https://orcid.org/0000-0002-6548-1509
ABSTRACT
Objective
Multiple myeloma (MM) varies in clinical behavior, response to treatment and prognosis due to the heterogeneity of the disease. Data on the association between the immunoparesis status during treatment and prognosis in nontransplant MM patients are limited.
Methods
In a retrospective analysis of 142 patients with MM, we examined the relationship between immunoparesis status and prognosis during treatment. All patients received novel agent-based therapy and did not undergo autologous stem cell transplantation. One, two, or three uninvolved immunoglobulins (Igs) below the lowest thresholds of normalcy were used to identify immunoparesis.
Results
Patients with a greater degree of immunoparesis during treatment had shorter progression-free survival (PFS) and overall survival (OS). A total of 46.5% of the patients had severe and continuous immunoparesis (at least two uninvolved Igs suppressed continuously during treatment), representing a worse prognosis than those with complete or partial normalization of Igs during treatment. Among patients who achieved at least complete remission, PFS was poor in patients with severe and continuous immunoparesis. Furthermore, severe and continuous immunoparesis during treatment was a poor prognostic factor for PFS and OS according to multivariate analyses.
Conclusion
The degree of immunoparesis during treatment is a follow-up indicator for survival in nontransplant myeloma patients, and severe and continuous immunoparesis in nontransplant myeloma patients might be a sign of poor prognosis.
Introduction
Multiple myeloma (MM) is a common hematological cancer [Citation1]. The abnormal expansion of malignant plasma cells that release monoclonal immunoglobulins (Igs) causes this very diverse illness to develop, resulting in dramatic variations in clinical behavior, therapeutic response, and prognosis [Citation2]. Autologous stem cell transplantation (ASCT) is a widely used treatment that has dramatically increased survival in MM patients. However, not all patients are candidates for such treatment due to many factors, such as age, other comorbidities or economic conditions. These patients are treated with proteasome inhibitor (PI)-based and/or immunomodulatory agent (IMID)-based (recently supplemented with daratumumab) initial and maintenance therapy with acceptable toxicity until disease relapse [Citation3,Citation4].
One of the causes of MM disease progression is immune cell dysfunction, which leads to the loss of tumor-specific immunity [Citation5,Citation6]. Immunoparesis refers to the phenomenon in which there is suppression of one or more uninvolved immunoglobulins (Igs). Immunoparesis affects between 81.0% and 93.5% of newly diagnosed MM patients [Citation7–9], and appears to be due to changes in the tumor microenvironment as well as the inhibition of normal immune cell activity. It has been demonstrated that immunoparesis carries a significant chance of developing into symptomatic MM in patients with plasma cell disorders [Citation10,Citation11]. Moreover, immunoparesis in newly diagnosed MM patients has been extensively reported to suggest a poor prognosis [Citation7,Citation12,Citation13].
Notably, polyclonal Ig recovery after ASCT or allogeneic transplantation in MM patients has been shown to be correlated with improved progression-free survival (PFS) and overall survival (OS) [Citation14–17]. In contrast, there are limited data on whether a change in the immunoparesis status during treatment also has prognostic significance in nontransplant patients treated with novel agents. Thus, the primary aim of our study was to evaluate the association between the immunoparesis status during treatment with novel drugs and prognosis in nontransplant MM patients.
Patients and methods
Study population
A total of 142 MM patients from January 1, 2010, to May 31, 2022, who were treated with PIs and/or IMIDs drugs and who did not undergo ASCT were identified in the database of our hospital and followed up until December 1, 2023. The diagnostic criteria for MM were based on the 2014 edition [Citation18]. Patients were not included if they had (1) concomitant malignant disease at the time of diagnosis of MM or (2) allogeneic transplantation. The details are shown in . Approval was obtained from the ethics committee of our hospital and was in accordance with the Declaration of Helsinki.
