Воздействие даратумумаба на костное заболевание у пациентов с недавно диагностированным множественным миелом: многоцентральное ретроспективное исследование.

Background

Multiple myeloma (MM) is the second most common hematologic malignancy [ 1 ]. It is characterized by the proliferation of malignant plasma cells in the bone marrow, resulting in osteolytic lesions [ 2 ], known as myeloma bone disease (MBD). At diagnosis, up to 80% of newly diagnosed multiple myeloma (NDMM) patients already present with varying levels of bone destruction [ 3 ]. Bone destruction is not only linked to tumor burden, but also significantly increases the risk of skeletal-related events (SREs) [ 3 – 5 ]. SREs include pathologic fractures, requirement for radiotherapy or surgical intervention and spinal cord compression. Moreover, pathological fractures prominently elevate mortality risk in MM patients [ 6 ]. In brief, MBD has a profound impact on patients’ quality of life and prognosis, as well as incurring substantial healthcare costs [ 7 ]. Therefore, effective management of bone disease is vital for the MM.

The pathological mechanism of MBD is primarily attributed to the disruption of the balance between bone formation and bone resorption [ 3 ]. The International Myeloma Working Group (IMWG) recommends the use bone-targeting agents, such as denosumab and bisphosphonates, for MM patients [ 8 ]. Moreover, anti-myeloma regimens including proteasome inhibitors seem to exert a beneficial effect on bone metabolism [ 9 – 12 ]. For instance, bortezomib has been demonstrated to significantly reduce the risk of SREs [ 13 ]. However, 80% to 90% of MM patients still suffer from different levels of SRE during treatment [ 14 ], suggesting that current treatment regimens are insufficient for controlling MBD progression. Therefore, the investigation into agents that simultaneously exert anti-myeloma and bone health-promoting effects is of great importance.

Daratumumab (Dara) is a humanized IgG-κ monoclonal antibody that targets CD38 [ 15 ], with mechanisms that include direct anti-tumor effects [ 16 ] and immunomodulatory functions [ 17 , 18 ]. The unique immune-targeting properties of Dara introduce a novel therapeutic approach for MM. Multiple phase III clinical trials, including MAIA, CASSIOPEIA, and POLLUX, have demonstrated that Dara, whether used as monotherapy or in combination with standard chemotherapy regimens, shows excellent safety and efficacy in patients with relapsed/refractory multiple myeloma (RRMM) as well as NDMM [ 19 – 21 ]. As a result, the NCCN guidelines recommend Dara in combination with lenalidomide and dexamethasone (DRd) as a first-line treatment for MM [ 22 ]. Apart from its notable efficacy in MM, studies have also indicated that Dara is well-tolerated in patients with renal impairment [ 23 , 24 ]. In addition, the potential of Dara in improving MBD has also garnered widespread attention. Although both MM cells and osteoclasts (OCs) express the CD38 molecule, studies have shown that the impact of Dara on osteoclastogenesis is limited. Instead, it primarily enhances the efficacy of immunotherapy by restoring T cell function, thereby alleviating bone disease [ 25 ]. Additionally, a prospective clinical trial has revealed that Dara has certain anabolic bone activity [ 26 ]. Nevertheless, there is limited information on the effects of Dara-based treatment on myeloma-related bone disease in real-world settings. In this retrospective study, we aimed to assess the influence of first-line Dara-based therapy on the occurrence of SRE in NDMM patients.

Methods

Patients and study design

This study was approved by the Institutional Review Board of Guangzhou Hospital of Integrated Traditional and Western Medicine and was conducted in accordance with the Declaration of Helsinki. Clinical data of 164 newly diagnosed MM patients were collected from the Hematology Departments of Jinan University Affiliated First Hospital, Sun Yat-sen University Cancer Center, and Nanfang Hospital between December 2019 and December 2023. Inclusion criteria: (1) Diagnosis based on the 2014 International Myeloma Working Group (IMWG) criteria [ 27 ]. (2) No previous treatment for MM. (3) Patients underwent either whole-body 18 F-FDG PET-CT or a combination of separate computed tomography (CT) scans covering at least the skull, cervical spine, thoracic spine, lumbar spine, chest, abdomen, and pelvis before the first induction therapy. (4) Availability of imaging follow-up data at 6 months post-treatment, with the assessment method (PET-CT or CT) chosen based on clinical practice at each center. Exclusion criteria: (1) History of bone-related diseases not attributable to MM, such as osteoporosis or fractures due to trauma. (2) Presence of another cancer. (3) Receipt of < 3 cycles of chemotherapy, with a follow-up duration of less than 3 months. A detailed patient selection process is described in Fig. 1 . Based on first-line treatment strategies, the patients were divided into two groups: the Dara-based group and the control group. The Dara-based group received treatments predominantly comprising Dara + IMiD + PI + dexamethasone , whereas the control group was treated mainly with regimens such as PI + IMiD + dexamethasone ± other agents (Supplementary Table 1). Baseline characteristics, including gender, age, ECOG performance status, myeloma type, ISS stage, mSMART stratification, circulating plasma cells, are listed in Table 1 .

