of all MM patients was 59 years (range, 30–85 years). According to the inclusion and exclusion criteria of our study, 216 patients receiving PI-dexamethasone-based therapy were finally concluded for further study with follow-up data available. 32.4% of these patients (n = 70) received doublet chemotherapy, while 67.6% (n = 146) were treated with triplet chemotherapy. 63 (29.2%) patients received hematopoietic stem cell transplantation (HSCT), of which one received allogeneic HSCT (allo-HSCT), leaving 62 patients undergoing ASCT. One received Busulfan/Melphalan (Bu/Mel) as the conditioning regimen. The remaining patients followed with high-dose melphalan at 200 mg/m2 or a dose of 100-140 mg/m2 followed by ASCT. Two patients underwent CAR-T cell therapy after relapse.
shows the baseline characteristics of the patients involved. The medium age of the 216 patients was 55 years (range 30–64 years). An equal incidence in gender was observed (the male-female ratio of 1.0). With regard to disease characteristics, International Staging System (ISS) stages I, II and III were present in 21.3%, 31.0% and 44.7%, respectively. CA was detected in 103 patients and presented in 65 individuals. Chromosomal abnormalities (ABN) were observed in 25 of 122 patients. It was validated that the prevalence of genetic abnormalities in the FHR group was significantly higher compared to FHR patients. However, no statistically significant association was found between the presence of genetic abnormalities and FHR status. After a median follow-up of 21 months, 59 (27.3%) patients died and 157 (72.7%) were censored alive. The median survival time was 91 months.
Table 1. Baseline characters between patients of FHR and FSR. Data are n (%) unless otherwise stated.
Therapeutic regimens and efficacies
To eliminate the influence of different treatment methods on MM outcomes, we compared the PFS and OS of patients receiving doublet or triplet chemotherapy. MM patients who received triplet chemotherapy showed better PFS and OS, compared to those who received PI-dexamethasone regimens (Supplemental Figure 1). There was no significance in PFS and OS during the first 12 months after diagnosis between these two groups. Univariate logistic regression analysis indicated no influence of treatment options on FHR status (p = 0.116). In addition, the baseline characteristics, including age, sex, diagnosing type, CA, clinical stage, the appliance of IMiDs, and history of cardiovascular or cerebrovascular diseases, were also confirmed with no significance of FHR. Only the transplant status, RI and ABN were considered statistically significant when it comes to the correlation between FHR status (with p-values of 0.001, 0.023 and 0.019, respectively). Thus, it is obvious that the highly functional risks of MM patients taking PI-based regimens could not be recognized merely through basic information.
Clinical characteristics of FHR patients
To confirm other clinical indexes associated with FHR status, patients were first divided into the FHR group (n = 45, 20.83%) and the FSR group (n = 171, 79.17%) based on the therapeutic efficacy. The flowchart is depicted in . Baseline demographics, disease characteristics and survival data for different functional risk subgroups were compared to identify specific features of MM patients with different functional risks (). There was no difference at age (p = 0.209), sex (p = 0.867), diagnosing type (0.559), CA (p = 0.466), Durie-Salmon (DS) stage (p = 0.789), ISS stage (p = 0.297) and R-ISS stage (p = 0.564) between the two groups.
Figure 1. Flow chart of the study.
In FHR patients, the median age was 58 years, higher than that of the FSR group (55 years). Meanwhile, the proportion of patients with CA in the FHR group was larger than that in FSR patients, but of no significance. The distribution of myeloma types between patients with different functional risks showed no statistical difference. Light chain (LC) and immunoglobulin G (IgG) myeloma weighed heavily among those two groups. In addition, there was no difference in the clinical stages of these patients, which was consistent with our results above. Overall response (ORR) percentages were 11.1% and 72.5% in each group, respectively. According to the K-M curves, patients with FHR showed worse performance in both PFS and OS (Supplemental Figure 2).
Clinical variables recognizing FHR MM patients
We next compared clinical data between FHR and FSR patients, including serum metabolites. Through the results, the levels of aspartate aminotransferase (AST), superoxide dismutase (SOD), uric acid (UA), and absolute lymphocyte count (ALC) were strongly significant between FHR and FSR groups. Moreover, the presence of RI was also well influencing factor for FHR status. While variables, such as albumin (ALB), beta2-microglobulin (beta2-MG), hemoglobin (Hb), lactate dehydrogenase (LDH) and FLC made no sense, as previously proved significantly associated with many malignancies.