Figure 1. A total of 142 patients were enrolled in the assessment. Abbreviations: PI, proteasome inhibitor; IMID, immunomodulatory agent; ASCT, autologous stem cell transplantation
The data were taken from a retrospective database as well as patient files. Serum Igs were measured by standard nephelometry at diagnosis and during the treatment period – every month during induction therapy and once every three to six months during maintenance therapy until progression or death. According to our laboratory reference range, immunoparesis was defined as a decrease in one, two, or three uninvolved Igs from the lowest level of normalcy, which was 0.7 g/L for IgA, 0.4 g/L for IgM and 7 g/L for IgG. This study revealed changes in immunoparesis in a dynamic pattern. The 142 patients were split into three groups: (1) Group i included those in whom all uninvolved Igs were preserved or recovered during treatment (complete Ig normalization); (2) Group ii included those who exhibited partial Ig preservation or recovery with one uninvolved Ig suppressed continuously during treatment (partial Ig normalization); and (3) Group iii included those in whom at least two uninvolved Igs were suppressed continuously during treatment (severe and continuous immunoparesis). High-risk cytogenetic abnormalities [Citation19] were detected by interphase fluorescence in situ hybridization (FISH). Magnetic anti-CD138 beads were used to separate myeloma cells. Four hundred interphase nuclei were analyzed by DNA probes for TP53 (17p13), IGH/MAF (14q32/16q23), IGH/FGFR3 (14q32/4p16), and 1q21, with reference thresholds of 8.30%, 8.00%, 8.00%, 5.00%, respectively.
Response and outcome
Patient responses and progression were assessed in accordance with the International Myeloma Working Group (IMWG) criteria [Citation20]. A stringent complete response (sCR) was incorporated into a complete response (CR) in our study due to the small proportion of patients with a sCR. PFS was calculated from the beginning of therapy to the first sign of illness progression or death, while OS was calculated from the time that therapy began to the time of death. Patients who were lost to follow-up were censored at the date of last contact.
Statistical analysis
The Kruskal–Wallis H test was used for comparisons with continuous variables, while the significance of discrepancies between categorical variables was established using χ2 tests. Patients with missing data were excluded. The Kaplan–Meier method was used to plot the survival curves, and log-rank tests were used to compare the survival curves among groups. Univariate Cox regression models were applied to investigate the effects of possible risk variables on progression or survival. Responses and immunoparesis (severe and continuous) were considered time-dependent covariates; they were analyzed via univariate models and incorporated into the final multivariate model, which included other outcome-related covariates. The outcomes are displayed as hazard ratios (HRs) with 95% confidence intervals (95% CIs). p<0.05 was considered to indicative of statistical significance. All the statistical analyses were performed with IBM SPSS version 26.
Results
Patient characteristics
This research included 142 MM patients who did not receive ASCT. provides a summary of the patients’ general characteristics. A total of 56 (39.4%) of the 142 participants were female, and the median age was 70 (42–89) years. The IgG or IgA subtypes made up the majority of the patients (72.5%). 37 patients (26.1%) had the light-chain type. In total, 46.8% of the individuals had International Scoring System (ISS) stage III. 99 patients (69.7%) were evaluated for the revised ISS (R-ISS) stage, and the majority (73/99, 73.7%) had R-ISS stage II. According to the Eastern Cooperative Oncology Group (ECOG) score, the majority (74.6%) of patients had a score < 2.
Table 1. Baseline characteristics at diagnosis, induction regimens and response rates of 142 nontransplant myeloma patients
All patients received initial treatment combined with novel agents. Less than half of the patients (40.1%) had received PI-based regimens, mainly Vd (bortezomib and dexamethasone) (21/142, 14.8%) and VCd (bortezomib, cyclophosphamide, and dexamethasone) (29/142, 20.4%), and bortezomib in combination with daratumumab was administered to one patient. 43 patients (43/142, 30.3%) received IMID-based regimens, which were mostly thalidomide (41/142, 28.9%) and lenalidomide (2/142, 1.41%). In addition, PIs in combination with IMIDs, mainly VTd (bortezomib, thalidomide, and dexamethasone) (18/142, 12.7%) and RVd (lenalidomide, bortezomib, and dexamethasone) (12/142, 8.5%), were administered. 26 (18.3%) patients were treated for fixed-duration therapy, and 116 (81.7%) patients received continuous therapy until progression.