Observation indicators

The purpose of this study is to investigate the impact of using Dara-based regimens in the initial treatment of NDMM patients on the occurrence of bone-related adverse events. Types of SREs include spinal cord compression, pathological fractures, bone surgery, and bone radiotherapy [ 28 ]. Any SRE that occurs within 12 months before the patient’s initial diagnosis or within 60 days after the start of initial treatment is defined as a baseline SRE [ 29 – 31 ]. The time to first SRE in this study is defined as the number of days from the start date of initial treatment to the date of the first occurrence of any SRE within the first 6 months of treatment.

Statistical analysis

Statistical analysis was performed with R software (version 4.2.3). Depending on the distribution of the data, measurement variables were characterized by median (M) and interquartile range (IQR: P25, P75) or mean ± standard deviation. For continuous variables with non-normal distribution, the Mann-Whitney U test was applied to compare differences between the two groups. Count data were expressed as percentages, and binary variables were analyzed using the χ² test or Fisher’s exact test, as appropriate. The time to the first bone-related event in patients was depicted using Kaplan-Meier curves, and the curves were compared with the Log-rank test. Statistical significance was set at p < 0.05. A Cox proportional hazards model was used to estimate the hazard ratio (HR) and its 95% confidence interval (CI). Multivariable Cox proportional hazards regression analysis was performed to identify independent factors associated with the time to first skeletal-related event (SRE) and to adjust for potential confounding. In subgroup analysis, an adjusted P value after Bonferroni correction ( P < 0.05/N, N = Total number of comparisons within the subgroup) was considered statistically significant.

Results

Baseline characteristics of the patients

In this study, 164 patients diagnosed with MM were enrolled and divided into two groups: the Dara-Based group ( n = 51) and the control group ( n = 113), depending on whether Dara was administered as a first-line treatment (Fig. 1 ). The baseline characteristics of the two groups are detailed in Table 1 . No statistically significant differences were observed between the groups in terms of age, gender, myeloma subtype, risk stratification, ECOG score, or other disease-related clinical parameters ( P > 0.05).

Effect of Dara-Based treatment on SRE in MM

In this study, the occurrence of the First SRE was the key evaluation endpoint. 29 out of total 164 patients (17.68%) experienced SRE, including 5 (9.80%) and 24 (21.23%) in the Dara-Based and control groups, respectively.

Kaplan-Meier survival analysis was performed to compare the SRE-free probability between the two groups over a period of 180 days. Kaplan-Meier analysis showed no statistically significant difference in SRE-free probability between the Dara-based and control groups (Log-rank P = 0.08) (Fig. 2 A). Similarly, the univariable Cox regression indicated a hazard ratio of 0.44 (95% CI: 0.17–1.15; P = 0.09) for Dara-Based treatment. After adjustment for covariates including ISS stage, risk stratification, EMD, and anti-bone resorption drug use, the multivariable analysis yielded an adjusted hazard ratio of 0.47 (95% CI: 0.17–1.28; P = 0.14) (Table 2 ). Overall, our analysis indicated no significant reduction in the incidence of SRE with Dara-Based treatment compared to control.

Exploratory subgroup analyses

Given the low frequency yet insignificant reduction of SRE in Dara-based therapy in the overall population, we sought to explore whether specific patient subgroups might demonstrate a greater benefit of Dara-based regimens. Significant differences were found in the subgroup analysis. According to the results of Kaplan-Meier survival curves, there was a significant difference in the first SRE between the patients without hypercalcemia at baseline (Fig. 2 B, Log-rank P = 0.01). The difference in the first SRE between the two groups among those in the standard-risk subgroup was also suggestive (Fig. 2 C, Log-rank P = 0.04). However, no difference in the first SRE was identified in other subgroups, including those with/without anti-bone resorption agents (Supplementary Fig. 1, Supplementary Table 2). We further performed Cox regression analysis to validate their associations (Table 3 ). Negative association between the Dara-based group and the first SRE was found among patients without hypercalcemia at baseline (HR = 0.19, 95% CI: 0.05–0.81; P = 0.02). A significant interaction was also observed between Dara-based regimens and hypercalcemia ( P = 0.03). Taken together, our data suggest that Dara-based therapies may reduce the incidence of SRE in MM patients without hypercalcemia.

