Prognostic value of the “dynamic” second revision of the international staging system (R2- ISS) in patients with multiple myeloma undergoing anti-CD38 antibody, carfilzomib, and dexamethasone therapy

doi:10.21203/rs.3.rs-4113413/v1

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Prognostic value of the “dynamic” second revision of the international staging system (R2- ISS) in patients with multiple myeloma undergoing anti-CD38 antibody, carfilzomib, and dexamethasone therapy

https://doi.org/10.21203/rs.3.rs-4113413/v1

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Recently, the second revision of the International Staging System (R2-ISS) has emerged as a prognostic tool for multiple myeloma (MM) and is known to be useful for prognostication at the time of diagnosis. Treatment outcomes for MM have significantly improved with the introduction of novel agents; however, eventual relapses nevertheless occur frequently, leading to refractory disease. Clonal evolution during relapse often results in high-risk cytogenetic abnormalities (HRCAs). Hence, a patient’s disease risk may change during their treatment course. We retrospectively analyzed whether R2-ISS influenced prognosis at treatment initiation in patients receiving anti-CD38 antibody, carfilzomib, and dexamethasone (Kd) treatments. HRCAs were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at treatment initiation and defined as dynamic R2-ISS. Data from 60 patients who underwent the defined treatments were analyzed. The median observation period was 13.0 months, with a median progression-free survival (PFS) of 20.7 months. Median overall survival (OS) was not reached. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS (P = 0.00011 and 0.023, respectively). The median PFS for patients with dynamic R2-ISS IV was 4.4 months, and the median OS was 14.6 months, indicating extremely poor outcomes. Multivariate analysis considering disease progression at treatment initiation, triple-class refractory status, and dynamic R2-ISS showed that only R2-ISS significantly affected both PFS and OS (P = 0.0041 and 0.019, respectively). Dynamic R2-ISS therefore shows potential as a prognostic tool in patients with MM who are treated via anti-CD38 antibody + Kd therapy.

R2-ISS

anti-CD38 antibody

carfilzomib

dexamethasone

multiple myeloma

high-risk cytogenetic abnormalities

The treatment outcomes for multiple myeloma (MM) have drastically improved with the use of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs (IMIDs), and monoclonal antibodies [1, 2]. Nevertheless, MM often ultimately relapses, leading to a refractory disease. In recent years, the second revision of the International Staging System (R2-ISS) has emerged as a useful prognostic tool for both newly diagnosed and untreated patients with MM and those undergoing autologous stem cell transplantation [3–5]. However, these prognostic tools are determined by factors such as beta-2 microglobulin (β2MG), albumin (Alb), lactate dehydrogenase (LDH), and the presence of high-risk chromosomal abnormalities (HRCAs) at the time of diagnosis. Even if these factors change during treatment, the R2-ISS score remains the same. Clonal evolution occurs during the treatment of MM, which can lead to the acquisition of various chromosomal abnormalities. Therefore, the risk determined at the time of diagnosis may change over the course of treatment [6–8].

In fact, it has been suggested that patients who achieve minimal residual disease (MRD) negativity after treatment have favorable prognoses, even in cases where they have adverse prognostic factors such as HRCAs—indicating the possibility of overcoming such negative indicators [9–12]. This suggests that the accurate evaluation of patient prognoses is challenging using prognostic tools based solely on diagnosis.

In this study, we retrospectively evaluated whether a recalculated R2-ISS (dubbed “dynamic R2-ISS”) at the initiation of treatment could better predict the prognoses of patients treated with an anti-CD38 antibody + carfilzomib + dexamethasone (anti-CD38 ab-Kd).

This retrospective, non-interventional cohort study included data from the electronic medical records of patients with MM who visited the Japanese Red Cross Medical Center (JRCMC). Patients previously treated with anti-CD38 ab-Kd for the first time were included in this study. The study was approved by the JRCMC Institutional Review Board, and was conducted under an informed consent procedure and an opt-out consent principle. None of the participants requested to be excluded from the study.

The recalculated R2-ISS was defined as “dynamic R2-ISS” and was based on β2MG, Alb, LDH at the initiation of anti-CD38 ab-Kd treatment, as well as the presence or absence of HRCAs and 1q abnormalities diagnosed any time between initial diagnosis to treatment initiation. HRCAs and 1q abnormalities were examined from diagnosis to treatment initiation and considered positive if detected once.

