multiple myeloma

Correlation of CD34+ Hematopoietic Stem Cells and CFU in Peripheral Blood Apheresis Products in Patients with Malignant Lymphoproliferative Diseases Before and After Cryopreservation Prior to auto-HSCT

BONE MARROW TRANSPLANTATION , , , , , , ,

VA Balashova, VI Rugal’, SS Bessmel’tsev, SV Gritsaev, NYu Semenova, SV Voloshin, ZhV Chubukina, AV Shmidt, AD Garifullin, IM Zapreeva, AA Kuzyaeva, II Kostroma, AYu Kuvshinov, AV Chechetkin

Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Valentina Andreevna Balashova, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-19-37; e-mail: vbspb37@mail.ru

For citation: Balashova VA, Rugal’ VI, Bessmel’tsev SS, et al. Correlation of CD34+ Hematopoietic Stem Cells and CFU in Peripheral Blood Apheresis Products in Patients with Malignant Lymphoproliferative Diseases Before and After Cryopreservation Prior to auto-HSCT. Clinical oncohematology. 2018;11(4):368–77.

DOI: 10.21320/2500-2139-2018-11-4-368-377

ABSTRACT

Aim. To establish correlation between CD34+ autologous hematopoietic stem cell (HSC) count and colony-forming units (CFU) in the same peripheral blood apheresis product samples before and after cryopreservation in multiple myeloma and lymphoma patients, and to assess clinical value of these parameters.

Materials & Methods. Cell samples of peripheral blood cytapheresis product and cell cultures were studied before and after cryopreservation in 32 multiple myeloma and 25 lymphoma patients who underwent autologous HSC transplantation. The material was analyzed using culture technique and flow cytometry.

Results. The paper provides information on the relationship between CD34+ HSC count obtained by flow cytometry, and CFU in cell culture obtained by cytapheresis of the same peripheral blood samples. A direct correlation was confirmed between CD34+ count and all the CFUs before and after cryopreservation in lymphoma patients. Correlation between CD34+ count and granulocyte-macrophage CFUs was revealed in multiple myeloma and lymphoma patients before cryopreservation.

Conclusion. The parameter of colony-forming capacity used for the assessment of the functional HSC was shown to be equally reliable criterion for condition evaluation of autotransplant proliferative pool than CD34+ cells. Both methods should be applied for qualitative and quantitative evaluation of an autotransplant for multiple myeloma and lymphoma patients.

Keywords: CD34+ cells, CFU, CFU-GM, correlation, lymphoma, multiple myeloma, apheresis, auto-HSCT.

Received: April 11, 2018

Accepted: July 28, 2018

Read in PDF 

REFERENCES

  1. Lansdorp PM. Self-renewal of stem cells. Biol Blood Marrow Transplant. 1997;3(4):171–8.

  2. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue specific stem cell. Am J Pathol. 2006;169(2):338–46. doi: 10.2353/ajpath.2006.060312.

  3. Wodnar-Filipowicz A. Biological properties of haematopoietic stem cells. The EBMT Handbook, 6th edition; 2012. pp. 61–72.

  4. Moreb JS, Salmosinia D, Hsu J, et al. Long-term outcome after autologous stem cell transplantation with adequate peripheral blood stem cell mobilization using plerixafor and G-CSF in poor mobilizer lymphoma and myeloma patients. Adv Hematol. 2011;2011:1–8. doi: 10.1155/2011/517561.

  5. Птушкин В.В., Жуков Н.В., Миненко С.В. и др. Роль высокодозной химиотерапии с трансплантацией стволовых кроветворных клеток у больных с неходжкинскими лимфомами. Онкогематология. 2006;1–2:86–96.

    [Ptushkin VV, Zhukov NV, Minenko SV, et al. Role of high-dose chemotherapy with hematopoietic stem cell transplantation in patients with non-Hodgkin’s lymphomas. Onkogematologiya. 2006;1–2:86–96. (In Russ)]

  6. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroup Francophone du Myeloma. Blood. 2007;109(8):3489–95. doi: 10.1182/blood-2006-08-040410.

  7. Avet-Loiseau H, Soulier J, Fermand JP, et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. 2010;24(3):623–8. doi: 10.1038/leu.2009.273.

  8. Dabusti M, Lanza F, Campioni D, et al. CXCR4 expression on bone marrow CD34+ cells prior to mobilization can predict mobilization adequacy in patients with hematological malignancy. J Hematother Stem Cell Res. 2003;12(4):425–34. doi: 10.1089/152581603322286051.

  9. Ratip S. Mobilization failure in hematopoietic stem cell transplantation. XXXIX Ulusal Hematoloji Kongresi. Antalya, Turkey; 2013. рр. 106–10.

  10. Артюхина З.Е., Семенова Н.Ю., Балашова В.А. и др. Кроветворная ткань и стромальное микроокружение больных множественной миеломой. Вестник гематологии. 2017;13(1):15–8.

    [Artyukhina ZE, Semenova NYu, Balashova VA, et al. Hematopoietic tissue and stromal microenvironment in patients with multiple myeloma. Vestnik gematologii. 2017;13(1):15–8. (In Russ)]

  11. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: МК, 2016. 504 с.

    [Bessmel’tsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for doctors.) Moscow: MK Publ.; 2016. 504 p. (In Russ)]

  12. Покровская О.С., Менделеева Л.П., Гальцева И.В. и др. Мобилизация гемопоэтических клеток крови у больных миеломной болезнью. Проблемы гематологии и переливания крови. 2003;2:55–65.

    [Pokrovskaya OS, Mendeleeva LP, Gal’tseva IV, et al. Mobilization of hematopoietic cells in myeloma patients. Problemy gematologii i perelivaniya krovi. 2003;2:55–65. (In Russ)]

  13. Покровская О.С. Кроветворная ткань и стромальное микроокружение в процессе интенсивной терапии и мобилизации гемопоэтических стволовых клеток у больных множественной миеломой: Автореф. дис.… канд. мед. наук. М., 2011.

    [Pokrovskaya OS. Krovetvornaya tkan’ i stromal’noe mikrookruzhenie v protsesse intensivnoi terapii i mobilizatsii gemopoeticheskikh stvolovykh kletok u bol’nykh mnozhestvennoi mielomoi. (Hematopoietic tissue and stromal microenvironment in intensive treatment and mobilization of hematopoietic stem cells in multiple myeloma ) [dissertation] Moscow; 2011. (In Russ)]

  14. Haizmann M, O’Meara AC, Moosmann PR, et al. Efficient mobilization of PBSC with vinorelbine/G-CSF in patients with malignant lymphoma. Bone Marrow Transplant. 2009;44(2):75–9. doi: 10.1038/bmt.2008.434.

  15. Haverkos BM, McBride A, O’Donnell L, et al. An effective mobilization strategy for lymphoma patients after failed upfront mobilization with plerixafor. Bone Marrow Transplant. 2014;49(8):1052–5. doi: 10.1038/bmt.2014.90.

  16. Lansdorp PM, Sutherland HJ, Eaves CJ. Selective expression of CD45 isoforms on functional subpopulations of CD34+ hemopoietic cells from human bone marrow. J Exp Med. 1990;172(1):363–6. doi: 10.1084/jem.172.1.363.

  17. Fritsch G, Buchinger P, Printz D, et al. Rapid discrimination of early CD34+ myeloid progenitors using CD45-RA analysis. Blood. 1993;1(9):2301–9.

  18. Fritsch G, Buchinger P, Printz D. Use of flow cytometric CD34 analysis to quantify hematopoietic progenitor cells. Leuk Lymphoma. 1993;10(6):443–51. doi: 10.3109/10428199309148201.

  19. Nissen-Druey C, Tichelli A, Mayer-Monard S. Human hematopoietic colonies in health and disease. Acta Haematol. 2005;113(1):5–10. doi: 10.1159/000081987.

  20. Takano H, Ema H, Sudo K, et al. Asymmetric division and lineage commitment at the level of hematopoietic stem cells: Inference from differentiation in daughter cell and granddaughter cell pairs. J Exp Med. 2004;199(3):295–302. doi: 10.1084/jem.20030929.