Of the 142 patients who achieved an estimated response after induction therapy, 122 patients (85.9%) had at least a partial response (PR), 50 patients (35.2%) had an sCR/CR, 32 (22.5%) had a PR, and 40 (28.2%) had a very good partial response (VGPR). The patients were followed for a median of 31.7 months, ranging from 3.6 to 128.9 months. A total of 108 patients (76.1%) experienced relapse or progression or died.
Immunoparesis recovery during treatment
A total of 88.0% (125/142) of myeloma patients had immunoparesis at the time of diagnosis. Among the 125 patients who had immunoparesis at diagnosis, 37 (37/125, 29.6%) had recovered uninvolved Igs during induction or maintenance therapy. Patients with recovered immunoparesis had better PFS and OS than did those without recovered immunoparesis (PFS: 39.3 versus 15.1 months, p<0.001; OS: 82.4 versus 37.1 months, p<0.001; Supplementary Figure 1A, 1B). No difference was observed in PFS or OS between patients who exhibited recovered immunoparesis and those who had no immunoparesis at diagnosis (PFS: 39.3 versus 74.3 months, p = 0.591; OS: 82.4 months versus not reached, p = 0.439; Supplementary Figure 1C, 1D).
Status of immunoparesis during treatment
In total, seventeen patients had no immunoparesis at diagnosis. One (5.9%, 1/17) patient had immunoparesis with one uninvolved Ig suppressed, and two (11.8%, 2/17) patients did not exhibit preservation of at least two Igs after initial therapy.
This study analyzed changes in the immunoparesis status during treatment and the potential impact of these changes on outcomes in a dynamic pattern. Nearly half of the patients (46.5%) had severe and continuous immunoparesis (Group iii), while 51 (35.9%, Group i) and 25 (17.6%, Group ii) patients exhibited complete and partial normalization of uninvolved Igs, respectively.
This analysis revealed that several clinical features at diagnosis were not associated with the patients in the three groups (): age; sex, Ig subtypes, creatinine level, hemoglobin level, calcium level, and lactate dehydrogenase level, percentage of bone marrow plasma cells, cytogenetics, R-ISS stage, and ECOG score. However, there were significant differences according to M-protein levels (p = 0.036), ISS stage (p = 0.004) and immunoparesis at diagnosis (p<0.001) among the three groups. With a high level of M-protein, a high ISS or the suppression of at least two Igs at diagnosis, the probability of patients in Group iii increased significantly.
Table 2. Comparisons of characteristics among the three groups of nontransplant myeloma patients (n = 142) according to the immunoparesis status during treatment
There were no differences regarding the administration of induction regimens among the three groups. There was a significant association between patient response and immunoparesis status during treatment (p<0.001; ). The percentage of patients with at least a PR in Group iii was lower than that in Group i or ii (73.3% versus 96.1% or 96.0%, p = 0.001 and p = 0.020, respectively). Furthermore, the percentages of patients who achieved a sCR/CR were significantly different (54.9% versus 32.0% versus 21.2%, Group i, ii, and iii, respectively; p = 0.001). Patients who received continuous therapy until progression had a greater frequency of severe and continuous immunoparesis than those who received fixed-duration therapy (p = 0.011; ).
Survival analysis was carried out based on the patients’ immunoparesis at the time of therapy (). PFS was poor in patients in Group iii [14.0 (Group iii) versus 39.4 (Group i) or 26.1 (Group ii) months, p<0.001 and p = 0.001; A]. The median OS was poorer in patients in Group iii than in those in Group i or ii (36.0 months versus not reached or 47.6 months, p<0.001 and p = 0.020; B). PFS and OS were compared between Group iii and Group i+ii. The findings showed that the median PFS and OS in Group iii were inferior to those in Group i+ii (PFS: 14.0 versus 34.3 months, p<0.001; C; OS: 36.0 versus 82.4 months, p<0.001; D). Furthermore, among patients with a sCR/CR, those in Group iii appeared to have worse PFS than did those in Group i+ii (PFS: 24.7 versus 39.8 months, p = 0.002; E), although the median OS was not significantly different (F).