Univariate analysis identified 10 variables at diagnosis significantly associated (p ≤ .1) to ask clinical influencing factors of progression within 12 months of MM patients. Each variable showed no collinearity with progression (Supplemental Table 1). We next concluded all serum parameters previously validated as meaningful in multivariate logistic regression analysis. It was found that only AST was an independent predictor, Hosmer-Lemeshow test p = 0.580 ().
Table 2. Univariable and multivariate logistic regression analyses for FHR in MM patients.
Survival of MM patients
We analyzed the prognostic value of CA in MM patients. K-M curves revealed that there was no difference between PFS and OS among patients with CA represented or not (Supplemental Figure 3). Nevertheless, MM patients along with amp (1q21) or del (17p13) had shorter PFS and OS (). While PFS and OS of those with del (13q14) or IGH rearrangement showed no difference compared to others without CAs mentioned above (Supplemental Figure 4).
Figure 2. PFS (A) and OS (B) of patients with and without amp (1q21). PFS (C) or OS (D) of patients with and without del (17p13).
In addition, in the prior univariate analysis, transplant status and RI were risk factors for FHR status. Subgroup analyses were performed considering the impact of the transplant. According to the Scr levels and transplant status, patients were clustered into four groups. K-M curves indicated a strong difference in PFS and OS between patients with and without RI (A,B). Besides, in patients undergoing transplants, there was no significance in PFS or OS regardless of the renal function, when transplants had apparently improved outcomes of MM patients with RI (C,D). According to the results of survival analyses of serum AST and SOD levels, those with higher AST levels (AST > 40 U/L) tended to have a worse outcome in transplant-eligible MM patients (A,B). In our data, the AST level was mildly elevated. There were only four cases with AST >2.5 ULN, which were serologically negative for hepatitis B and C. As a consequence, a slight increase in AST level may lead to worse outcomes. For those receiving transplant therapy, a slight increase in AST level did not seem to affect PFS and OS (C,D). Next, we aimed to evaluate the prognostic value of abnormal AST levels in RI patients. It was shown that an abnormality in any one of those indicators was sufficient for poorer outcomes (A,B).
Figure 3. PFS (A) and OS (B) of patients with and without RI. PFS (C) or OS (D) of patients whether undertaking transplants with and without RI.
Figure 4. PFS (A) and OS (B) of patients with different levels of serum AST. PFS (C) or OS (D) of patients whether undertaking transplants with different serum AST levels.
Figure 5. PFS (A) and OS (B) of patients with different serum Scr and AST levels.
Discussion
MM is characterized as an incurable neoplasm of plasma cells. The success of MM treatment is primarily measured by achieving profound and long-lasting responses, which have a positive impact on both PFS and OS. In the first-line therapy, ASCT remains the optimal choice for transplant-eligible MM patients. The implementation of drugs, such as PIs and IMiDs used in induction, consolidation or maintenance therapy has resulted in more profound responses. However, a considerable number of patients continue to suffer early progression or even mortality after the first-line therapy. A study compared outcomes of 3783 MM patients diagnosed from 2004 to 2018 at MAYO (Mayo Clinic) with 57,654 patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute showed that the early mortality declined steadily (MAYO: 11% to 6%, SEER: 23% to 16%, respectively) [Citation30]. Despite the great progress in treating MM, still many people die within the first year of diagnosis [Citation31]. Moreover, emerging research studies have confirmed that MM progression is one of the major causes of early mortality [Citation32].
Researchers in the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) demonstrated that MM patients with disease progression within 12 months since therapy initiation, who were defined as FHR patients, had a median survival time of about 20 months [Citation12]. In addition, it is validated that FHR patients could not be characterized by known gene expression signatures of high-risk diseases, including proliferation, chromosomal instability, centrosome, cell death, as well as combinations of high-risk features, which is in accordance with our results that CA has nothing to do with FHR status [Citation13]. Notably, the presence of mutations within the FHR group did not exhibit a discernible concentration pattern. However, mutations in KIAA1549L, LUZP2, and BMPR1B were predominantly observed in the FHR group. Furthermore, upon evaluating the enrichment of mutated genes, it was determined that the IL6-JAK-STAT3 pathway exhibited a significant enrichment. A separate investigation demonstrated an increased occurrence of mutations in MKI67, ERN1, and EML4 among FHR patients [Citation33]. However, due to the absence of clinical next-generation sequencing (NGS) data at our institution, the comprehensive analysis of the mutational profile of MM patients at diagnosis and relapse was not feasible. Consequently, this study primarily aimed to identify readily accessible clinical indicators for recognizing FHR patients.