The responses were evaluated according to the International Myeloma Working Group (IMWG) response criteria [13]. The HRCAs evaluated included del (17p), t(4;14), and t(14;16). Triple-class refractory disease was defined as a disease refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMIDs), or anti-CD38 monoclonal antibodies. The overall response rate was defined as a partial response or better, according to the IMWG response criteria, evaluated based on the best response after the initiation of anti-CD38 ab-Kd treatment. Fisher’s exact test was used for intergroup comparisons of categorical variables. Overall survival (OS) was defined as the interval between the first day of anti-CD38 ab-Kd treatment and the day of death from any cause, or the last follow-up. Progression-free survival (PFS) was defined as the interval between the first day of anti-CD38 ab-Kd treatment and the day of disease progression, death from any cause, or the last follow-up. Data were censored for patients who were alive or had no disease progression at the last follow-up. The last follow-up date was set at February 28, 2024. Survival rates were calculated using the Kaplan–Meier method. To evaluate the association of PFS and OS with the factors of interest, univariate and multivariate Cox proportional hazards regression analyses were used to determine the hazard ratios (HRs) and associated 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. EZR software (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html) was used to perform all statistical analyses [14].

We extracted data from 60 patients who received their first cycle of anti-CD38 ab-Kd at JRCMC between April 2021 and December 2023. Their characteristics are presented in Table 1. The median age was 61 years (range, 39–78 years), and 25 of the patients (41.7%) were female. The patients had received a median of one prior treatment line (range, 1–9), and 16 had triple-class refractory disease at the time of anti-CD38 ab-Kd initiation. Thirty-four of the patients showed progressive disease at the time of anti-CD38 ab-Kd treatment initiation. Owing to a lack of routine testing for 1q abnormalities, R2-ISS could only be calculated at the time of diagnosis for 34 of the patients. It was calculated at the initiation of treatment in 53 of the patients. At the initial diagnosis, 2 of the patients were in R2-ISS stage I, 2 in stage II, 20 in stage III, and none in stage IV. At the initiation of anti-CD38 ab-Kd treatment, 10 patients were in stage I, 11 in stage II, 23 in stage III, and 9 in stage IV. At initial diagnosis, del17p was present in 21.7% and 1q abnormalities were present in 31.7% of the patients. These percentages increased to 30% and 63.3%, respectively, at the initiation of anti-CD38 ab-Kd treatment. In 10 of the patients, anti-CD38 ab-Kd was changed without disease progression, owing to adverse events or patient preferences. Nine patients underwent autologous stem cell transplantation (ASCT) after anti-CD38 ab-Kd treatment, five of whom resumed anti-CD38 ab-Kd treatment after ASCT. One patient underwent further allogeneic stem cell transplantation after ASCT.

The overall response (ORR), stringent complete response, complete response, and very good partial response (VGPR) rates were 80.0% (48 patients), 43.3% (26 patients), 5.0% (3 patients), and 18.3% (11 patients), respectively.

The median follow-up period was 13.0 months (range, 2.3–34.8 months). The median PFS and OS were 20.7 months (95% CI, 7.6 months–not reached [NR]) and NR (95% CI, NR–NR), respectively (Fig. S1). The results of univariate analyses of PFS and OS are shown in Table 2. The dynamic R2-ISS significantly stratified both PFS and OS (P = 0.00011, 0.023, respectively; Fig. 1A,B). In particular, patients with dynamic R2-ISS IV had extremely poor PFS and OS, at 4.4 months and 14.6 months, respectively. Anti-CD38 antibody resistance, triple-class refractory disease, and 1q abnormalities significantly affected PFS and OS (Table 2, Fig. S2A–D). Progressive disease was significantly associated with longer PFS, but not OS (Table 2, Fig. S2E,F). Multivariate analysis considering disease progression at treatment initiation, triple-class refractory status, and dynamic R2-ISS showed that only R2-ISS significantly affected both PFS and OS (P = 0.0041 and 0.019, respectively; Table 3). Of the 32 patients who had R2-ISS scores available at both diagnosis and anti-CD38 ab-Kd treatment initiation, R2-ISS scores increased from diagnosis to treatment initiation in 4 cases, remained unchanged in 15, and decreased in 13 (Fig. 2). The median PFS and OS in the worsening group tended to be significantly shorter, at 3.6 months (95% CI, 1.6 months-NR) and 14.5 months (95% CI, 11.7 months-NR), respectively (P = 0.0041 and 0.10, respectively; Fig. 3A,B).

