Факторы, влияющие на прогноз у пациентов с внебольничной миеломой: опыт работы в одном центре.

1. Introduction

Multiple myeloma is a malignancy caused by the uncontrolled proliferation of monoclonal plasma cells. After Non-Hodgkin lymphomas, it is the second most common hematological malignancy. Myeloproliferative neoplasms and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are other frequently observed malignancies [ 1 ]. Extramedullary involvement of myeloma has been reported in 15–20% of newly diagnosed patients [ 2 ]. Extramedullary disease (EMD) in multiple myeloma is primarily categorized according to its association with osseous structures, temporal origin, and tissue engagement [ 3 ]. In our study, we classified extramedullary multiple myeloma based on its relationship with bone.

Extramedullary myeloma-bone (EM-B) refers to bone-only disease, while extramedullary myeloma-soft tissue (EM-S) indicates soft tissue myeloma, which would be located in the gastrointestinal tract, lungs, or upper aerodigestive system [ 3 ]. Extramedullary dissemination of the disease is now diagnosed in the earlier course of myeloma, mainly due to advanced imaging studies [ 4 ]. From a clinicopathological perspective, EM-B and EM-S can exhibit differences across a range of parameters, such as site of involvement, tumor burden, laboratory findings, hematologic-cytogenetic findings, and response to treatment. Mostly, individuals with EM-S exhibit a more severe disease manifestation, increased tumor load, and poorer survival rates relative to those with EM-B in multiple myeloma [ 5 ].

Strong evidence for EM prognosis, treatment, and correlation with other disease features and prognostic indices is quite limited. In general, studies have shown that patients with extramedullary multiple myeloma experience sub-optimal response rates and have a dismal prognosis [ 5 ]. Due to the limited number of studies conducted, there is no established standard treatment for patients with extramedullary myeloma, unlike solitary plasmacytoma. The relationship between CD56 expression and extramedullary involvement is not clear, while studies have yielded inconsistent results [ 6 , 7 ]. Furthermore, the revised version of the International Staging System (R-ISS) has limited sensitivity in extramedullary myeloma [ 8 ].

In this study, we aimed to examine the prognosis, surface markers, and their relationship with laboratory values, genetic risk factors, and clinical course of a total of 281 patients diagnosed with multiple myeloma, 147 of whom had extramedullary myeloma.

2. Materials and Methods

This single-center, retrospective, and non-randomized observational study was conducted with the approval of the Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital Ethics Committee (Approval No: 2023-04/41) and adhered to the principles outlined in the Declaration of Helsinki.

2.1. Study Design and Patients

A total of 281 newly diagnosed multiple myeloma patients followed at our center between 2011 and 2023 were screened. International Myeloma Working Group (IMWG) multiple myeloma diagnostic criteria were used for the myeloma diagnosis [ 9 ]. All patients aged 18 and older were included. Patients with incomplete clinical records or concurrent hematologic malignancies were excluded.

Demographic data, blood type, complete blood counts and biochemistry panel at diagnosis, Eastern Clinical Oncology Group (ECOG) performance score, heavy and light chain subtypes, ISS and R-ISS stages, EM disease status, and comorbidities were recorded.

Patients were treated with first-line bortezomib/cyclophosphamide/dexamethasone (VCD), bortezomib/dexamethasone (VD), or bortezomib/adriamycin/dexamethasone (VAD) due to national reimbursement requirements and the standard operating procedure of our clinic. Autologous hematopoietic stem cell transplant (ASCT) was also standard for eligible patients.

Routine immunophenotyping of bone marrow samples was performed using flow cytometry (Becton Dickinson FACS Lyric, Franklin Lakes, NJ, USA) in the Immunology Laboratory of Ankara Oncology Hospital. Samples were prepared and incubated with fluorescently labeled monoclonal antibodies per the manufacturer’s guidelines. Flow cytometry analyses were conducted using BD FACSuite software (version 1.5) and verified by pathologists and specialists. CD56 positivity was defined as expression in at least 20% of plasma cells. Clonal plasma cells were identified based on their characteristic CD38/CD138 expression pattern and light chain restriction.

2.2. Definitions

EM-B and EM-S are distinct patterns of EM involvement: EM-B is classically defined as myeloma with bone plasmacytomas, whereas EM-S is composed of soft-tissue-dwelling plasmacytomas and medullary disease [ 3 ]. New diagnoses were made based on IMWG criteria. IMWG criteria were used for response assessment ( Table 1 and Table 2 ) [ 10 ]. The Eastern Cooperative Oncology Group (ECOG) performance status is a standardized scale used to assess a patient’s functional status and ability to perform daily activities, ranging from 0 (fully active) to 4 (completely disabled) [ 11 ]. Progression-free survival (PFS) was estimated as the time between the first treatment and relapse, death, or last contact. Overall survival (OS) was defined as the time between the first treatment and death or last contact.

2.3. Endpoints

The primary endpoint of the study was OS. Secondary endpoints were selected as; PFS, CD56 positivity in EM.

2.4. Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics version 29 (Armonk, NY, USA). Statistical significance was set at p < 0.05. Patient characteristics were summarized as medians (min–max), means and standard deviations for continuous variables, and frequencies (%) for categorical variables. Univariate and multivariate logistic regression models were applied to identify factors influencing treatment response. Results are presented as odds ratios (OR) with 95% confidence intervals (CI). Kaplan–Meier survival curves were generated to evaluate progression-free survival (PFS) and overall survival (OS). Log-rank tests were used to compare survival distributions. Cox proportional hazards regression models were utilized to identify independent predictors of survival. Results are reported as hazard ratios (HR) with 95% CI.