Figure 2. Survival curves of (A, C, E) PFS and (B, D, F) OS were plotted. The outcomes among the 3 groups according to immunoparesis status during treatment were compared. (A, B) Survival outcomes of the 3 groups. Survival outcomes between Group i+ii and Group iii in (C, D) all patients and in (E, F) sCR/CR patients. Group i-complete Ig normalization during treatment; Group ii-partial Ig normalization during treatment; Group iii-severe and continuous immunoparesis during treatment
Univariate and multivariate analysis of PFS and OS
The following potential prognostic parameters were identified in the univariate analysis by the Cox regression model for PFS: ISS stage III, calcium>2.65 mmol/L, immunoparesis at diagnosis, lactate dehydrogenase >246 U/L, ECOG score ≥2, and time-dependent covariates including ≥VGPR and immunoparesis (severe and continuous). A total of 127 patients were included in the PFS model, which revealed that severe and continuous immunoparesis during treatment was an independent factor for predicting PFS (). Moreover, 125 patients were included in the model for OS. The potential OS-related variables identified in the univariate analysis included age ≥75 years, Creatinine ≥177 μmol/L, ISS stage III, lactate dehydrogenase >246 U/L, immunoparesis at diagnosis, ECOG score ≥2, and time-dependent covariates including ≥VGPR and immunoparesis (severe and continuous) during treatment; the multivariate Cox model was subsequently fit. We found that severe and continuous immunoparesis during treatment was also independently correlated with OS ().
Table 3. Cox regression analysis of covariates for progression-free survival in nontransplant patients
Table 4. Cox regression analysis of covariates for overall survival in nontransplant patients
Discussion
The impact of the degree of immunoparesis on outcomes in 142 MM patients who were treated with novel drug-based therapy and did not undergo ASCT was analyzed in a retrospective study. The first observation was that immunoparesis (at least one uninvolved Ig suppressed) was commonly detected at diagnosis, nearly one-third of which recovered during treatment. The patients who exhibited recovered uninvolved Igs had a better prognosis than did those who did not, in agreement with previously published studies [Citation9]. Furthermore, the patients who recovered from immunoparesis had no differences in outcomes from those with a normal immune status at diagnosis. It can be speculated that the recovery of normal humoral immunity during treatment rebuilds tumor-specific immunity, playing a role in prolonging survival outcomes in MM patients.
Second, more than half of the 142 patients had completely or partially normalized Igs during treatment, but 46.5% of the patients still had severe and continuous immunoparesis (at least two Igs were suppressed continuously). Patients with a higher ISS stage, degree of immunoparesis and tumor burden at diagnosis had a greater probability of developing severe and continuous immunoparesis during treatment. Uninvolved Igs were suppressed before initial therapy in patients with a high ISS or high tumor burden at diagnosis [Citation7,Citation21] and might be associated with poor responses [Citation12]. Thus, we speculated that this is because patients with ISS stage III or a high tumor burden at diagnosis have poor responses, and the amount of residual tumor may suppress the secretion of normal plasma cells, resulting in long-term immunoparesis of the humoral immune environment. Our other result supporting this hypothesis is that patients with severe and continuous immunoparesis are usually those who achieve adverse responses. Similarly, Dávila J et al. mentioned [Citation9] that a lower probability of immunoparesis recovery was related to a higher ISS stage and a lower CR rate.
Several studies have reported the relationship between the degree of immunoparesis and patient prognosis. The suppression of at least two uninvolved Igs combined with deep immunoparesis was independently related to adverse outcomes in patients with newly diagnosed MM [Citation22]. Gao W et al. [Citation23] reported that survival was better in patients who exhibited complete and partial Ig recovery 1 year after ASCT than in those with at least two suppressed Igs. Jimenez-Zepeda VH et al. [Citation8] reported that complete or partial recovery of polyclonal Igs was a good predictor of prognosis in MM patients by 12 months post-ASCT. In non-ASCT-treated MM patients, a greater degree of immunoparesis during treatment, shorter PFS and OS. An independent poor prognostic value of severe and continuous immunoparesis was confirmed in our study, indicating that the degree of immunoparesis in not only ASCT-eligible patients, as previously reported, but also nontransplant patients during treatment is a follow-up indicator predicting survival outcome.
