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English
Sažetak
Uvod/Cilj. Multipli mijelom je maligna imunoproliferativna bolest koju karakteriše klonska proliferacija i nagomilavanje patološki izmenjenih plazmocita. Petogodišnje preživljavanje pacijenata sa multiplim mijelomom u svetu iznosi 60-70% zahvaljujući novim modalitetima lečenja. U našoj zemlji se primenjuju konvencionalnije metode lečenja, a terapijski protokoli sa monoklonskim antitelima nedavno su ušli u upotrebu i rezervisani su za relaps/refraktarne bolesnike. Cilj istraživanja bio je praćenje uspešnosti lečenja multiplog mijeloma u odnosu na primenjenu terapiju i prognostičke faktore.
Metode. Retrospektivno – prospektivnim ispitivanjem obuhvaćeno je 200 bolesnika sa multiplim mijelomom. Određivan je uticaj različitih modaliteta lečenja, bioloških karakteristika bolesti i kliničkih karakteristika bolesnika na nivo terapijskog odgovora, dužinu vremena do progresije i ukupno preživljavanje, kao i najefikasniji terapijski protokol za različite prognostičke grupe pacijenata uz identifikovanje visoko rizičnih pacijenata.
Rezultati. U našoj grupi, najbolji stepen terapijskog odgovora imali su bolesnici sa dobrim opštim stanjem i bez značajnijih komorbiditeta, tretirani VTD protokolom u prvoj liniji, dok je terapijom po CTD protokolu zabeleženo najduže prosečno preživljavanje u grupi bolesnika mlađih od 65 godina. Primena PAD protokola dala je najviši stepen odgovora i najbolje preživljavanje kod bolesnika sa mijelomom u drugoj liniji lečenja. Pacijenti sa odmaklom životnom dobi i visokim Charlsonovim skorom imali su korist od terapije po MPT protokolu, dok je do najvišeg procenta progresija doveo Vel-Dex protokol.
Zaključak. Od izuzetnog je značaja odrediti prognostički profil svakog bolesnika, što dalje vodi individualizovanom terapijskom pristupu i uspešnijem lečenju.
Ključne reči: multipli mijelom, prognostički faktori, stratifikacija rizika, terapijski protokoli, ishod lečenja
Reference
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2. Bowcock S, Atkin C, Iqbal G, Pratt G, Yong K, Neal RD, Planche T, Karunanithi K, Jenkins S, Stern S, Arnott S, Toth P, Wandroo F, Dunn J, Drayson MT; TEAMM Trial Management Group and Trial Investigators. Presenting Symptoms in Newly Diagnosed Myeloma, Relation to Organ Damage, and Implications for Symptom-Directed Screening: A Secondary Analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) Trial. Cancers (Basel). 2023 Jun 25;15(13):3337.
3. Mitrović M, Sretenović A, Bila J .The significance of prognostic profiling in the treatment of patients with multiple myeloma. Medicinski podmladak 2020, 71(4):17-24.
4. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multi¬ple myeloma: A report from international myeloma working group. J Clin Oncol. 2015 Sep 10;33(26):2863-9.
5. Wang, J., Li, J., Zhang, R.et al. Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma. Discov Oncol. 2024 Feb 17;15(1):38.
6. Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322.
7. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011 Mar 17;364(11):1046-60.
8. Fischer J, Knop S, Danhof S, et al. The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: A prospective observational study. Research Square; 2022.
9. Caulier A, Roussel M, Morel P. Epidemiological landscape of young patients with multiple myeloma diagnosed before 40 years of age: the French experience. Blood. 2021; 138(25):2686-2695.
10. Jurczyszyn A, Nahi H, Avivi I. Characteristics and outcomes of patients with multiple myeloma aged 21-40 years versus 41-60 years: a multi-institutional case-control study. Br J Haematol. 2016; 175(5):884-891.
11. Bird S, Cairns D, Menzies T, Boyd K, Davies F, Cook G, Drayson M, Gregory W, Jenner M, Jones J, Kaiser M, Owen R, Jackson G, Morgan G, Pawlyn C. Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial. Clin Lymphoma Myeloma Leuk. 2021 Oct;21(10):667-675.
12. Boyd KD, Ross FM, Tapper WJ, Chiecchio L, Dagrada GP, Konn ZJ, et al. Gender disparities in the tumor genetics and clinical outcome of multiple myeloma. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1703-7.
