Воздействие сердечного амилоида на пациентов с множественной миеломой: систематический обзор и метаанализ.

Introduction

Multiple myeloma (MM) is a plasma-cell dyscrasia characterized by the presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth leading to destructive bone lesions, kidney injury, anemia, and hypercalcemia. The abnormal plasma cells produce excessive amounts of light chains, which misfold and aggregate into insoluble fibrils that deposit in various tissues, leading to organ dysfunction and ultimately resulting in the development of immunoglobulin light chain (AL) amyloidosis [ 1 , 2 ]. Previous studies have suggested that up to 38% of MM patients may have subclinical AL amyloidosis, and 10–15% of patients may develop clinically overt AL during the course of the disease [ 3 – 7 ]. MM-associated AL is considered an independent prognostic factor for worse outcomes in MM patients, even in the absence of symptoms at diagnosis [ 4 ]. Cardiac involvement is common in AL amyloidosis, occurring in approximately two-thirds of patients [ 8 ]. It results from the deposition of amyloid fibrils in the extracellular space, leading to myocardial stiffening without compensatory dilation, which in turn causes restrictive cardiomyopathy and ultimately progresses to heart failure [ 9 ]. Cardiac involvement in systemic amyloidosis is commonly considered the most critical factor influencing survival, representing the primary cause of death. In light chain amyloidosis, median survival after diagnosis ranges from less than 6 months to 5 years [ 10 ]. However, only a limited number of studies have explored the prognostic impact of cardiac involvement in patients with MM. We therefore conducted a systematic review and meta-analysis to compare the prognosis of MM patients with and without concomitant cardiac AL amyloidosis.

Methods

This systematic review and meta-analysis was performed and reported in accordance with the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement guidelines [ 11 , 12 ].

Studies included in this meta-analysis met all of the following eligibility criteria: (1) prospective or retrospective observational studies; (2) enrollment of adult patients with a confirmed diagnosis of MM according to internationally recognized criteria (e.g., IMWG); (3) inclusion of patients with and without concomitant cardiac AL amyloidosis; (4) direct comparison of clinical outcomes between MM patients with cardiac AL amyloidosis and those without cardiac involvement; and (5) a minimum follow-up duration of 12 months for mortality.

The following exclusion criteria were applied: (1) absence of a direct comparison between MM patients with and without cardiac AL amyloidosis; (2) lack of a confirmed diagnosis of cardiac AL amyloidosis based on appropriate diagnostic criteria (e.g., biomarkers, imaging, or histopathology); (3) failure to report relevant clinical outcomes or provide sufficient data to calculate risk estimates; or (4) inclusion of overlapping patient cohorts already represented in other eligible studies, in which case the most comprehensive or recent dataset was retained.

The primary outcome was all-cause mortality at 12 months (short-term), while secondary outcomes included all-cause mortality at 24 and 36 months (long-term).

Search strategy and data extraction

We systematically searched in Pubmed, Scopus and Cochrane Central Register of Controlled Trials from inception to December 24th 2024 with the following search strategy: (“Cardiac amyloidosis” OR “AL amyloidosis” OR “light chain amyloidosis”) AND (“myeloma” OR mm) AND (“cardiac event” OR “death” OR “heart failure” OR “coronary artery disease” OR “ischemic heart disease” OR hf OR ihd OR “heart involvement” OR “cardiac involvement”).

The references from all included studies, previous systematic reviews and meta-analyses were screened for any additional study.

Two authors (F.S. and C.O.) independently performed the search and extracted the data according to pre-defined search criteria. Any disagreements were resolved by consensus between the authors.

Quality assessment

We evaluated the risk of bias in observational studies using the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) 13 . Two independent authors completed the risk of bias assessment (F.S. and F.D.). Disagreements were resolved through a consensus after discussing reasons for discrepancy.