  21. Sieburg HB, Cho RH, Dykstra B, et al. The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood. 2006;107(6):2311–6. doi: 10.1182/blood-2005-07-2970.

  22. Guo Y, Lubbert M, Engelhard M. CD34-hematopoietic stem cells: current concepts and controversies. Stem Cell. 2003;21(1):15–20. doi: 10.1634/stemcells.21-1-15.

  23. Donahue RE, Yang YC, Clark SC. Human P40 T-cell growth factor (interleukin-9) supports erythroid colony formation. Blood. 1990;75(12):2271–5.

  24. Ema H, Suda T, Miura Y, Nakauchi H. Colony formation of clone-sorted human haematopoietic progenitors. Blood. 1990;75(10):1941–6.

  25. Serke S, Sauberlich S, Huhn D. Multiparameter flow-cytometrical quantitation of circulating CD34+ cells: correlation to the quantitation of circulating haemopoietic progenitor cells by in vitro colony-assay. Br J Haematol. 2008;77(4):453–9. doi: 10.1111/j.1365-2141.1991.tb08609.x.

  26. Bensinger WI, Longin K, Appelbaum F, et al. Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): An analysis of factors correlating with the tempo of engraftment after transplantation. Br J Haematol. 1994;87(4):825–31. doi: 10.1111/j.1365-2141.1994.tb06744.x.

  27. Bensinger WI, Appelbaum F, Rowley S, et al. Factors that influence collection and engraftment of autologous peripheral blood stem cells. J Clin Oncol. 1995;13(10):2547–55. doi: 10.1200/jco.1995.13.10.2547.

  28. Weaver CH, Haselton B, Birch R, et al. An analysis of engrafment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after administration of myeloablative chemotherapy. Blood. 1995;86(10):3961–9.

  29. Weaver CH, Potz J, Redmond J, et al. Engraftment and outcomes of patients receiving myeloablative therapy followed by autologous peripheral blood cells with a low CD34+ cell content. Bone Marrow Transplant. 1997;19(11):1103–10. doi: 10.1038/sj.bmt.1700808.

  30. Watts MJ, Sullivan AM, Jamieson E, et al. Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor, an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma. J Clin Oncol. 1997;15(2):535–46. doi: 10.1200/jco.1997.15.2.535.

  31. Serke S, Watts M, Knudsen LM, et al. In-vitro clonogenity of mobilized peripheral blood CD34 expressing cells: inverse correlation to both relative and absolute number of CD34-expressing cells. Br J Haematol. 1996;95(2):234–40. doi: 10.1046/j.1365-2141.1996.d01-1918.x.

  32. Fritsch G, Emminger W, Buchinger P, et al. CD34-positive cell proportions in peripheral blood correlate with colony-forming capacity. Exp Hematol. 1991;19(11):1079–83.

  33. Fritsch G, Emminger W, Buchinger P, et al. CD34 analysis in peripheral blood correlates with colony-forming capacity. Progr Clin Biol Res. 1992;377:531–6.

  34. Scott MA, Ager S, Apperley JF, et al. Peripheral blood progenitor cell harvesting in multiple myeloma and malignant lymphoma. Leuk Lymphoma. 1995;19(5–6):479–84. doi: 10.3109/10428199509112208.

  35. Buzzi M, Granchi D, Bacci G, et al. CD34+ cells and clonogenicity of peripheral blood stem cells during chemotherapy treatment in association with granulocyte colony stimulating factor in osteosarcoma. J Chemother. 1999;11(4):293–300. doi: 10.1179/joc.1999.11.4.293.

  36. Андреева Л.Ю., Тупицын Н.Н., Овумян Г.Ш. и др. Гемопоэтические предшественники в крови онкологических больных: взаимосвязь колониеобразования и экспрессии CD Вестник РОНЦ им. Н.Н. Блохина РАМН. 2000;11(1):5–10.

    [Andreeva LYu, Tupitsyn NN, Ovumyan GSh, et al. Hematopoietic progenitors in blood of cancer patients: relationship between colony formation and CD34 expression. Vestnik RONTs im NN Blokhina RAMN. 2000;11(1):5–10. (In Russ)]

  37. Healy LE, Nirsimloo N, Scott M, et al. In vitro proliferation by cells mobilized into the peripheral blood for collection and autologous transplantation. Exp Hematol. 1994;22(13):1278–82.

  38. Magagnoli M, Spina M, Balzarotti M, et al. IGEV regimen and a fixed dose of lenograstim: an effective mobilization regimen in pretreated Hodgkin’s lymphoma patients. Bone Marrow Transplant. 2007;40(11):1019–25. doi: 10.1038/sj.bmt.1705862.

  39. Koutna I, Peterkova M, Simara P, et al. Proliferation and differentiation potential CD133+ and CD34+ populations from the bone marrow and mobilized peripheral blood. Ann Hematol. 2011;90(2):127–37. doi: 10.1007/s00277-010-1058-2.

  40. Балашова В.А., Ругаль В.И., Грицаев С.В. и др. Колониеобразующая способность гемопоэтических стволовых клеток мобилизованной периферической крови больных множественной миеломой до и после криоконсервирования. Трансфузиология. 2016;17(4):63–70.

    [Balashova VA, Rugal’ VI, Gritsaev SV, et al. Colony-forming capacity of hematopoietic stem cells of mobilized peripheral blood in multiple myeloma patients before and after cryopreservation. Transfuziologiya. 2016;17(4):63–70. (In Russ)]

  41. Балашова В.А., Ругаль В.И., Бессмельцев С.С. и др. Колониеобразующая способность гемопоэтических стволовых клеток мобилизованной периферической крови больных злокачественными лимфомами до и после криоконсервирования. Medline. 2018;19(3):45–54.

    [Balashova VA., Rugal VI., Bessmeltsev SS. et al. Colonyforming capacity of hematopoietic stem cells of mobilized peripheral blood in patients with malignant lymphomas before and after cryopreservation. Medline. 2018;19(3):45–54. (In Russ)]

Magnetic Resonance Imaging of Bone Marrow and its Results as a Criterion for Administration of Maintenance Therapy After Auto-HSCT in Multiple Myeloma Patients

BONE MARROW TRANSPLANTATION , , , ,

MV Solov’ev, LP Mendeleeva, GA Yatsyk, NS Lutsik, MV Firsova, EG Gemdzhian, VG Savchenko

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Maksim Valer’evich Solov’ev, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-31-92; е-mail: maxsolovej@mail.ru

For citation: Solov’ev MV, Mendeleeva LP, Yatsyk GA, et al. Magnetic Resonance Imaging of Bone Marrow and its Results as a Criterion for Administration of Maintenance Therapy After Auto-HSCT in Multiple Myeloma Patients. Clinical oncohematology. 2018;11(4):360–7.

DOI: 10.21320/2500-2139-2018-11-4-360-367

ABSTRACT

Aim. To evaluate the efficacy of maintenance therapy in multiple myeloma (MM) patients after autologous hematopoietic stem cell transplantation (auto-HSCT) based on the results of MRI of bone marrow.

Materials & Methods. The study included 32 MM patients aged 36 to 66 years (median 57 years) with complete remission after a single auto-HSCT. MRI of spine and pelvic bones was performed to identify the nature of bone marrow lesions and to determine the volume of tumor tissue on the day 100 after auto-HSCT. As maintenance therapy after auto-HSCT 14 patients received daily 15 mg lenalidomide in the period from day 1 to day 21 of the 28-day treatment course within 1 year. Monitoring of 18 patients was conducted without maintenance therapy. Statistical analysis included the assessment of progression-free survival (PFS) and relapse risk relationship to clinical and laboratory parameters.

Results. Twenty patients had a positive MRI (tumor volume > 1 cm3). Zero variation of MR signal in bone marrow and detection of a < 1 cm3 tumor were regarded as a negative MRI, which was the case in 12 patients. After reaching the negative MRI the best rates of 2-year PFS were registered: 100 % with maintenance therapy and 84 % without maintenance therapy. In patients with tumor load on MR scans the 2-year PFS significantly (p = 0.03) varied and accounted for 80 % in patients who received maintenance therapy vs. 33 % in patients without maintenance therapy. Administration of maintenance therapy after detecting residual tumor on MR scans on day 100 after auto-HSCT has a positive effect on PFS rates. Multivariate analysis confirmed the residual tumor on MR scans of bone marrow to be the most important parameter PFS depends on.