13. Pawlyn C, Melchor L, Murison A, Wardell CP, Manwani D, Kaiser MF, et al. Gender influences the molecular and clinical features of multiple myeloma at diagnosis. Haematologica. 2021 Aug 1;106(8):2163-73.
14. Ozerova M, Nefedova Y. Estrogen promotes multiple myeloma through enhancing the immunosuppressive activity of MDSC. Leuk Lymphoma. 2019 Jan 2;60(6):1557–62.
15. Spasov S, Goranova-Marinova V, Konstantinov SM, Spasova N, Topouzov M. Survival of patients with multiple myeloma depends on renal impairment at diagnosis. J BUON. 2005 Apr-Jun;10(2):239-42.
16. Jang H, Park H, Kim YK, Kim HJ, Kim WS, Kim K, et al. Improved survival of patients with multiple myeloma in the era of novel agents: a population-based study in Korea. Blood Cancer J. 2022 May 6;12(5):72.
17. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015 Mar 12;125(13):2068-74.
18. Yin X, Fan F, Zhang B, Hu Y, Sun C. Cardiovascular-specific mortality among multiple myeloma patients: a population-based study. Ther Adv Hematol. 2022 Mar 31;13:20406207221086755.
19. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7.
20. Antlanger M, Dust T, Reiter T, Böhm A, Lamm WW, Gornicec M, et al. Impact of renal impairment on outcomes after autologous stem cell transplantation in multiple myeloma: a multi center, retrospective cohort study. BMC Cancer. 2018;18:1008.
21. Kushwaha N, Kumar S, Sheikh MA, Philip J, Sharma S, Biswas AK, et al. Association of CD34 positive cell dose with engraftment kinetics in autologous peripheral blood stem cell transplant patients of multiple myeloma. Med J Armed Forces India. 2021;78(3):296–301.
22. Kim JS, Kim K, Cheong JW, Min YH, Suh C, Kim H, et al. Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. Biol Blood Marrow Transplant. 2009;15(4):463–70.
23. Qin X, Xu Y, An G, Qin Y, Feng X, Sui W, Deng S, Zang M, Lyu R, Wang T, Li Z, Yi S, Qiu L. The impact of renal function on prognostic value of β₂-microglobulin of ISS stage system in multiple myeloma patients--Clinical data analysis of 666 patients in a single center. Zhonghua Xue Ye Xue Za Zhi. 2015 May;36(5):393-7.
24. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019 Jan;33(1):159-170.
25. Hanamura I. Multiple myeloma with high-risk cytogenetics and its treatment approach. Int J Hematol. 2022 Jun;115(6):762-777.
26. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone significantly prolongs time to progression versus melphalan and prednisone in newly diagnosed, transplant ineligible multiple myeloma: results of the phase III VISTA trial. J Clin Oncol. 2008;26(13):2137-43.
27. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch A, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-17.
28. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-27.
29. Vasquez J, Ruiz R, Aliaga K, et al. Cyclophosphamide, Thalidomide, and Dexamethasone (CTD) as Initial Therapy for Patients with Newly Diagnosed Multiple Myeloma in a Middle-Income Country: 7-Year Follow-Up. JCO Glob Oncol. 2021;7:1199-1205.
30. Mikhael JR, Reeder CB, Libby EN, et al. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27.
31. Hulin C, Dimopoulos MA, Dispenzieri A, et al. Continuous lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma. N Engl J Med. 2014;371(10):906-917.
32. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14.
33. San-Miguel JF, Vidriales MB, Cibeira MT, et al. Superiority of bortezomib, thalidomide, and dexamethasone over thalidomide and dexamethasone or VBMCP/VBAD/B in previously untreated multiple myeloma: PETHEMA/GEM clinical trial. Blood. 2012 Aug 23;120(8):1589-96.
34. Kiba T, Kawano Y, Takahashi K, et al. Retrospective analysis of bortezomib and dexamethasone combination therapy in multiple myeloma patients. BMC Cancer. 2014 Jul 4;14:462.
35. Zhang W, Wang Y, Ma X, et al. Efficacy of bortezomib, doxorubicin, and dexamethasone (PAD) in relapsed/refractory multiple myeloma patients with extramedullary disease: a retrospective study. Leuk Lymphoma. 2018;59(2):422-429.
36. Lonial S, Lee HC, Badros A, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, multicentre, phase 2 trial. Lancet. 2016 Jan 23;387(10027):1551-60.
37. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Jun 3;384(8):705-716.
38. Cho SF, Anderson KC, Tai YT. T-cell redirecting bispecific antibodies targeting BCMA for multiple myeloma treatment. Immunotherapy. 2020 Sep;12(12):963-973.