Statistical analysis

To evaluate the impact of cardiac amyloidosis on survival in patients with MM, individual patient-level data (IPD) were reconstructed from Kaplan–Meier survival curves reported in the included studies. Specifically, we extracted time-to-event data from published survival plots using a graphical digitization tool ( https://www.trialdesign.org/ ). For each group (MM without cardiac involvement and MM with AL cardiac amyloidosis), we extracted raw data points including survival time and corresponding survival probability at each time interval. These data were then processed to reconstruct survival curves using the R package survminer, which enabled us to generate cumulative Kaplan–Meier plots for comparative analysis. To quantify the survival benefit and assess time lost due to cardiac amyloidosis, we calculated the Restricted Mean Survival Time (RMST) for each group using the R package survRM2. RMST estimates the average survival time up to a common truncation point to account for differences in follow-up duration between the two groups. Confidence intervals (95% CI) and P-values were calculated accordingly.

In parallel, we also extracted the number of deaths and total number of patients per group from each study to calculate pooled risk ratios (RR) and 95% CIs for overall mortality at 12, 24 and 36 months. We assessed heterogeneity with Cochran Q test and I 2 with < 25% indicating low, 25% to 50% low to moderate, 50% to 75% moderate to high and > 75% high heterogeneity. We adopted Restricted Maximum Likelihood (REML) random-effects model.

A subgroup analysis was performed among patients with MM and amyloidosis, comparing individuals with cardiac involvement to those with non-cardiac amyloid involvement.

A leave-one-out sensitivity analysis was performed to evaluate the stability and robustness of the pooled estimates, assessing the potential influence of individual studies on the overall results. Specifically, this method systematically excluded each study in turn to examine its impact on the pooled effect size and statistical heterogeneity.

Publication bias was investigated by funnel-plot analysis of point estimates in relation to study weights.

Forest plots were generated using Cochrane Review Manager (RevMan, version 8.13), while aggregated Kaplan–Meier curves and RMST analyses were performed using R (version 2025.05.1). P-values less than 0.05 were considered statistically significant.

Results

Study selection and baseline characteristics

The search strategy yielded 948 results (Fig. 1 ). After the removal of duplicate records and studies with an exclusion criterion based on title and abstract review, 10 remained and were fully reviewed for the inclusion and exclusion criteria. Four observational studies [ 14 – 17 ] met al.l inclusion criteria. An additional study was identified during the screening process in the form of a conference abstract [ 18 ]. The corresponding author was contacted to request supplementary information regarding study design, population characteristics, exposure and outcome definitions, and analytical methods. The study was considered for inclusion in the final analysis only after the requested additional information was received and reviewed to confirm its eligibility.

A total of 272 patients with MM were included, of whom 110 (40%) with concomitant cardiac AL amyloidosis and 162 without cardiac involvement. The baseline characteristics of the study population are presented in Table 1 .

Pooled analysis

Of the five studies included, four reported Kaplan–Meier curves and contributed to the pooled survival analysis; one study was excluded from this analysis due to the absence of time-to-event data. Over a common follow-up period of 83.3 months, patients with MM + AL cardiac amyloidosis had significantly shorter survival compared to those with MM alone (Fig. 2 ). The RMST was 45.02 months (95% CI: 39.04–50.99) in the MM group and 17.74 months (95% CI: 13.27–22.21) in the MM + AL group. The difference in RMST between groups was 27.28 months (95% CI: 19.82–34.74; P < 0.0001), indicating a substantial loss in average life expectancy associated with cardiac involvement within the defined follow-up period.

To provide complementary, time-specific pooled risk estimates at clinically relevant follow-up intervals, all-cause mortality was additionally analyzed at 12, 24, and 36 months. All-cause mortality at 12 months was four times higher in MM patients with concomitant cardiac AL amyloidosis compared to those without cardiac involvement (RR 4.25; 95% CI 1.99–9.04; p = 0.0002; I 2= =53%; Fig. 3 ). This trend remained consistent at long-term follow-up, with increased mortality observed in patients with cardiac involvement at 24 months (RR 1.84; 95% CI 1.19–2.84; p = 0.006; I 2= =47%; Fig. 4 ) and 36 months (RR 1.78; 95% CI 1.26–2.52; p = 0.001; I 2= =47%; Fig. 5 ), although with a lower magnitude of effect.