Discussion

Numerous studies have demonstrated the safety and efficacy of Dara in the treatment of multiple myeloma (MM). However, it remains unclear whether Dara can delay the occurrence of the first skeletal-related event (SRE) in patients with newly diagnosed MM. This retrospective study analyzed the clinical data of patients from three medical centers. Based on whether Dara was used as first-line therapy, patients were divided into a control group and a Dara-based group. The incidence of SREs within six months was compared between the two groups of NDMM patients. Although the incidence of the first SRE was lower in the Dara-based group than in the control group (9.80% vs. 21.23%) across the entire cohort, this difference did not reach statistical significance. However, in the subgroup of patients without baseline hypercalcemia, Dara-based treatment was significantly associated with a reduced risk of the first SRE (HR = 0.19, P = 0.02). These findings provide clinical evidence for the management of MM-related bone disease.

Previous studies have indicated that approximately 56% of NDMM patients present with one or more SREs at diagnosis, the occurrence of which not only affects the quality of life of patients and increases treatment costs but also significantly elevates the risk of mortality in MM patients [ 32 , 33 ]. Therefore, effective prevention of SREs is crucial for improving the overall prognosis of MM patients. Multiple studies have previously confirmed the significant benefits of Dara in improving patient prognosis and renal function [ 24 ]. However, our findings suggest that, in the short-term treatment period (< 6 months), no difference was observed in the first occurrence of SRE between NDMM patients receiving Dara-based and those not (HR = 0.47, 95% CI: 0.17–1.28; P = 0.14). This outcome appears inconsistent with the potential bone-protective effects of Dara suggested by earlier mechanistic studies. One study proposed that Dara may indirectly improve bone disease by targeting CD38, modulating osteoclast function, and enhancing T-cell immune responses [ 25 ]. Additionally, Terpos et al. reported that in patients treated with Dara for ≥ 6 months, bone formation inhibitors such as DKK1 were significantly reduced, suggesting that Dara may help restore bone homeostasis and promote osteogenesis [ 26 ]. The failure to detect the effect of Dara-Based regimens in our study could be attributed to the limited sample size (insufficient statistical power, approximately 29.4%) and the relatively short 6-month follow-up period, which prevents us from fully assessing the benefits of Dara on bone improvement.

We further evaluated the potential value of Dara in controlling SREs through subgroup analysis and found that it provides significant benefits in patients without baseline hypercalcemia. Dara-based treatment significantly reduced the risk of the first SRE. Our results suggest that hypercalcemia may be an important predictive factor influencing the efficacy of Dara-based regimens. This finding, although derived from a subgroup analysis, resonates with the overarching survival benefits consistently demonstrated in the pivotal ALCYONE and MAIA trials [ 19 , 34 ]. Although SREs were not the primary endpoint in those studies, the efficient disease control achieved with daratumumab-based regimens, leading to significantly improved progression-free and overall survival, is the most likely reason why the bone complications are ultimately reduced. Our analysis extends this understanding by proposing that patients without hypercalcemia might benefit from the bone-protective effects of Dara-based regimes earlier in the treatment course. Hypercalcemia, a severe metabolic complication of MM, often reflects target organ damage and is primarily associated with osteolytic lesions [ 35 , 36 ]. Malignant plasma cells secrete cytokines (such as RANKL, MIP-1α, and DKK1), either directly or indirectly, activate osteoclasts and enhance their bone-resorptive function, leading to the release of large amounts of calcium from the bone matrix into the bloodstream. Simultaneously, impaired renal function reduces calcium excretion, further exacerbating hypercalcemia [ 37 ]. In our study, Dara demonstrated significant protective effects in patients without hypercalcemia. This may be related to its multifaceted regulation of the bone marrow microenvironment and inhibition of tumor-associated bone destruction [ 38 , 39 ]. Moreover, in patients without severe metabolic disorders (such as hypercalcemia), the bone microenvironment may be more amenable to modulation, making Dara’s bone-protective effects more pronounced [ 36 ]. Furthermore, the observed reduction in SRE risk may primarily be attributed to the potent anti-myeloma effects of daratumumab and chemotherapy agents, leading to better overall disease control, rather than its specific, direct bone-protective action. However, the significant interaction between daratumumab use and the absence of hypercalcemia suggests that the baseline skeletal microenvironment may modulate the drug’s benefits. Exploring the individual contributions of direct bone effects versus indirect effects via tumor control warrants further investigation.