Conclusion. A negative MRI after auto-HSCT is a favourable prognostic factor determining a long-lasting (> 2 years) MM free period, despite the lack of maintenance therapy.

Keywords: multiple myeloma, magnetic resonance imaging (MRI), autologous hematopoietic stem cell transplantation (auto-HSCT), maintenance therapy, minimal residual disease.

Received: May 11, 2018

Accepted: August 29, 2018

Read in PDF 

REFERENCES

  1. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]

  2. Kumar SK, Rajkumar SV, Dispenzieri A, et Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.

  3. Mendeleeva LP, Solovev MV, Alexeeva A, at al. Multiple Myeloma in Russia (First Results of the Registration Trial). Blood. 2017;130(Suppl 1):5408.

  4. Passweg JR, Baldomero H, Bader Р, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018. doi: 10.1038/s41409-018-0153-1. [Epub ahead of print]

  5. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786–92. doi: 10.1038/bmt.2016.20.

  6. Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. Leukemia. 2017;31(8):1727–34. doi: 10.1038/leu.2016.381.

  7. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712–7. doi: 10.1200/JCO.2013.54.8164.

  8. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(Suppl 4):iv52–61. doi: 10.1093/annonc/mdx096.

  9. Syed YY. Lenalidomide: A Review in Newly Diagnosed Multiple Myeloma as Maintenance Therapy After ASCT. Drugs. 2017;77(13):1473–80. doi: 10.1007/s40265-017-0795-0.

  10. Goldschmidt H, Lokhorst HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018;32(2):383–90. doi: 10.1038/leu.2017.211.

  11. Rosinol L, Oriol A, Teruel AI, et al. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017;31(9):1922–7. doi: 10.1038/leu.2017.35.

  12. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013;121(23):4647–54. doi: 10.1182/blood-2012-11-464503.

  13. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55. doi: 10.1200/JCO.2011.39.6820.

  14. McCarthy PL, Owzar K, Hofmeister C, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770–81. doi: 10.1056/NEJMoa1114083.

  15. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012;366(19):1782–91. doi: 10.1056/NEJMoa1114138.

  16. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. doi: 10.1056/NEJMoa1402888.

  17. Solovev MV, Mendeleeva LP, Pokrovskaya OS, et al. Maintenance Therapy after Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) in Multiple Myeloma Patients with and without Minimal Residual Disease (MRD). Blood. 2016;128(22):2260.

  18. Solovev MV, Mendeleeva LP, Pokrovskaya OS, et al. The Duration of MRD-Negative Status in Multiple Myeloma (MM) Patients after Auto-HSCT Is a Criterion for Prolonged Remission without Maintenance Therapy. Blood. 2017;130(Suppl 1):3294.

  19. Dutoit JC, Verstraete KL. Whole-body MRI, dynamic contrast-enhanced MRI, and diffusion-weighted imaging for the staging of multiple myeloma. Skelet Radiol. 2017;46(6):733–50. doi: 10.1007/s00256-017-2609-6.

  20. Latifoltojar A, Hall‐Craggs M, Rabin N, et al. Whole body magnetic resonance imaging in newly diagnosed multiple myeloma: early changes in lesional signal fat fraction predict disease response. Br J Haematol. 2017;176(2):222–33. doi: 10.1111/bjh.14401.

  21. Lasocki A, Gaillard F, Harrison SJ. Multiple myeloma of the spine. Neuroradiol J. 2017;30(3):259–68. doi: 10.1177/1971400917699426.

  22. Bray TJ, Singh S, Latifoltojar A, et al. Diagnostic utility of whole body Dixon MRI in multiple myeloma: A multi-reader study. PLoS One. 2017;12(7):e0180562. doi: 10.1371/journal.pone.0180562.

  23. Sabour S. Whole-body ultra-low dose computed tomography in comparison with spinal magnetic resonance imaging in the assessment of disease in multiple myeloma; Methodological issues on Diagnostic value. Br J Haematol. 2017. doi: 10.1111/bjh.14849. [Epub ahead of print]

  24. Chantry A, Kazmi M, Barrington S, et al. Guidelines for the use of imaging in the management of patients with myeloma. Br J Haematol. 2017;178(3):380–93. doi: 10.1111/bjh.14827.

  25. Moulopoulos LA, Gika D, Anagnostopoulos A, et al. Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma. Ann Oncol. 2005;16(11):1824–8. doi: 10.1093/annonc/mdi362.

  26. Mai EK, Hielscher T, Kloth JK, et al. Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology. Eur Radiol. 2016;26(11):3939–48. doi: 10.1007/s00330-015-4195-0.

  27. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25(9):1121–8. doi: 10.1200/JCO.2006.08.5803.

  28. Richardson PG, Holstein SA, Schlossman RL, et al. Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma: a review of options for and against. Expert Opin Pharmacother. 2017;18(18):1975–85. doi: 10.1080/14656566.2017.1409207.

  29. Pulte ED, Dmytrijuk A, Nie L, et al. FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma. Oncologist. 2018;23(6):734–9. doi: 10.1634/theoncologist.2017-0440.

  30. Sengsayadeth S, Malard F, Savani BN, et al. Posttransplant maintenance therapy in multiple myeloma: the changing landscape. Blood Cancer J. 2017;7(3):e545. doi: 10.1038/bcj.2017.23.

  31. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol. 2017;35(29):3279–89. doi: 10.1200/JCO.2017.72.6679.

  32. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. doi: 10.1182/blood-2016-01-631200.

  33. Sivaraj D, Green MM, Li Z, et al. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(2):262–8. doi: 10.1016/j.bbmt.2016.11.010.

  34. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study. Blood. 2016;128(22):1143.

  35. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8. doi: 10.1182/blood-2011-09-379164.

  36. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial. Blood. 2017;130(Suppl 1):436.

  37. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013;121(23):4647–54. doi: 10.1182/blood-2012-11-464503.

  38. Phase III Studies Present Additional Evidence for REVLIMID® (lenalidomide) as Maintenance Therapy in Multiple Myeloma. Available from: http://ir.celgene.com/releasedetail.cfm?releaseid=1003026 (accessed 2.05.2018).

  39. Соловьев М.В., Менделеева Л.П., Покровская О.С. и др. Множественная миелома: поддерживающая терапия после трансплантации аутологичных гемопоэтических стволовых клеток в зависимости от минимальной остаточной болезни. Терапевтический архив. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31.

    [Solovyev MV, Mendeleeva LP, Pokrovskaya OS, et al. Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease. Terapevticheskii arkhiv. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31. (In Russ)]

 

The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure

NOVEL DRUGS , ,

IG Rekhtina, MV Nareiko, LP Mendeleeva

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Germanovna Rekhtina, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-49-66; e-mail: rekhtina.i@blood.ru

For correspondence: Rekhtina IG, Nareiko MV, Mendeleeva LP. The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure. Clinical oncohematology. 2018;11(4):283–7.

DOI: 10.21320/2500-2139-2018-11-4-283-287

ABSTRACT

The present review includes data on efficacy and safety of pomalidomide, an immunomodulating 3rd generation drug used for treatment of relapsed and refractory multiple myeloma patients with renal failure. The results of multicenter randomized trials proved similar efficacy and comparable safety profile in patients with normal renal function and patients with moderate and/or severe renal failure. All patients received the standard starting dose. Pomalidomide dose needs to be reduced in response to hematological toxicity. The paper provides practical guidelines on the use of pomalidomide and treatment of adverse events adopted by consensus of international experts. Current approaches to multiple myeloma with renal failure, and the use of pomalidomide in particular, are demonstrated by means of a clinical case.

Keywords: multiple myeloma, pomalidomide, renal failure.

Received: March 28, 2018

Accepted: July 16, 2018

Read in PDF 

REFERENCES

  1. Qian Y, Bhowmik D, Bond C, et al. Renal impairment and use of nephrotoxic agents in patients with multiple myeloma in the clinical practice setting in the United States. Cancer Med. 2017;6(7):1523–30. doi: 10.1002/cam4.1075.