Sensitivity analysis

Two subgroup analyses were performed. In the first, we compared patients with MM and cardiac amyloidosis to those with MM and extracardiac amyloidosis (RR 3.35; 95% CI 1.32–8.52; p = 0.01; I 2= =51%; Fig. 6 A). In the second analysis, outcomes were compared between patients with MM and cardiac amyloidosis and those with MM without any evidence of amyloid involvement (RR 6.60; 95% CI 2.65–16.41; p < 0.0001; I 2= =0%; Fig. 6 B)

The test for subgroup differences ( p = 0.31; I²=3.5%) did not demonstrate a statistically significant difference between the two comparisons.

To assess the robustness of our findings and ensure that no single study disproportionately influenced the overall results, we conducted a leave-one-out sensitivity analysis. We systematically removed one study at a time from the meta-analysis and recalculated the pooled estimates. The analysis showed that the effect sizes remained stable, confirming the robustness of our findings and indicating that no single study disproportionately influenced the overall results (Supplemental Appendix, Table S1 ).

Quality assessment

Regarding the quality assessment of the studies, one of them had a high risk of bias, while the remaining four had a moderate risk of bias (Supplemental Appendix, Table S2).

A funnel plot analysis was conducted to assess the presence of publication bias. Although the funnel plot appears asymmetrical, with most studies reporting increased mortality in patients with cardiac AL amyloidosis, this pattern may reflect the consistently poor prognosis associated with cardiac involvement rather than true publication bias. This is likely due to the well-established association between cardiac amyloid infiltration and adverse outcomes, rather than selective reporting (Supplemental Appendix, Figure S1 ).

Discussion

In this systematic review and meta-analysis of five observational studies including 272 patients, we evaluated the prognostic implications of cardiac AL amyloidosis in patients diagnosed with MM. The primary findings of this study can be summarized as follows: (1) the presence of cardiac AL amyloidosis was associated with increased short-term mortality at 12 months compared to MM patients without cardiac involvement; (2) this negative prognostic impact persisted in the medium to long term, demonstrated by significantly increased all-cause mortality at both 24 months and 36 months; (3) subgroup analyses revealed that the adverse prognostic impact associated with cardiac amyloid involvement remains significant and pronounced, whether compared to patients with extracardiac amyloidosis or to those without any amyloid involvement.

AL amyloidosis, together with transthyretin amyloidosis, is one of the most common forms of amyloidosis. In AL amyloidosis, abnormal plasma clones produce excessive amounts of light chains, which misfold and deposit in various tissues, leading to systemic involvement. Prior studies have shown the predominance of λ light-chain isotype in patients with primary systemic amyloidosis, a finding that has been attributed to the greater “amyloidogenicity” of the λ chains [ 19 ]. Nevertheless, some authors report that this phenomenon may be due to the broken balance of the light-chain removal and deposition speed rather than the higher ability of the λ light chain to cause AL amyloidosis [ 7 ].

Cardiac involvement is particularly serious and typically present with a thickened left and right ventricular wall with a restrictive cardiomyopathy leading to heart failure, frequently with preserved ejection fraction [ 20 ]. In advanced stages of the disease a reduction of left ventricular ejection fraction can also occur. Clinical manifestations include dyspnea and signs of pulmonary and systemic congestion as well as arrhythmias and hypotension [ 17 ].