39. Lonial S, Lee HC, Wang H, et al. Belantamab Mafodotin for Relapsed or Refractory Multiple Myeloma (DREAMM-2): A Two-Arm, Randomised, Open-Label, Phase 2 Study. Lancet Oncol. 2020 Feb;21(2):207-221.
40. Costa LJ, Shain KH, Shih A, et al. Emerging therapies for multiple myeloma: an update. Expert Opin Investig Drugs. 2021;30(8):779-796.
41. Perrot A, Lauwers-Cances V, Tournay E, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018 Jan 11;132(23):2456-2464.
42. Landgren O, Iskander K. Minimal Residual Disease in Multiple Myeloma: Current Landscape and Future Applications With Immunotherapeutic Approaches. Front Oncol. 2020;10:664.
43. Perrot A, Tournay E, Lauwers-Cances V, et al. Measurable Residual Disease–Guided Therapy in Newly Diagnosed Multiple Myeloma. N Engl J Med. 2025 Jun 12;392(24):2296-2308.
2. Bowcock S, Atkin C, Iqbal G, Pratt G, Yong K, Neal RD, Planche T, Karunanithi K, Jenkins S, Stern S, Arnott S, Toth P, Wandroo F, Dunn J, Drayson MT; TEAMM Trial Management Group and Trial Investigators. Presenting Symptoms in Newly Diagnosed Myeloma, Relation to Organ Damage, and Implications for Symptom-Directed Screening: A Secondary Analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) Trial. Cancers (Basel). 2023 Jun 25;15(13):3337.
3. Mitrović M, Sretenović A, Bila J .The significance of prognostic profiling in the treatment of patients with multiple myeloma. Medicinski podmladak 2020, 71(4):17-24.
4. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multi¬ple myeloma: A report from international myeloma working group. J Clin Oncol. 2015 Sep 10;33(26):2863-9.
5. Wang, J., Li, J., Zhang, R.et al. Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma. Discov Oncol. 2024 Feb 17;15(1):38.
6. Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322.
7. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011 Mar 17;364(11):1046-60.
8. Fischer J, Knop S, Danhof S, et al. The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: A prospective observational study. Research Square; 2022.
9. Caulier A, Roussel M, Morel P. Epidemiological landscape of young patients with multiple myeloma diagnosed before 40 years of age: the French experience. Blood. 2021; 138(25):2686-2695.
10. Jurczyszyn A, Nahi H, Avivi I. Characteristics and outcomes of patients with multiple myeloma aged 21-40 years versus 41-60 years: a multi-institutional case-control study. Br J Haematol. 2016; 175(5):884-891.
11. Bird S, Cairns D, Menzies T, Boyd K, Davies F, Cook G, Drayson M, Gregory W, Jenner M, Jones J, Kaiser M, Owen R, Jackson G, Morgan G, Pawlyn C. Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial. Clin Lymphoma Myeloma Leuk. 2021 Oct;21(10):667-675.
12. Boyd KD, Ross FM, Tapper WJ, Chiecchio L, Dagrada GP, Konn ZJ, et al. Gender disparities in the tumor genetics and clinical outcome of multiple myeloma. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1703-7.
13. Pawlyn C, Melchor L, Murison A, Wardell CP, Manwani D, Kaiser MF, et al. Gender influences the molecular and clinical features of multiple myeloma at diagnosis. Haematologica. 2021 Aug 1;106(8):2163-73.
14. Ozerova M, Nefedova Y. Estrogen promotes multiple myeloma through enhancing the immunosuppressive activity of MDSC. Leuk Lymphoma. 2019 Jan 2;60(6):1557–62.
15. Spasov S, Goranova-Marinova V, Konstantinov SM, Spasova N, Topouzov M. Survival of patients with multiple myeloma depends on renal impairment at diagnosis. J BUON. 2005 Apr-Jun;10(2):239-42.
16. Jang H, Park H, Kim YK, Kim HJ, Kim WS, Kim K, et al. Improved survival of patients with multiple myeloma in the era of novel agents: a population-based study in Korea. Blood Cancer J. 2022 May 6;12(5):72.
17. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015 Mar 12;125(13):2068-74.
18. Yin X, Fan F, Zhang B, Hu Y, Sun C. Cardiovascular-specific mortality among multiple myeloma patients: a population-based study. Ther Adv Hematol. 2022 Mar 31;13:20406207221086755.
19. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7.