  2. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).

    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]

  3. Имновид® (инструкция по медицинскому применению). Будри, Швейцария: Celgene International, Sarl. Доступно по: https://www.vidal.ru/drugs/imnovid__44356. Ссылка активна на 30.06.2018.

    [Imnovid® (package insert). Boudry, Switzerland: Celgene International, Sarl. Available from: https://www.vidal.ru/drugs/imnovid__44356. (accessed 30.06.2018) (In Russ)]

  4. Dimopoulos MA, Palumbo A, Corradini P, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128(4):497–503. doi: 10.1182/blood-2016-02-700872.

  5. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826–32. doi: 10.1182/blood-2014-04-566661.

  6. Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomized, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.

  7. Siegel DS, Weisel KC, Dimopoulosc MA, et al. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials. Leuk Lymphoma. 2016:57(12):2833–8. doi: 10.1080/10428194.2016.1177181.

  8. Matous J, Siegel DS, Lonial S, et al. A Phase 1 Study of the Pharmacokinetics (PK) and Safety of Pomalidomide + Low Dose Dexamethasone (POM+LODEX) in Patients (PTS) With Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI). Clin Lymph Myel Leuk. 2015;15:e265. doi: 10.1016/j.clml.2015.07.557.

  9. Sonneveld P, Dimopoulos M, Ramasamy K, et al. Treatment (Tx) With Pomalidomide (POM) and Low-Dose Dexamethasone (LoDEX) in Patients (Pts) With Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI) Including Those on Dialysis. Clin Lymph Myel Leuk. 2015;15:e265. doi: 10.1016/j.clml.2015.07.556.

  10. Weisel K, Dimopoulos M, Van de Donk N, et al. Phase 2 Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): An Updated Safety Analysis. Clin Lymph Myel Leuk. 2017;17(1):e145. doi: 10.1016/j.clml.2017.03.261.

  11. Sonneveld P, Weisel K, Van de Donk N et al. MM-013 phase 2 multicenter study of pomalidomide plus low-dose dexamethasone in patients with RRMM and renal impairment. 22nd Congress of the European Hematology Association (EHA). 2017. Abstract P343.

  12. Li Y, Wang X, O’Mara E, et al. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function. Clin Pharmacol Adv Appl. 2017;9:133–45. doi: 10.2147/CPAA.S144606.

  13. Dimopoulos M, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573–85. doi: 10.1038/leu.2014.60.

Hematopoietic Stem Cell Collection in Multiple Myeloma Patients: Influence of the Lenalidomide-Based Therapy and Mobilization Regimen Prior to Auto-HSCT

BONE MARROW TRANSPLANTATION , , , , , ,

II Kostroma, AA Zhernyakova, ZhV Chubukina, IM Zapreeva, SA Tiranova, AV Sel’tser, NYu Semenova, SS Bessmel’tsev, AV Chechetkin, SV Gritsaev

Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Ivan Ivanovich Kostroma, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Теl.: +7(921)784-82-82; e-mail: obex@rambler.ru

For citation: Kostroma II, Zhernyakova AA, Chubukina ZhV, et al. Hematopoietic Stem Cell Collection in Multiple Myeloma Patients: Influence of the Lenalidomide-Based Therapy and Mobilization Regimen Prior to Auto-HSCT. Clinical oncohematology. 2018;11(2):192–7.

DOI: 10.21320/2500-2139-2018-11-2-192-197

ABSTRACT

Background. A prompt graft acceptance is essential for positive autologous hematopoietic stem cell transplantation (auto-HSCT) outcome in multiple myeloma patients (MM). Prompt and favourable hematopoietic regeneration is associated with CD34+ cell count in a transplant. Although the indicators of low autotransplant cellularity have been defined, the practical application of new drug products and HSC mobilization regimens strengthens the relevance of determining their influence on the transplant quality.

Aim. To determine the factors that are associated with low efficacy of auto-HSCT in MM patients and to evaluate the impact of lenalidomide during induction period and of vinorelbine as a mobilization regimen on the prognosis.

Materials & Methods. The authors performed a retrospective analysis of autotransplant collection results in 68 MM patients treated with two mobilization regimens: 3 g/m2 cyclophosphamide with granulocyte colony-stimulating factor (G-CSF) and 30 mg/m2 vinorelbine with G-CSF. Mobilization was aimed at collecting not less than 2–4 × 106 CD34+ cells per kg body mass. CD34+ cell count was determined by four-color analysis on the Cytomics FC 500 laser flow cytometer.

Results. The analysis showed that age or MM immunochemical specificity were not associated with CD34+ cell count in the transplant. Prior lenalidomide treatment compared to therapy without immunomodulators (4.1 × 106/kg vs. 7.76 × 106/kg) tends to decrease CD34+ count (р = 0.066). Cyclophosphamide included into mobilization regimen compared to vinorelbine (3.96 × 106/kg vs. 6.8 × 106/kg) significantly increased CD34+ cell count (р = 0.022).

Conclusion. The decrease of CD34+ cell count in the autotransplant of the MM patients treated with lenalidomide prior to auto-HSC collection, and a lower mobilization activity of vinorelbine provide a basis for a differentiated selection of mobilization regimens. Vinorelbine may be administered to patients with a single auto-HSCT, i.e. elderly people and patients with complete response. In case of substantial lenalidomide treatment prior to auto-HSCT, intermediate-dose cyclophosphamide is preferred.

Keywords: auto-HSCT, multiple myeloma, mobilization regimen, cyclophosphamide, vinorelbine, lenalidomide, predictors.