Despite improved detection rates, the differences in clinical characteristics between MM patients with and without coexistent AL amyloidosis remain unclear. AL amyloidosis is frequently underdiagnosed in clinical practice, as patients are often asymptomatic in the early stages, leading to delays in diagnosis. Even with systematic screening efforts, the diagnosis of AL amyloidosis can be challenging. Subcutaneous fat aspiration, bone marrow biopsy, and gastrointestinal or rectal mucosal biopsy are recommended for diagnostic evaluation [ 21 ]. Serum Amyloid Protein (SAP) scans can be diagnostic when positive. Endomyocardial biopsy remains the gold standard for the diagnosis of cardiac amyloidosis, although it is invasive and requires considerable expertise [ 22 ].

Cardiac involvement is traditionally considered the main determinant of prognosis in patients with MM. Patients with MM are at risk for cardiovascular complications, including heart failure, poorly controlled systemic hypertension, accelerated atherosclerotic disease, arterial and venous thromboembolism, and arrhythmias. These complications may result from the cardiotoxic effects of antineoplastic therapies, often exacerbating pre-existing cardiovascular risk factors, as well as from amyloid deposition within the myocardium [ 23 ].

To the best of our knowledge, this is the first meta-analysis evaluating the impact of cardiac amyloidosis on the survival of MM patients. Our findings demonstrate that the presence of overt cardiac AL amyloidosis in patients with MM significantly worsens short-term mortality. Specifically, the risk of death at 12 months was more than fourfold higher in patients with concomitant cardiac involvement compared to those without cardiac amyloidosis. This striking difference highlights the critical prognostic impact of early cardiac infiltration by amyloid deposits. However, at longer follow-up intervals of 24 and 36 months, although mortality remained higher in the group with MM and cardiac amyloidosis, the magnitude of the difference was markedly reduced. This observation may be explained by the high competing risk of myeloma-related mortality in both groups over time. Additionally, early deaths in patients with cardiac amyloidosis could have led to a survival bias in long-term analyses. Subgroup analyses confirmed that cardiac involvement is the major determinant of prognosis, with patients with cardiac amyloidosis experiencing worse outcomes compared to both those with extracardiac amyloidosis and those without amyloid deposition. Cacoub et al. 24 highlighted that cardiac involvement in patients with histologically confirmed amyloidosis often remains clinically silent but can be detected early through echocardiography. Patients who initially present without overt cardiac symptoms but show echocardiographic signs of myocardial infiltration tend to progress to symptomatic cardiac disease over time. The development of cardiac complications, particularly heart failure, is associated with a markedly adverse prognosis, with overall survival being substantially reduced once cardiac dysfunction becomes clinically evident. These findings emphasize the pivotal role of systematic echocardiographic assessment in identifying subclinical cardiac involvement and guiding timely management strategies in AL amyloidosis.

Overall, these findings highlight the critical importance of early detection and management of cardiac amyloidosis in patients with MM. The clinical suspicion may be raised through non-invasive strategies based on biomarker assessment (natriuretic peptides and troponins) [ 14 , 16 , 25 ] and echocardiography, integrated by speckle tracking analysis which may show typical red flags (e.g., the apical sparing sign).

Strengths and limitations

The major strength of this meta-analysis is to have included a relatively large sample size of patients with MM, increasing the power to estimate the impact of systemic amyloid deposition and in particular cardiac involvement, in the prognosis of MM patients according to existing data.

However, this study has several limitations that should be considered when interpreting the results. First, all included studies were retrospective and observational in nature, with an inherent risk of confounding between exposure and outcomes. Consistent with this, the overall data quality was moderate, with one study judged at high risk of bias and the remaining studies at moderate risk of bias according to the ROBINS-E tool. Second, variability in patient inclusion criteria across studies has led to increased clinical and statistical heterogeneity. This includes the potential that cohorts are not matched for the stage of MM at presentation, other CV diseases or risk factors, and CV medication at baseline MM diagnosis which could influence outcomes including all cause mortality. Third, not all studies reported Kaplan–Meier survival curves: one study was excluded from the pooled time-to-event analysis due to the absence of such data, and most of the included curves lacked information on the number at risk over time, limiting the ability to estimate the number of censored patients. Fourth, included studies spanned a broad time period during which diagnostic criteria, therapeutic options, and supportive care strategies for MM and cardiac amyloidosis have evolved, potentially influencing patient prognosis and outcomes. Moreover, it was not possible to determine neither the effect of antineoplastic therapy on survival, nor to assess the distinct prognostic impact of ejection fraction, myocardial wall thickness, and the severity of diastolic dysfunction.