Proteasome inhibitors, initially approved in 2003, have emerged as highly efficacious anti-myeloma agents and are now widely acknowledged as standard therapies globally, representing the most commonly employed first-line treatments for MM patients [Citation32,Citation34]. However, the presence of resistance poses a significant hindrance to the efficacy of therapy, primarily contributing to the advancement of the disease. Numerous underlying mechanisms have been postulated. Proteasome (26S), a substantial multicatalytic molecular apparatus responsible for protein degradation, comprises a minimum of 33 distinct proteasomal subunits that can be categorized into two components: the 19S regulatory complex and the 20S catalytic core (encoded by PSMA and PSMB) [Citation35,Citation36]. The mechanisms of resistance are diverse and impact various modes of gene regulation. For instance, genomic mutations in PSMB5 result in steric or conformational alterations in the drug-binding site of the proteasome [Citation37]. Epigenetic dysregulation of PSMB5 leads to the downregulation of individual subunits within the 19S regulatory complex and enhances the cell's proteolytic capacity [Citation38,Citation39]. Nevertheless, it is worth noting that in vivo, the occurrence of mutations in PSMB5 and other genes encoding the proteasome is too infrequent to account for the development of resistance in the majority of affected individuals. Therefore, to elucidate additional resistance mechanisms beyond proteasome subunit genes, it is imperative to conduct further genome-wide investigations on clinically well-annotated patients who are unresponsive to PI treatment.
In the past two decades, with the introduction of drugs represented by bortezomib and lenalidomide, outcomes have been apparently improved in MM patients with RI [Citation19]. However, in our research, renal insufficiency was frequently observed in FHR patients. And RI was still an affecting factor for FHR status. RI is common in MM patients, occurring in 15–40% of patients, which is acknowledged as a detrimental factor related to worse outcomes [Citation15]. MM-associated RI is mostly caused by the precipitation of immunoglobulin LC, subsequently resulting in the obstruction of tubular and cast nephropathy [Citation40]. In addition, our study reported the role of serum AST level in early disease progression of MM patients for the first time. It was found that AST was one of the independent risk factors for FHR status in transplant-eligible MM patients. In this study, only four patients showed AST levels over 2.5 ULN, who were serologically negative for hepatitis B and C. Therefore, mildly elevated AST levels may cause early progression. Moreover, higher AST levels were related to worse outcomes, which correspond with previous findings [Citation41]. One retrospective study of 44 MM patients undertaking bortezomib plus dexamethasone therapy demonstrated that patients with high AST levels showed worse prognosis. However, owing to an inadequate sample size, investigators did not find statistical significance between AST and PFS [Citation41]. As a specific drug for HCC, bortezomib shows no hepatotoxicity in human hepatocytes and is effective in alleviating drug-induced liver injury (DILI) [Citation42,Citation43]. To date, only a few researchers reported cases of hepatotoxicity receiving bortezomib therapy [Citation44–46]. Thus the inhibited liver function during treatment could be ignored as an influential factor in causing disease progression. What’s more, it was revealed that an abnormality in any one of the indicators including Scr and AST would definitely result in a poor prognosis, which needs more attention at first diagnosis and treatment.
Nevertheless, our study still had some limitations. First, due to the retrospective nature of our analysis, the presence of selection bias might reduce the reliability of the results. What’s more, the chemotherapy regimens were determined by the treating physicians, with some consideration of the economic situation of the patients, which may be subject to additional selection bias. Therefore, further investigation in prospective studies is needed. Second, since this is a single-center study, the sample size was relatively small, and the geographical and other variations cannot be ruled out. But as a preliminary study, these results are sufficient. Besides, in further clinical treatment of MM patients, we would be more focused on the genetic pattern of MM patients when diagnosis and relapse, for a comprehensive understanding of the genetic risks of a disease process.
Overall, our study showed that there was a significant difference in biochemical parameters between FHR and FSR MM patients. Serum AST level was an independent risk factor for recognizing FHR status. Patients with different serum Scr and AST levels showed various outcomes. But, the prognostic effects could be improved by receiving transplants. Therefore, in the PIs era, transplants are still effective therapies for MM patients.
Author contributions
Linquan Zhan and Dai Yuan designed the study. Xueling Ge, Mei Ding, Jianhong Wang, Xiangxiang Zhou and Xin Wang analyzed the data. Linquan Zhan and Dai Yuan co-wrote the manuscript. All authors approved the final version of the manuscript before submission.
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References
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