Received: November 29, 2017

Accepted: February 9, 2018

Read in PDF 

REFERENCES

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: МК, 2016. 504 с.[Bessmel’tsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for physicians.) Moscow: MK Publ.; 2016. 504 p. (In Russ)]
  2. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).[Mendeleeva OP, Votyakova OM, Pokrovskaya OS, et al. National clinical recommendations in diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]
  3. Bender JG, To LB, Williams S, Schwartzberg LS. Defining a therapeutic dose of peripheral blood stem cells. J Hematother. 1992;1(4):329–41. doi: 10.1089/scd.1.1992.1.329.
  4. Olivieri A, Offidani M, Montanari M, et al. Factors affecting hemopoietic recovery after high-dose therapy and autologous peripheral blood progenitor cell transplantation: a single center experience. 1998;83(4):329–37.
  5. Nakasone H, Kanda Y, Ueda T, et al. Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma. Am J Hematol. 2009;84(12):809–14. doi: 1002/ajh.21552.
  6. Stiff PJ, Micalef I, Nademanee AP, et al. Transplanted CD34+ cell dose associated with long-term platelet count recovery following autologous peripheral blood stem cell transplant in patients with non-Hodgkin lymphoma or multiple myeloma. Biol Blood Marrow Transplant. 2011;17(8):1146–53. doi: 1016/j.bbmt.2010.11.021.
  7. Hamadani M, Kochuparambil T, Osman S, et al. Intermediate-dose versus low-dose cyclophosphamide and granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in patients with multiple myeloma treated with novel induction therapies. Biol Blood Marrow Transplant. 2012;18(7):1128–35. doi: 1016/j.bbmt.2012.01.005.
  8. Грицаев С.В., Кузяева А.А., Волошин С.В. и др. Заготовка трансплантата для аутологичной трансплантации гемопоэтических стволовых клеток онкогематологическим больным: частота и причины неудачных сборов. Русский медицинский журнал. 2013;1:30–[Gritsaev SV, Kuzyaeva AA, Voloshin SV, et al. Transplant collection for autologous stem cell transplantation in patients with oncohematological diseases: frequency and reasons for poor mobilization. Russkii meditsinskii zhurnal. 2013;1:30–5. (In Russ)]
  9. Stockerl-Goldstein KE, Reddy SA, Horning SF, et al. Favorable treatment outcome in nonHodgkin’s lymphoma patients with ‘poor’ mobilization of peripheral blood progenitor cells. Biol Blood Marrow Transplant. 2000;6(5):506–12. doi: 1016/s1083-8791(00)70021-8.
  10. Watts MJ, Ings SJ, Flynn M, et al. Remobilization of patients who fail to achieve minimal progenitor thresholds at the first attempt is clinically worthwhile. Br J Haematol. 2000;111(1):287–91. doi: 1111/j.1365-2141.2000.02346.x.
  11. Sugrue MW, Williams K, Pollock BH, et al. Characterization and outcome of ‘hard to mobilize’ lymphoma patients undergoing autologous stem cell transplantation. Leuk Lymphoma. 2000;39(5–6):509–19. doi: 3109/10428190009113381.
  12. Грицаев С.В., Кузяева А.А., Бессмельцев С.С. Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе. Клиническая онкогематология. 2017;10(1):7–12. doi: 21320/2500-2139-2017-10-1-7-12.[Gritsaev SV, Kuzyaeva AA, Bessmel’tsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12. doi: 10.21320/2500-2139-2017-10-1-7-12. (In Russ)]
  13. Down JD, Boudewijn A, Dillingh JH, et al. Relationships between ablation of distinct haematopoietic cell subsets and the development of donor bone marrow engraftment following recipient pretreatment with different alkylating drugs. Br J 1994;70(4):611–6. doi: 10.1038/bjc.1994.359.
  14. Lokhorst HM, Sonneveld P, Wijermans PW, et al. Intermediate-dose melphalan (IDM) combined with G-CSF (filgrastim) is an effective and safe induction therapy for autologous stem cells in multiple myeloma. Br J Haematol. 1996;92(1):44–8. doi: 1046/j.1365-2141.1996.00306.x.
  15. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035– doi: 10.1038/sj.leu.2404801.
  16. Mazumder A, Kaufman J, Niesvizky R, et al. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia. 2008;22(6):1280–1. doi: 1038/sj.leu.2405035.
  17. Mark T, Stern J, Furst JR, et al. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Biol Blood Marrow Transplant. 2008;14(7):795–8. doi: 1016/j.bbmt.2008.04.008.
  18. Popat U, Saliba R, Thandi R, et al. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biol Blood Marrow Transplant. 2009;15(6):718–23. doi: 10.1016/j.bbmt.2009.02.011.
  19. Nazha A, Cook R, Vogl DT, et al. Stem cell collection in patients with multiple myeloma: impact of induction therapy and mobilization regimen. Bone Marrow Transplant. 2011;46(1):59– doi: 10.1038/bmt.2010.63.
  20. Cavallo F, Bringhen S, Milone G, et al. Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy. Leukemia. 2011;25(10):1627–31. doi: 10.1038/leu.2011.131.
  21. Bhutani D, Zonder J, Valent J, et al. Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma. Supp Care Cancer. 2013;21(9):2437–42. doi: 10.1007/s00520-013-1808-5.
  22. Elliot C, Samson DM, Armitage S, et al. When harvest peripheral blood stem cells after mobilization therapy: prediction of CD34-positive cell yield by preceding day CD34-positive concentration in peripheral blood. J Clin Oncol. 1996;14(3):970–3. doi: 1200/JCO.1996.14.3.970.
  23. Remes K, Matinlauri I, Grenman S, et al. Daily measurements of blood CD34+ cells after stem cell mobilization predict stem cell yield and post-transplant hematopoietic recovery. J Hematother. 1997;6(1):13–9. doi: 10.1089/scd.1.1997.6.13.
  24. Knudsen LM, Gaarsdal E, Jensen L, et al. Evaluation of mobilized CD34+ cell counts to guide timing and yield of large-scale collection by leukapheresis. J Hematother. 1998;7(1):45–52. doi: 10.1089/scd.1.1998.7.45.
  25. Corso A, Caberlon S, Pagnucco G, et al. Blood stem cell collections in multiple myeloma: definition of a scoring system. Bone Marrow Transplantat. 2000;26(3):283–6. doi: 1038/sj.bmt.1702514.
  26. Perea G, Sureda A, Martino R, et al. Predictive factors for a successful mobilization of peripheral blood CD34+ cells in multiple myeloma. Ann Hematol. 2001;80(10):592–7. doi: 1007/s002770100351.
  27. Gojo I, Guo C, Sarkodee-Adoo C, et al. High dose cyclophosphamide with or without etoposide for mobilization of peripheral blood progenitor cells in patients with multiple myeloma: efficacy and toxicity. Bone Marrow Transplant. 2004;34(1):69–76. doi: 1038/sj.bmt.1704529.
  28. Гальцева И.В., Давыдова Ю.О., Гапонова Т.В. и др. Абсолютное количество гемопоэтических стволовых клеток CD34+ в периферической крови перед процедурой лейкоцитафереза как параметр, прогнозирующий эффективность сбора стволовых клеток. Терапевтический архив. 2017;89(7):18–24. doi: 17116/terarkh201789718-24.[Gal’tseva IV, Davydova YuO, Gaponova TV, et al. Absolute numbers of peripheral blood CD34+ hematopoietic stem cells prior to a leukapheresis procedure as a parameter predicting the efficiency of stem cell collection. Terapevticheskii arkhiv. 2017;89(7):18–24. doi: 10.17116/terarkh201789718-24. (In Russ)]
  29. Fu P, Bagai RK, Meyerson H, et al. Pre-mobilization therapy blood CD34+ cell count predicts the likelihood of successful hematopoietic stem cell mobilization. Bone Marrow Transplant. 2006;38(3):189–96. doi: 1038/sj.bmt.1705431.
  30. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14(9):1045–56. doi: 1016/j.bbmt.2008.07.004.
  31. Ozsan GH, Micallef IN, Dispenzieri A, et al. Hematopoietic recovery kinetics predicts for poor CD34+ cell mobilization after cyclophosphamide chemotherapy in multiple myeloma. Am J Hematol. 2012;87(1):1–4. doi: 10.1002/ajh.22179.
  32. Duarte RF, Shaw BE, Marin P, et al. Plerixafor plus granulocyte CSF can mobilize hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilization attempts: EU compassionate use data. Bone Marrow Transplant. 2011;46(1):52–8. doi: 10.1038/bmt.2010.54.
  33. Fruehauf S, Ehninger G, Hubel K, et al. Mobilization of peripheral blood stem cells for autologous transplant in non-Hodgkin’s lymphoma and multiple myeloma patients by plerixafor and G-CSF and detection of tumor cell mobilization by PCR in multiple myeloma patients. Bone Marrow Transplant. 2010;45(2):269–75. doi: 1038/bmt.2009.142.

Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of New Drugs

BONE MARROW TRANSPLANTATION , ,

OV Pirogova, EI Darskaya, VV Porunova, OV Kudyasheva, AG Smirnova, IS Moiseev, EV Babenko, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Ol’ga Vladislavovna Pirogova, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: dr.pirogova@gmail.com.

For citation: Pirogova OV, Darskaya EI, Porunova VV, et al. Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of New Drugs. Clinical oncohematology. 2018;11(2):187–91.

DOI: 10.21320/2500-2139-2018-11-2-187-191

ABSTRACT

Background & Aims. The present retrospective single-center study analysed the impact of high-dose chemotherapy with melphalan with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) on survival in multiple myeloma (MM) in the era of new induction regimens.

Materials & Methods. The clinical trial included 133 MM patients aged from 31.2 to 78.2 years (the median age was 55.3 years). There were 66 female and 67 male patients. Bortezomib-based regimens as first-line treatment were administered in 133 MM patients, 74 of them received high-dose chemotherapy with melphalan and either single (n = 25), or double (n = 49) auto-HSCT as consolidation therapy in the period from 2006 to 2016.