3. Results

A total of 281 multiple myeloma patients were included in the study. The median age of the patients was 60 years, and the median follow-up period was 35.4 months. Demographic and clinical characteristics of the patients are summarized in Table 3 and Table 4 .

The median overall survival (OS) could not be reached during the study period ( Table 5 ).

Advanced ECOG performance score was associated with worse prognosis ( Figure 1 ) ( p < 0.001). Similarly, patients with higher ISS score had significantly worse prognosis ( Figure 2 ) ( p = 0.041).

OS was significantly lower in patients with extramedullary involvement ( Figure 3 ) ( p : 0.049).

When patient PFS was evaluated, the median PFS (months) could not be reached ( Table 6 ). The median PFS (months) was not found to be statistically significant according to the variables ( Figure 4 , Figure 5 and Figure 6 ) ( p > 0.05).

As shown in Table 5 , ECOG, ISS stage, and extramedullary involvement variables were found to be significant in univariate analyses. Variables found to be significant in univariate analyses were included in the multivariate Cox regression model ( Table 7 ). According to the model results, having an ECOG of 2 or higher increased the risk of death 3.78 times (HR: 3.78, 95% CI: 1.54–9.28, p = 0.004), having ISS Stage-3 increased the risk 2.93 times (HR: 2.93, 95% CI: 1.30–6.62, p = 0.010), and having extramedullary involvement increased the risk 2.46 times (HR: 2.46, 95% CI: 1.17–5.17, p = 0.017).

The relationship between CD56 expression and extramedullary involvement was investigated, and no statistically significant results were obtained ( Table 8 ). ( p = 0.281).

4. Discussion

Our study showed (i) lower OS but similar PFS between EM and non-EM, (ii) no significant association of flow cytometric CD56 expression between EM and non-EM.

Studies in the literature have shown that patients with extramedullary involvement at the time of diagnosis or after recurrence have a worse prognosis [ 5 , 12 ]. A retrospective study by Çiftçiler et al. demonstrated that the 5-year OS rate was significantly lower in patients presenting with either EM-B or EM-S compared to those without any plasmacytoma presentation [ 5 ]. This inferior prognostic impact is further justified by a large-scale, multi-institutional study conducted by Beksac et al., which evaluated 226 myeloma patients across the Balkan Myeloma Study Group and Barcelona University. They reported that, even within the era of novel therapies, true extramedullary organ/tissue plasmacytomas carry a highly aggressive clinical course. In their cohort, patients with EM-S at initial diagnosis achieved a median OS of only 46.5 months, whereas the median OS for the paraosseous EM-B group was not reached [ 12 ]. In our study, consistent with the literature, patients with extramedullary involvement had a lower overall survival rate and a significantly higher risk of death. No significant difference was found in PFS among the three groups: EM-B, EM-S, and those without plasmacytoma.

Unsurprisingly, in our study, ISS stage and elevated ECOG were associated with a worse prognosis.

There are studies that hypothesize that CD56 expression, which ensures the fixation of plasma cells to the stromal structure, may lead to more frequent extramedullary involvement and have prognostic significance when deficient. In our study, similar to the studies by Ceran et al., no association was found between CD56 expression and extramedullary involvement [ 13 ]. Studies in the literature suggest that CD56 negativity is more frequently associated with extramedullary involvement [ 14 ]. In our study, we did not find an association between CD56 expression and prognosis.

The importance of surface markers in targeted therapies is increasing day by day. Identifying such a specific target in patients with extramedullary myeloma could offer great hope for treatment. Further research in this direction could be significant in terms of making progress in treatment. At least in our study, we concluded that CD56 is not currently such a target.

The lack of a close association between R-ISS and extramedullary myeloma may indicate that factors other than chromosomal abnormalities play a role in extramedullary involvement.

One of the limitations of our study is that not all patients received the same treatment. The efficacy of novel agents such as lenalidomide, selinexor, pomalidomide, and elranatamab could not be evaluated in our study, which constitutes another limitation. The number of studies investigating the efficacy of novel treatment modalities on extramedullary myeloma is quite limited and contradictory [ 15 , 16 ]. In the new era of myeloma, more studies with longer follow-up periods and larger patient numbers are needed to investigate the efficacy of many novel agents that can be added to treatment for extramedullary myeloma.

5. Conclusions

This study shows that the prognosis is worse in patients with extramedullary myeloma even after autologous stem cell transplantation. Higher tumor burden, genetic mutation differences, and inherently aggressive clones independent of the bone marrow may be associated with a poor prognosis. Further studies involving more patients and multiple centers to determine the association between different surface markers and genetic mutations and extramedullary myeloma appear to be crucial for elucidating the pathogenesis and offering hope for treatment.

Acknowledgments

The authors thank all members of the study team, as well as the patients and their families, for their valuable contributions to this research.

Author Contributions

Conceptualization, E.B., M.E.D., B.A.C., D.İ., B.U.U. and M.S.D.; methodology, S.Y., B.B., D.İ. and F.A.; software, G.B.; validation, M.E.D.; formal analysis, U.H.; investigation, S.Y., U.H. and M.S.D.; resources, S.Y., M.E.D., U.H. and B.B.; data curation, E.B., G.B., M.E.D. and U.H.; writing—original draft preparation, E.B. and B.B.; writing—review and editing, E.B., B.B., T.N.Y. and F.A.; supervision, B.A.C., B.U.U., T.N.Y. and F.A.; project administration, G.B., B.A.C., B.U.U. and T.N.Y. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital Ethics Committee (Approval No: 2023-04/41; date of approval: 27 April 2023) for studies involving humans.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

For original data, please contact the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research received no external funding.

Footnotes

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Associated Data

Data Availability Statement

For original data, please contact the corresponding author.