This study has several limitations. First, its retrospective nature introduces potential selection and information biases, which may affect the interpretation of the results. Second, the sample size analyzed was small because of the high cost, short market entry time in China, and limited early clinical adoption of Dara. Also, the imaging requirements for MM patients in the study further reduced sample size. Consequently, the small sample size resulted in low statistical power (post-hoc power = 29.4%). This low power increases the risk of type II error, implying that our study may have been underpowered to detect the effects of Dara, and all non-significant findings should be interpreted with caution as inconclusive rather than no effect. Third, the absence of serial biochemical bone turnover markers (e.g., CTX, PINP) restricted a more dynamic assessment of bone metabolic activity. Fourth, standardized hematologic response and response depth assessments were not uniformly available at the 6-month timepoint for all patients due to the retrospective nature of study design, which prevented us from controlling for this potential confounder. Therefore, the observed reduction in SRE risk in the Dara group may stem either from Daratumumab’s superior systemic antitumor efficacy, or its unique direct immunomodulatory effects on the bone microenvironment, or the synergistic action of both. Future prospective studies are warranted to delineate these underlying mechanisms. Fifth, the relatively short follow-up duration of 6 months may be insufficient to evaluate the long-term durability of the treatment effects and the incidence of late-onset complications. Due to high cost and concern regarding accumulating irradiation injury, most patients in clinical practice are unwilling to go for long-term and regular radiological follow-up. Thereby compromising the thoroughness of long-term efficacy assessments. Finally, the lack of centralized imaging review may have introduced variability in evaluation. It should also be noted that heterogeneity in imaging techniques (PET-CT vs. comprehensive CT) could be a potential source of bias in assessing osteolytic burden. However, as our primary outcome was the occurrence of clinical SREs rather than radiographic progression, this particular limitation is likely mitigated. Moreover, this investigation did not delve into a comparative analysis of the efficacies of various treatment modalities and their combinations. Therefore, future prospective multicenter studies with larger sample sizes, longer follow-up, integrated biomarker profiles, and centralized imaging review are necessary to better elucidate the role of Dara-based regime in bone protection.

Conclusions

In conclusion, while Dara-based treatment did not yield a statistically significant reduction in the risk of SREs across the entire cohort, exploratory subgroup analyses revealed a beneficial effect in specific patient populations. Particularly, daratumumab was associated with a significantly lower incidence of first SRE in patients without baseline hypercalcemia. These findings suggest that Dara may offer a bone protective effect in well-defined subgroups, providing a novel direction for its potential application in the prevention of MBD.

Supplementary Information

Supplementary Material 1.

Acknowledgements

This study is supported by the National Natural Science Foundation of China (No. 82270167 and 82470155) and the Talents Program from the Guangdong Provincial People’s Hospital to H.Z.

Abbreviations

Multiple myeloma

Daratumumab

Myeloma bone disease

Skeletal-related events

Computed tomography

Positron emission tomography/computed tomography

International Myeloma Working Group

Mayo Stratification of Myeloma And Risk-adapted Therapy

Durie-Salmon staging

International Staging System staging

Revised ISS staging

Eastern Cooperative Oncology Group

Fluorescence in situ hybridization

Extramedullary disease

Circulating plasma cells

Confidence interval

Hazard ratio

Authors’ contributions

H. Z. and J. D. designed the project; X. L., H. W., Y. L., J. Z., N. Y., X. W., X. C., Z. X. collected the data and assisted the data analysis; X. L., H. W., J. D. analyzed the data; X. L., H. W., wrote the manuscript. X. L., Y. L., J. D. and H. Z. revised the manuscript. All authors have read and H. Z. approved the final submitted manuscript.

Data availability

The datasets used or analyzed in the current study are available from the corresponding authors upon reasonable request.

Declarations

Ethics approval and consent to participate

This multicenter retrospective study was approved by the Institutional Review Board of Guangzhou Hospital of Integrated Traditional and Western Medicine (IRB-GHITWM), which served as the central ethics committee for all other involved hospitals (IRB#: GZTCWM2025153). The requirement for written informed consent was waived by IRB-GHITWM. The International Conference on Harmonization’s Good Clinical Practice standards and the 1964 Helsinki Declaration and its later revisions served as the foundation for the study’s methodology.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xinrong Li, Hua Wang and Yizhen Li contributed equally to this work.

Contributor Information

Juan Du, Email: du.juan@u.nus.edu.

Hui Zeng, Email: zenghui@gdph.org.cn.

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Associated Data

Supplementary Materials

Supplementary Material 1.

Data Availability Statement

The datasets used or analyzed in the current study are available from the corresponding authors upon reasonable request.