Results. The overall 5-year survival (OS) rates were 86.5 % for the auto-HSCT treated group vs. 72.9 % for the non-auto-HSCT treated group (p = 0.03); 5-year progression-free survival (PFS) rates were 64.9 vs. 39 % for the auto-HSCT and non-auto-HSCT treated groups, respectively (p = 0.0016). MM relapse/progression occurred more frequently in the non-auto-HSCT treated patients (52.5 vs. 28.4 %; p = 0.0016). In multivariate analysis the age above 60 was determined as prognostic factor of lower PFS and increase in relapse/progression rate (p = 0.004 and p = 0.04, respectively). The variant of monoclonal protein (Bence-Jones myeloma) was determined as prognostic factor of higher OS and decrease in relapse/progression rate (p = 0.02 and p = 0.04, respectively). Complete nonresponsiveness to induction therapy has proved to be an independent predictor of both poor OS and PFS (p = 0.04 and p = 0.041, respectively). 2-year bortezomib-based maintenance therapy following the auto-HSCT treatment resulted in a statistically significant improvement in 5-year PFS (67.4 vs. 60.7 %; p = 0.03) and a decrease in relapse/progression frequency (26.1 vs. 32.1 %; p = 0.05).

Conclusion. High-dose chemotherapy with melphalan with subsequent auto-HSCT is an effective MM treatment strategy, and a subsequent long-term maintenance therapy results in a PFS improvement and a decrease in relapse/progression frequency.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, maintenance therapy.

Received: November 20, 2017

Accepted: February 9, 2018

Read in PDF 

REFERENCES

  1. Дарская Е.И., Марами-Зонузи Н.Э., Осипов Ю.С. и др. Эффективность терапии пациентов с множественной миеломой, получавших в качестве первой линии трансплантацию аутологичных гемопоэтических стволовых клеток.Онкогематология. 2014;9(1):6–10.[Darskaya EI, Marami-Zonuzi NE, Osipov YuS, et al. Therapy efficacy in multiple myeloma patients received autologous stem cells transplantation as first line therapy. Onkogematologiya. 2014;9(1):6–10. (In Russ)]
  2. Barlogie B, Gahrton G. Bone marrow transplantation in multiple myeloma. Bone Marrow Transplant. 1991;7(2):71–9.
  3. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875–83. doi: 10.1056/nejmoa022340.
  4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335(2):91–7. doi: 1056/nejm199607113350204.
  5. Lenhoff S, Hjorth M, Holmberg E, et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Blood. 2000;95(1):7–11.
  6. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495–502. doi: 10.1056/nejmoa032290.
  7. Singhal S, Mekta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71. doi: 10.1056/nejm199911183412102.
  8. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609–17. doi: 10.1056/nejmoa030288.
  9. Kropff MH, Bisping G, Wenning D, et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk Res. 2005;29(5):587–90. doi: 10.1016/j.leukres.2004.11.004.
  10. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–64. doi: 10.1182/blood-2006-04-015909.
  11. Brenner H, Gondos A, Pulte D. Recent major improvements in long-term survival of younger patients with multiple myeloma. Blood. 2008;111(5):2521–6. doi: 10.1182/blood-2007-08-104984.
  12. Schaapveld M, Visser O, Siesling S, et al. Improved survival among younger but not among older patients with multiple myeloma in the Netherlands, a population- based study since 1989. Eur J Cancer. 2010;46(1):160–9. doi: 10.1016/j.ejca.2009.07.006.
  13. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.
  14. Moreau P, Avet-Loiseau H, Harrousseau JL, Attal M. Current trends in autologous stem cell transplantation for myeloma in the era of novel therapies. J Clin Oncol. 2011;29(14):1898–906. doi: 10.1200/jco.2010.32.5878.
  15. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–73. doi: 10.1038/sj.leu.2404284.
  16. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075–85. doi: 10.1016/s0140-6736(10)61424-9.
  17. Koreth J, Cutler CS, Djulbegovic B, et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007;13(2):183–96. doi: 10.1016/j.bbmt.2006.09.010.
  18. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55. doi: 10.1200/jco.2011.39.6820.
  19. Rosinnol L, Oriol A, Teruel AI, et al. Maintenance Therapy After Stem-Cell Transplantation for Multiple Myeloma with Bortezomib/Thalidomide Vs. Thalidomide Vs. alfa2b-Interferon: Final Results of a Phase III Pethema/GEM Randomized Trial. ASH Annual Meeting Abstracts. 2012;120(21):334.

Evolution of Anti-Cancer Treatment and its Impact on Surrogate Prognostic Factors in Multiple Myeloma

LYMPHOID TUMORS , , ,

AS Luchinin1, SV Semochkin2, NV Minaeva1, NM Pozdeev1, IV Paramonov1

1 Kirov Research Institute of Hematology and Transfusiology, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027

2 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Aleksandr Sergeevich Luchinin, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027; Tel.: +7(919)506-87-86; e-mail: glivec@mail.ru

For citation: Luchinin AS, Semochkin SV, Minaeva NV, et al. Evolution of Anti-Cancer Treatment and its Impact on Surrogate Prognostic Factors in Multiple Myeloma. Clinical oncohematology. 2018;11(2):175–81.

DOI: 10.21320/2500-2139-2018-11-2-175-181

ABSTRACT

Aim. To assess prognostic value of surrogate clinical and laboratory markers in current therapy of multiple myeloma (MM).

Materials & Methods. The analysis included 567 patients (215 men and 352 women), the Kirov region inhabitants with newly diagnosed MM over the period from January 1, 1994 to December 31, 2016. The median age was 64 years (range 29–90). Patients were divided into two groups: the first group received treatment from 1994 to 2005 (n = 269), the second group received treatment from 2006 to 2016 (n = 298). Impact of factors on overall survival (OS) was evaluated by multivariate logistic regression analysis using the Cox method.

Results. Over the period from 2006 to 2016 the number of patients treated with traditional chemotherapy decreased from 78.4 to 32.5 %. At the same time the number of patients treated with bortezomib-based regimens increased from 1.9 to 56.3 % and autologous hematopoietic stem cell transplantation (auto-HSCT) protocols — from 1.4 to 14.0 %. Median OS over the period from 1994 to 2005 was 27 months. It increased to 55 months in the period of 2006–2016. In the reference decades 5-year overall survival increased from 21 % (95% confidence interval [95% CI] 17–27 %) to 47 % (95% CI 39–55 %), respectively (hazard ratio [HR] 0.51; 95% CI 0.41–0.64; p < 0,0001). In patients treated with bortezomib-based regimens over the period from 2006 to 2016 median OS increased to 73 months compared to 27 months in 1994–2005. In patients aged ≤ 65 years and treated with auto-HSCT median OS was not reached, and median OS in patients without auto-HSCT treatment was 54 months.

Conclusions. Surrogate prognostic markers, such as the age over 65, hemoglobin level < 100 g/L, β2-microglobulin ≥ 6 mg/L, serum creatinine ≥ 177 µmol/L and stage III according to ISS and Durie-Salmon, are unfavourable predictors of survival of MM patients.

Keywords: multiple myeloma, prognosis, bortezomib, auto-HSCT, overall survival.