20. Antlanger M, Dust T, Reiter T, Böhm A, Lamm WW, Gornicec M, et al. Impact of renal impairment on outcomes after autologous stem cell transplantation in multiple myeloma: a multi center, retrospective cohort study. BMC Cancer. 2018;18:1008.
21. Kushwaha N, Kumar S, Sheikh MA, Philip J, Sharma S, Biswas AK, et al. Association of CD34 positive cell dose with engraftment kinetics in autologous peripheral blood stem cell transplant patients of multiple myeloma. Med J Armed Forces India. 2021;78(3):296–301.
22. Kim JS, Kim K, Cheong JW, Min YH, Suh C, Kim H, et al. Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. Biol Blood Marrow Transplant. 2009;15(4):463–70.
23. Qin X, Xu Y, An G, Qin Y, Feng X, Sui W, Deng S, Zang M, Lyu R, Wang T, Li Z, Yi S, Qiu L. The impact of renal function on prognostic value of β₂-microglobulin of ISS stage system in multiple myeloma patients--Clinical data analysis of 666 patients in a single center. Zhonghua Xue Ye Xue Za Zhi. 2015 May;36(5):393-7.
24. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019 Jan;33(1):159-170.
25. Hanamura I. Multiple myeloma with high-risk cytogenetics and its treatment approach. Int J Hematol. 2022 Jun;115(6):762-777.
26. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone significantly prolongs time to progression versus melphalan and prednisone in newly diagnosed, transplant ineligible multiple myeloma: results of the phase III VISTA trial. J Clin Oncol. 2008;26(13):2137-43.
27. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch A, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-17.
28. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-27.
29. Vasquez J, Ruiz R, Aliaga K, et al. Cyclophosphamide, Thalidomide, and Dexamethasone (CTD) as Initial Therapy for Patients with Newly Diagnosed Multiple Myeloma in a Middle-Income Country: 7-Year Follow-Up. JCO Glob Oncol. 2021;7:1199-1205.
30. Mikhael JR, Reeder CB, Libby EN, et al. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27.
31. Hulin C, Dimopoulos MA, Dispenzieri A, et al. Continuous lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma. N Engl J Med. 2014;371(10):906-917.
32. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14.
33. San-Miguel JF, Vidriales MB, Cibeira MT, et al. Superiority of bortezomib, thalidomide, and dexamethasone over thalidomide and dexamethasone or VBMCP/VBAD/B in previously untreated multiple myeloma: PETHEMA/GEM clinical trial. Blood. 2012 Aug 23;120(8):1589-96.
34. Kiba T, Kawano Y, Takahashi K, et al. Retrospective analysis of bortezomib and dexamethasone combination therapy in multiple myeloma patients. BMC Cancer. 2014 Jul 4;14:462.
35. Zhang W, Wang Y, Ma X, et al. Efficacy of bortezomib, doxorubicin, and dexamethasone (PAD) in relapsed/refractory multiple myeloma patients with extramedullary disease: a retrospective study. Leuk Lymphoma. 2018;59(2):422-429.
36. Lonial S, Lee HC, Badros A, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, multicentre, phase 2 trial. Lancet. 2016 Jan 23;387(10027):1551-60.
37. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Jun 3;384(8):705-716.
38. Cho SF, Anderson KC, Tai YT. T-cell redirecting bispecific antibodies targeting BCMA for multiple myeloma treatment. Immunotherapy. 2020 Sep;12(12):963-973.
39. Lonial S, Lee HC, Wang H, et al. Belantamab Mafodotin for Relapsed or Refractory Multiple Myeloma (DREAMM-2): A Two-Arm, Randomised, Open-Label, Phase 2 Study. Lancet Oncol. 2020 Feb;21(2):207-221.
40. Costa LJ, Shain KH, Shih A, et al. Emerging therapies for multiple myeloma: an update. Expert Opin Investig Drugs. 2021;30(8):779-796.
41. Perrot A, Lauwers-Cances V, Tournay E, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018 Jan 11;132(23):2456-2464.
42. Landgren O, Iskander K. Minimal Residual Disease in Multiple Myeloma: Current Landscape and Future Applications With Immunotherapeutic Approaches. Front Oncol. 2020;10:664.
43. Perrot A, Tournay E, Lauwers-Cances V, et al. Measurable Residual Disease–Guided Therapy in Newly Diagnosed Multiple Myeloma. N Engl J Med. 2025 Jun 12;392(24):2296-2308.
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2025/11/19
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Originalni rad / Original article