Notably, PFS and OS were prolonged in patients with immunoparesis who recovered in the ≥VGPR group after ASCT [Citation8]. Another study showed that immunoparesis recovery was not associated with PFS or OS in the sCR/CR cohort [Citation9,Citation15]. In our study, among patients with a sCR/CR, those who had severe and continuous immunoparesis during treatment appeared to have worse PFS but not worse OS. However, further studies are needed to investigate the association between long-term immunoparesis and outcomes in non-ASCT patients with good responses. It is hoped that risk stratification might be considered for patients with a sCR/CR through this simple indicator for immune surveillance.
Long-term use of corticosteroid and proteasome inhibitors have antimyeloma and immunosuppressive effects, delaying disease progression but deepening immunoparesis [Citation13]. Immunoparesis is highly likely to be recovered in MM patients receiving lenalidomide [Citation24], which has antitumour activity and immunomodulatory effects on the tumor microenvironment. These agents might affect immunoparesis recovery and normal humoral immunity, seeming to explain our observation that the frequency of severe and continuous immunoparesis was greater in patients receiving PI- or IMID-based continuous therapy than in those receiving fixed-duration therapy. Not consistent with our results, Dávila J et al. [Citation9] showed that immunoparesis was not associated with duration of the therapy, perhaps because their study included nearly half of the patients who received only conventional agents, which might have fewer immunosuppressive effects than novel drugs.
Immunoparesis due to a reduced amount of normal Igs is related to the incidence of infections. Uninvolved Igs or heavy/light chain pair suppression in patients with newly diagnosed MM could be used to predict the risk of early infection and death [Citation25,Citation26]. Severe and continuous immunoparesis contributes to a focus on the administration of anti-infection prophylaxis and treatment. Recent guidelines [Citation27] for MM management do not specify the optimal duration of maintenance therapy, which may be adjusted according to the results of minimal residual disease (MRD). A study indicated that immune reconstitution during maintenance therapy in ASCT patients combined with MRD monitoring supplies prognostic information [Citation28]. We suggest that the assessment of immune status during treatment might provide another prognostic metric for indefinite maintenance therapy in nontransplant patients. When patients with severe and continuous immunoparesis are MRD negative or achieve a CR during maintenance therapy, stopping therapy or receiving immune therapy to restore immune system homeostasis might contribute to preventing the excessive use of antitumor drugs and possible adverse effects of chemotherapies. Due to the deep response of patients receiving high-intensity tumor-targeted therapy, the prognostic significance of immune reconstitution might be limited in this scenario [Citation29]. However, the disadvantage of continuous therapy is that patients might be vulnerable to severe and continuous immunoparesis, resulting in humoral immunodeficiency and increased the risk of infection, which might be associated with adverse survival outcomes. Therefore, maintaining a balance between good responses and reduced immunoparesis during treatment is crucial in nontransplant patients. Moreover, the prognostic value of changes in immune status should be discussed in patients receiving daratumumab-based therapy or chimeric antigen receptor T-cell immunotherapy, which targets CD38 expressed on all plasma cells for additional prospective studies, preferably investigated in combination with other immune indicators, such as peripheral blood B lymphocytes or normal plasma cells of the bone marrow, for comprehensive analysis.
The limitation of this study is that it is a single-center retrospective study based on real-world data from China. The sample size was not sufficiently large, and a small portion of patient data were missing. These limitations might contribute to the difference in prognostic factors compared to those of other studies, especially in the subgroup analysis. This was a preliminary discovery and study, requiring additional complete records and larger population studies for verification.
In general, our study showed that outcomes for nontransplant MM patients were correlated with the degree of immunoparesis during therapy. Severe and continuous immunoparesis during treatment might be an independent poor prognostic factor for patients. This observation indicator is simple feasible and suitable for continuous surveillance. Rebuilding a good immune microenvironment during treatment to normalize Igs might be an important therapeutic strategy, especially for patients in complete remission or better.
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki (as was revised in 2013). The study was approved by the Ethics Committee of The Affiliated People's Hospital of Ningbo University. The requirement for informed consent was waived by the Ethics Committee due to the retrospective nature of the study.
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We are particularly grateful to all the people who have given us help with our article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data Availability statement
The relevant supporting data are available from the author upon request.
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