Received: December 21, 2017

Accepted: February 25, 2018

Read in PDF 

REFERENCES

  1. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).[Mendeleeva OP, Votyakova OM, Pokrovskaya OS, et al. National clinical recommendations in diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]
  2. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: МК, 2016. 504 с.[Bessmel’tsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for physicians.) Moscow: MK Publ.; 2016. 504 p. (In Russ)]
  3. Ghobrial IM, Landgren O. How I treat smoldering multiple myeloma. Blood. 2014;124(23):3380–8. doi: 10.1182/blood-2014-08-551549.
  4. Hsu P, Lin TW, Gau JP, et al. Risk of early mortality in patients with newly diagnosed multiple myeloma. Medicine. 2016;94(50):e2305. doi: 1097/MD.0000000000002305.
  5. Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol. 2015;171(2):189–96. doi: 10.1111/bjh.13537.
  6. Libby E, Garcia D, Quintana D, et al. Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups. Leuk Lymphoma. 2014;55(12):2850–7. doi: 10.3109/10428194.2014.89770
  7. Митина Т.А., Голенков А.К., Трифонова Е.В. и др. Эффективность леналидомида, бортезомиба и преднизолона при лечении пациентов с рецидивирующей и рефрактерной множественной миеломой. Онкогематология. 2015;4(10):8–14. doi: 10.17650/1818-8346-2015-10-4-8-14.[Mitina TA, Golenkov AK, Trifonova EV, et al. Efficacy of lenalidomide, bortezomib, and prednisolone in patients with relapsed or refractory multiple myeloma. Oncohematology. 2015;4(10):8–14. doi: 10.17650/1818-8346-2015-10-4-8-14. (In Russ)]
  8. Hungria VTМ, Maiolino A, Martinez G, et al. Confirmation of the utility of the International Staging System and identification of a unique pattern of disease in Brazilian patients with multiple myeloma. Haematologica. 2008;93(5):791–2. doi: 10.3324/haematol.11637.
  9. Lu J, Lu J, Liu A, et al. The applicability of the International Staging System in Chinese patients with multiple myeloma receiving bortezomib or thalidomide-based regimens as induction therapy: a multicenter analysis. Biomed Res Int. 2015;2015:1–7. doi: 10.1155/2015/856704.
  10. Dosani T, Covut F, Beck R, et al. Significance of the absolute lymphocyte/monocyte ratio as a prognostic immune biomarker in newly diagnosed multiple myeloma. Blood Cancer J. 2017;7(6):e579. doi: 10.1038/bcj.2017.60.
  11. Hanbali A, Hassanein M, Rasheed W, et al. The evolution of prognostic factors in multiple myeloma. Adv Hematol. 2017;2017:1–11. doi: 10.1155/2017/4812637.
  12. Chng WJ, Dispenzieri A, Chim CS, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014;28(2):269–77. doi: 10.1038/leu.2013.247.
  13. Rajkumar SV, Kumar S. Multiple Myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91(1):101–18. doi: 10.1016/j.mayocp.2015.11.007.
  14. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for multiple myeloma: a report from IMWG. J Clin Oncol. 2015;33(26):2863–6. doi: 10.1200/JCO.2015.61.2267.

Classification of Conditioning Regimens for Bone Marrow Transplantation: Historical Background and Current Perspectives

BONE MARROW TRANSPLANTATION , , , , , ,

KN Melkova, GD Petrova, NV Gorbunova, TZ Chernyavskaya, OP Trofimova

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Kapitolina Nikolaevna Melkova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: frolov63@bk.ru

For citation: Melkova KN, Petrova GD, Gorbunova NV, et al. Classification of Conditioning Regimens for Bone Marrow Transplantation: Historical Background and Current Perspectives. Clinical oncohematology. 2017;10(4):494–500 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-494-500

ABSTRACT

Hematopoietic stem cells transplantation is a current standard treatment for many oncohematological diseases. The milestone of any type of transplantation is the choice of conditioning regimen. This article presents the principles of classification of conditioning regimens in terms of myeloablativity and discusses the concepts of “autologous transplantation”, “high-dose chemotherapy supported by hematopoietic stem cells”, “allogeneic transplantation” and “immunotherapy”. Up-to-date uniform classification of conditioning regimens may serve an important prognostic component in assessing both the risks and efficacy of hematopoietic stem cells transplantation.

Keywords: conditioning regimens, allogeneic hematopoietic stem cell transplantation, autologous hematopoietic stem cell transplantation, total therapeutic exposure, acute leukemia, Hodgkin’s lymphoma, multiple myeloma.

Received: March 29, 2017

Accepted: July 8, 2017

Read in PDF

REFERENCES

  1. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50(4):476–82. doi: 10.1038/bmt.2014.312.
  2. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Трансплантация костного мозга при острых лейкозах. Клиническая онкогематология. 2010;3(4):395–9.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Bone Marrow Transplantation in Case of Acute Leukemia. Klinicheskaya onkogematologiya. 2010;3(4):395–9. (In Russ)]
  3. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Аутологичная трансплантация гемопоэтических стволовых клеток при первично-рефрактерном течении лимфомы Ходжкина: мнимый цугцванг или промежуточный ход? Клиническая онкогематология. 2015;8(3):321–30. doi: 10.21320/2500-2139-2015-8-3-321-330.[Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug? Clinical oncohematology. 2015;8(3):321–30. doi: 10.21320/2500-2139-2015-8-3-321-330. (In Russ)]
  4. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Первично-рефрактерное течение лимфомы Ходжкина и аутологичная трансплантация гемопоэтических стволовых клеток. Результаты одноцентрового проспективного исследования. Российский онкологический журнал. 2015;20(3):4–11.[Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Primary-Refractory Course of Hodgkin’s Lymphoma and Autologous Hematopoietic Stem Cell Transplantation. Results of Single Center Prospective Study. Rossiiskii onkologicheskii zhurnal. 2015;20(3):4–11. (In Russ)]
  5. Петрова Г.Д., Мелкова К.Н., Горбунова Н.В. и др. Аутологичная трансплантация гемопоэтических стволовых клеток для консолидации ремиссии острого миелобластного лейкоза с факторами неблагоприятного прогноза в дебюте заболевания. Онкогематология. 2016;11(1):52–61. doi: 10.17650/1818-8346-2016-11-1-52-61.[Petrova GD, Melkova KN, Gorbunova NV, et al. Autologous Hematopoietic Stem Cell Transplantation for Remission Consolidation of Acute Myeloblastic Leukemia with Factors of Poor Prognosis in Disease Onset. Oncohematology. 2016;11(1):52–61. doi: 10.17650/1818-8346-2016-11-1-52-61. (In Russ)]
  6. Мелкова К.Н., Петрова Г.Д., Чернявская Т.З. Заготовка гемопоэтических стволовых клеток для проведения аутологичной трансплантации у пациентов с лимфомой Ходжкина неблагоприятного прогноза. Вестник ФГБНУ «РОНЦ им. Н.Н. Блохина». 2015;26(3):51–6.[Melkova KN, Petrova GD, Chernyavskaya TZ. Hematopoietic Stem Cells Preparation for Autologous Transplantation in Patients with Hodgkin’s Lymphoma of Poor Prognosis. Vestnik FGBNU «RONTs im. N.N. Blokhina». 2015;26(3):51–6. (In Russ)]
  7. Чернявская Т.З., Мелкова К.Н., Горбунова Н.В. и др. Использование стимулированного костного мозга для трансплантации в онкологии. Онкология. 2012;(2, приложение):28–33.[Chernyavskaya TZ, Melkova KN, Gorbunova NV, et al. Usage of Stimulated Bone Marrow for Oncology Transplantation. Onkologiya. 2012;(2 Suppl):28–33. (In Russ)]
  8. Melkova K, Chernyavskaya T, Abdusalamov S, et al. Application of autologous stimulated bone marrow as a source of hematopoietic material for transplantation. Cell Ther Transplant. 2011;3(12):33.
  9. Melkova K, Chernyavskaya T, Abdusalamov S, et al. Using stimulated bone marrow as a source of hematopoietic stem cells for allogenic transplantation. Cell Ther Transplant. 2011;3(12):34.
  10. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Интенсивная сопроводительная терапия в онкологии и гематологии. Вестник московского онкологического общества. 2011;2:3–4.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Intensive Supportive Therapy in Oncology and Hematology. Vestnik moskovskogo onkologicheskogo obshchestva. 2011;2:3–4. (In Russ)]
  11. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Интенсивная сопроводительная терапия в гематологии. Клиническая онкогематология. 2011;4(1):70–4.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Intensive Supportive Therapy in Hematology. Klinicheskaya onkogematologiya. 2011;4(1):70–4. (In Russ)]
  12. Мелкова К.Н. Аллогенная трансплантация костного мозга. Клиническая онкогематология. 2012;5(1):1–12.[Melkova KN. Allogeneic Bone Marrow Transplantation. Klinicheskaya onkogematologiya. 2012;5(1):1–12. (In Russ)]
  13. Vriesendorp HM. Aims of the conditioning. Exp Hematol. 2003;31(10):844–54. doi: 10.1016/s0301-472x(03)00229-7.
  14. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation. Haematologica. 2004;89(10):1238–47.
  15. Мелкова К.Н., Горбунова Н.В., Чернявская Т.З. и др. Тотальное облучение организма человека при трансплантации костного мозга. Клиническая онкогематология. 2012;5(2):96–114.[Melkova KN, Gorbunova NV, Chernyavskaya TZ, et al. Total Human Body Irradiation at Bone Marrow Transplantation. Klinicheskaya onkogematologiya. 2012;5(2):96–114. (In Russ)]
  16.  Gratwohl A, Carreras E. Principles of conditioning. In: Apperley J, Carreras E, Gluckman E, Masszi T, eds. Hematopoietic Stem Cell Transplantation, 6th edition. Genoa: Forum service editore; 2012. pp. 122–37.
  17. Bensinger WI. High-dose preparatory regimens. In: Forman SJ, Negrin RS, Antin JH, eds. Thomas’ Hematopoietic Cell Transplantation, 5th edition. Willey Blackwell; 2016. Vol. 1. pp. 223–31.
  18. Лебеденко И.М., Ратнер Т.Г., Водяник В.В. и др. Проведение тотального облучения пациента перед трансплантацией костного мозга. Радиационная онкология и ядерная медицина. 2012;2:30–6.[Lebedenko IM, Ratner TG, Vodyanik VV, et al. Performance of Total Patient Irradiation before Bone Marrow Transplantation. Radiatsionnaya onkologiya i yadernaya meditsina. 2012;2:30–6. (In Russ)]
  19. Лебеденко И.М., Ратнер Т.Г., Водяник В.В. и др. Техническое и дозиметрическое обеспечение тотального облучения пациента перед трансплантацией костного мозга. Медицинская физика. 2012;3(55):11–9.[Lebedenko IM, Ratner TG, Vodyanik VV, et al. Technical and Radiation-Monitoring Supply of Total Patient Irradiation before Bone Marrow Transplantation. Meditsinskaya fizika. 2012;3(5):11–9. (In Russ)]
  20. Лебеденко И.М., Чернявская Т.З., Ставицкий Р.В. и др. Технический контроль состояния организма и его систем в процессе химио-лучевой терапии и трансплантации костного мозга при острых лейкозах. Медицинская техника. 2014;5:32–7.[Lebedenko IM, Chernyavskaya TZ, Stavitskii RV, et al. Technical Control of Patient’s Body State and Its Systems in Process of Chemoradiotherapy and Bone Marrow Transplantation. Meditsinskaya tekhnika. 2014;5:32–7. (In Russ)]
  21. Storb RF, Champlin R, Riddell SR, et al. Non-myeloablative transplants for malignant disease. Hematology Am Soc Hematol Educ Program. 2001;1:375–91. doi: 10.1182/asheducation-2001.1.375.
  22. Мелкова К.Н., Петрова Г.Д. Материалы 41-го конгресса Европейского общества по трансплантации костного мозга. Клиническая онкогематология. 2015;8(3):343–52.[Melkova KN, Petrova GD. Materials of 41st Congress of European Society of Bone Marrow Transplantation. Clinical oncohematology. 2015;8(3):343–52. (In Russ)]
  23. Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood. 2004;104(4):961–8. doi: 10.1182/blood-2004-02-0545.
  24. Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15(3):367. doi: 10.1016/j.bbmt.2008.12.497.
  25. Khouri I, Giralt S, Champlin R. Non-Myeloablative Allogeneic Hematopoietic Transplantation and Induction of Graft-Versus-Malignancy. In: Bashey A, Ball ED, eds. Cancer Treatment and Research. Boston: Springer; 2002. рр. 137–47. doi: 10.1007/978-1-4615-0919-6_7.