Conclusion

In this systematic review and meta-analysis of observational studies, the presence of concomitant cardiac AL amyloidosis was associated with significantly higher short-term and long-term mortality in patients with MM, if compared to those without cardiac involvement. These findings highlight the the crucial prognostic role of cardiac infiltration in this population and therefore, importance of early cardiac involvement detection. Further prospective studies with standardized diagnostic criteria and longer follow-up are warranted.

Supplementary Information

Supplementary Material 1.

Acknowledgements

None.

Abbreviations

Confidence Interval

Heart Failure

International Myeloma Working Group

Interquartile Range

Mean Difference

Multiple Myeloma

New York Heart Association

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

Restricted Mean Survival Time

Risk of Bias in Non-randomized Studies of Interventions

Standard Deviation

Authors’ contributions

F.S. and G.N. wrote the main manuscript text. D.D.L., C.M., F.D., C.O., and S.J. contributed to data extraction and statistical analysis. M.C. and S.B. provided methodological and critical revisions. P.v.d.M., A.R.G., and A.R.L. critically reviewed the manuscript. All authors contributed to the conception and design of the study and reviewed and approved the final version of the manuscript.

Funding

None.

Data availability

We declare that all the raw data supporting the conclusions of this meta-analysis are available upon reasonable request.

Declarations

Ethics approval and consent to participate

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.

Giuseppina Novo and Francesco Stabile contributed equally to this work.

References

1. Gertz MA. Immunoglobulin light chain amyloidosis: 2024 update on diagnosis, prognosis, and treatment. Am J Hematol. 2024;99:309–24.

2. Albagoush SA, Shumway C, Azevedo AM. Multiple Myeloma. 2025. https://www.ncbi.nlm.nih.gov/books/NBK534764/ .

3. Vela-Ojeda J, García-Ruiz Esparza MA, Padilla-González Y, Sánchez-Cortes E, García-Chávez J, Montiel-Cervantes L, Reyes-Maldonado E, Majluf-Cruz A, Mayani H. Multiple myeloma-associated amyloidosis is an independent high-risk prognostic factor. Ann Hematol. 2009;88:59–66.

4. Bahlis NJ, Lazarus HM. Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted? Bone Marrow Transpl. 2006;38:7–15.

5. Gertz MA, Lacy MQ, Dispenzieri A. AMYLOIDOSIS. Hematol Oncol Clin North Am. 1999;13:1211–33.

6. Rajkumar SV, Gertz MA, Kyle RA. Primary systemic amyloidosis with delayed progression to multiple myeloma. Cancer. 1998;82:1501–5.

7. Desikan KR, Dhodapkar MV, Hough A, Waldron T, Jagannath S, Siegel D, Barlogie B, Tricot G. Incidence and impact of light chain associated (AL) amyloidosis on the prognosis of patients with multiple myeloma treated with autologous transplantation. Leuk Lymphoma. 1997;27:315–9.

8. Milani P, Dispenzieri A, Scott CG, Gertz MA, Perlini S, Mussinelli R, Lacy MQ, Buadi FK, Kumar S, Maurer MS, Merlini G, Hayman SR, Leung N, Dingli D, Klarich KW, Lust JA, Lin Y, Kapoor P, Go RS, Pellikka PA, Hwa YL, Zeldenrust SR, Kyle RA, Rajkumar SV, Grogan M. Independent prognostic value of stroke volume index in patients with Immunoglobulin light chain amyloidosis. Circ Cardiovasc Imaging. 2018;11:e006588.

9. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) cardiac amyloidosis. J Am Coll Cardiol. 2016;68:1323–41.

10. Martinez-Naharro A, Hawkins PN, Fontana M. Cardiac amyloidosis. Clin Med. 2018;18:s30–5.

11. Anon. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). Cochrane, 2024. Available from www.training.cochrane.org/handbook .

12. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021:n71. https://www.bmj.com/content/372/bmj.n71 .

13. Higgins JPT, Morgan RL, Rooney AA, Taylor KW, Thayer KA, Silva RA, Lemeris C, Akl EA, Bateson TF, Berkman ND, Glenn BS, Hróbjartsson A, LaKind JS, McAleenan A, Meerpohl JJ, Nachman RM, Obbagy JE, O’Connor A, Radke EG, Savović J, Schünemann HJ, Shea B, Tilling K, Verbeek J, Viswanathan M, Sterne JAC. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environ Int. 2024;186. https://www.rti.org/publication/tool-assess-risk-bias-non-randomized-follow-studies-exposure-effects-robins-e .

14. Xu J, Wang M, Shen Y, Yan M, Xie W, Wang B, Liu H, Cen X. Effects of amyloid light-chain amyloidosis on clinical characteristics and prognosis in multiple myeloma: A single-center retrospective study. Cancer Manag Res. 2021;13:1343–56.

15. Madan S, Dispenzieri A, Lacy MQ, Buadi F, Hayman SR, Zeldenrust SR, Rajkumar SV, Gertz MA, Kumar SK. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc. 2010;85:232–8.

16. Wang J, Yang S, Liao P, Zeng L, Ling W, Wan L, Weng J, Zhong L. Incidence and effect of secondary cardiac amyloidosis on outcomes of patients with t(11;14) multiple myeloma. Front Cardiovasc Med. 2022;9:994384.

17. Yu Y, Huang Z, Hu W, Li X, Shen M, Zhang J, Tang R, Chen S, Chen W. Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis. Clin Lymphoma Myeloma Leuk. 2020;20:519–e5251.

18. Lisi D, Di, Madaudo C, Damerino G, Damiani F, Stabile F, Puccia G, Scelfo D, Galassi AR, Novo G. Multiple myeloma and al cardiac amyloidosis: the predictive role of HFA/ICOS risk score and other parameters. Eur Heart J Supplements. 2025;27. https://academic.oup.com/eurheartjsupp/article/27/Supplement_6/suaf083.089/8220078 .

19. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med. 1991;324:1845–51.

20. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909.

21. van Gameren II, Hazenberg BPC, Bijzet J, van Rijswijk MH. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. 2006;54:2015–21.

22. Pellikka PA. Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement. Arch Intern Med. 1988;148:662–6.

23. Camilli M, Vecchia G, La, Lillo R, Iannaccone G, Lamendola P, Montone RA, Hohaus S, Aspromonte N, Massetti M, Lanza GA, Crea F, Graziani F, Lombardo A. Cardiovascular involvement in patients affected by multiple myeloma: a comprehensive review of recent advances. Expert Rev Hematol. 2021;14:1115–28.

24. Cacoub P, Axler O, Zuttere D, De, Hausfater P, Amoura Z, Walter S, Wechsler B, Godeau P, Piette J. Amyloidosis and cardiac involvement. Ann Med Interne (Paris). 2000;151:611–7.

25. Lilleness B, Ruberg FL, Mussinelli R, Doros G, Sanchorawala V. Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis. Blood. 2019;133:215–23.

Associated Data

Supplementary Materials

Supplementary Material 1.

Data Availability Statement

We declare that all the raw data supporting the conclusions of this meta-analysis are available upon reasonable request.