This study showed that R2-ISS calculated at the time of treatment initiation can be used as a prognostic factor for PFS and OS in patients with MM who are treated with anti-CD38 ab-Kd. Patients who become MRD-negative during the course of treatment have been reported to have good prognoses [9, 10, 15]. Additionally, several reports have indicated that prognoses are poor for patients who become MRD-positive or relapse early [10, 15, 16]. However, these prognostic predictions reflect treatment outcomes and differ from those before the initiation of treatment. Elevated LDH levels have been associated with poor prognosis [17, 18] and suggested to reflect tumor burden and disease activity. In patients undergoing ASCT, favorable outcomes have been demonstrated in those who achieve complete response with induction therapy prior to ASCT initiation [19]. However, prognostic tools for predicting outcomes at the time of treatment change are limited. In an era of diverse treatment modalities, the ability to predict prognoses at the time of treatment change may facilitate more appropriate treatment choices. The prognoses for patients with triple-class refractory MM is extremely poor [20, 21]. However, notably, in our study, the dynamic R2-ISS at the initiation of anti-CD38 ab-Kd treatment demonstrated a significant impact on prognosis in multivariate analysis, including triple-class refractory status. In R2-ISS, 1q abnormalities and del17p carry weights of 0.5 and 1 point, respectively [3]. In our cohort, an increase in these genetic abnormalities was observed at the initiation of anti-CD38 ab-Kd treatment compared with the case at initial diagnosis. This suggests that clonal evolution occurs with disease progression, contributing to the higher dynamic R2-ISS observed in this study. The ISS and the Revised-ISS have been reported to be useful for risk classification, even in cases of relapse[22]. However, whether R2-ISS can be used as a prognostic classification other than at the time of diagnosis has not yet been reported. To the best of our knowledge, our study is the first to suggest the potential utility of the R2-ISS as a dynamic prognostic model.

This study has several key limitations worth noting. First, this was a retrospective study with a small number of cases performed at a single institution, which therefore warrants further evaluation in a larger cohort. Second, owing to the limited number of patients with measured 1q abnormalities at diagnosis, the number of patients for whom R2-ISS at diagnosis could be evaluated was also limited. Consequently, prognostic predictions based on the R2-ISS at diagnosis could not be made accurately. Third, this study analyzed patients with and without disease progression who underwent anti-CD38 ab-Kd treatment. As anticipated, the treatment outcomes tended to decrease in the group with disease progression. Nevertheless, the significant impact of dynamic R2-ISS on treatment outcomes in our multivariate analysis, which included these factors, is a meaningful finding.

This study demonstrated the potential clinical utility of R2-ISS as a dynamic prognostic model not only for the diagnosis, but also for predicting the prognoses, of patients with MM who undergo anti-CD38 ab-Kd treatment. Further larger-scale investigations are warranted to confirm whether these results can be extrapolated to other treatment approaches. Recognizing that risks may change with treatment, risk assessments and treatment choices may improve the outcomes of patients with MM.

Statements and Declarations

Funding: The authors have received no particular funding for this study.

Conflicts of interest: TK received personal fees from Janssen, Takeda, and Sanofi. NT received personal fees from Janssen and Sanofi. TI received honoraria from Ono, Takeda, Celgene/Bristol-Myers Squibb, and Janssen. KS received honoraria from Takeda, Celgene, Ono, Amgen, Novartis, Sanofi, BMS, AbbVie, and Janssen; consultancy fees from Takeda, Amgen, Janssen, and Celgene; and research funding from BMS, Celgene, and Amgen. The authors declare no competing financial interests related to this study.

Ethics statement: This study was approved by the JRCMC Institutional Review Board and was conducted under an abbreviated informed consent procedure and an opt-out consent principle. None of the participants requested to be excluded from the study.

Author contributions: TK treated the patients, collected and analyzed the data, and wrote the manuscript. NT treated the patients and provided important guidance. CM and OH provided the data. KK, MNY, YO, KS, TT, MO, YA, and KS treated the patients. TI provided important guidance. All the authors critically reviewed and approved the final version of the manuscript.

Data availability: The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Tables 1-3 is available in the Supplementary Files section.

Competing interest reported. TK received personal fees from Janssen, Takeda, and Sanofi. NT received personal fees from Janssen and Sanofi. TI received honoraria from Ono, Takeda, Celgene/Bristol-Myers Squibb, and Janssen. KS received honoraria from Takeda, Celgene, Ono, Amgen, Novartis, Sanofi, BMS, AbbVie, and Janssen; consultancy fees from Takeda, Amgen, Janssen, and Celgene; and research funding from BMS, Celgene, and Amgen. The authors declare no competing financial interests related to this study.

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Prognostic value of the “dynamic” second revision of the international staging system (R2- ISS) in patients with multiple myeloma undergoing anti-CD38 antibody, carfilzomib, and dexamethasone therapy

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Abstract

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Introduction

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Conclusion

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References

Tables

Additional Declarations

Supplementary Files

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