Plasma cell neoplasms in HIV-Infected Patients: A Literature Review and Case Series

LYMPHOID TUMORS , ,

RA Leigton2, AV Pivnik1, EP Sergeeva1, NV Kremneva1, OV Mukhin1

1AS Loginov Moscow Clinical Scientific Center, 86 Entuziastov sh., Moscow, Russian Federation, 111123

2Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya str., Moscow, Russian Federation, 117198

For correspondence: Prof. Aleksandr Vasil’evich Pivnik, MD, PhD, 86 Entuziastov sh., Moscow, Russian Federation, 111123; Tel.: 8(495)304-30-39; e-mail: pivnikav@gmail.com

For citation: Leigton RA, Pivnik AV, Sergeeva EP, et al. Plasma cell neoplasms in HIV-Infected Patients: A Literature Review and Case Series. Clinical oncohematology. 2017;10(4):464–70 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-464-470

ABSTRACT

Aim. Analysis of 37 published and 2 author’s cases of multiple myeloma (MM) in HIV-positive patients.

Materials & Methods. Description of 37 patients and 2 author’s previously unpublished observations.

Results. The median age of patients was 37 years (66 in the general population), only 2 % being under 40 years. Abnormal MM progression was observed including the emergence of extramedullary lesions, low levels of M-gradient, and the development of plasmoblastic leukemia. Historically, before highly active antiretroviral therapy (HAART) was introduced, a rapid progression of MM with a short life expectancy was observed. HAART in combination with chemotherapy showed the best results of MM treatment in terms of overall and relapse-free survival. According to the literature data HAART may also be used to treat HIV-negative patients with MM. The cytological analysis of MM showed atypical myeloma cells with no lysozyme, leukocyte common antigen, CD19, and CD20. The CD38 was clearly identified. Anaplastic MM may be regarded as the first manifestation of AIDS. The author’s results were similar to the published data.

Conclusion. MM in HIV-infected patients in stage with secondary diseases is still considered to be not HIV-related. In HIV-positive MM patients on HAART overall and relapse-free survival rates were higher than that in HIV-negative patients with MM. The serum levels M-gradient was shown to decrease or even become indeterminate in MM patients receiving HAART for HIV infection. Thus, the HAART was proposed for MM HIV-negative patients.

Keywords: plasma cell neoplasms, HIV-infection in stage with secondary disease, HAART.

Received: April 7, 2017

Accepted: July 6, 2017

Read in PDF

REFERENCES

  1. Покровский В.В. Инфекция, вызываемая вирусом иммунодефицита человека в России. Терапевтический архив. 2016;88(11):4–11.[Pokrovskii VV. Infection, caused by human immunodeficiency virus in Russia. Terapevticheskii arkhiv. 2016;88(11):4–11. (In Russ)]
  2. Israel AM, Koziner B, Strauss DJ. Plasmacytoma and the acquired immunodeficiency syndrome. Ann Intern Med. 1983;99(3):635–6. doi: 10.7326/0003-4819-99-5-635.
  3. ВИЧ-инфекция и СПИД: Национальное руководство. Под ред. В.В. Покровского. М.: ГЭОТАР-Медиа, 2013. 608 с.[Pokrovskii VV, ed. VICh-infektsiya i SPID: natsional’noe rukovodstvo. (HIV and AIDS: national guidelines.) Moscow: GEOTAR-Media Publ.; 2013. 608 p. (In Russ)]
  4. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2014;5(1, приложение 3):1–24.[Mendeleyeva LP, Votyakova OM, Pokrovskaya OS, et al. Natsional’nye klinicheskie rekomendatsii po diagnostike i lecheniyu mnozhestvennoi mielomy. (National clinical recommendations for diagnosis and therapy of multiple myeloma.) Gematologiya i transfuziologiya. 2014;5(1, Suppl 3):1–24. (In Russ)]
  5. Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371–82. doi: 10.4065/80.10.1371.
  6. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121–7. doi: 10.1038/leu.2010.60.
  7. Konstantinopoulos PA, Dezube BJ, Pantanowitz L, et al. Protein electrophoresis and immunoglobulin analysis in HIV-infected patients. Am J Clin Pathol. 2007;128(4):596–603. doi: 10.1309/QWTQFGA9FXN02YME.
  8. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362–9. doi: 10.1056/NEJMoa054494.
  9. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105(11):1684–92. doi: 10.1038/bjc.2011.450.
  10. Thomas MAB, Isbister JO, IbelsLS, et al. IgA kappa multiple myeloma and lymphadenopathy syndrome associated with AIDS virus infection. Aust NZ J Med. 1986;16(3):402–4. doi: 10.1111/j.1445-5994.1986.tb01198.x.
  11. Kaplan MH, Susin M, Pahwa SG, et al. Neoplastic complications of HTLV-III infection. Lymphomas and solid tumors. Am J Med. 1987;82(3):389–96. doi: 10.1016/0002-9343(87)90435-9.
  12. Voelkerding KV, Sandhaus LM, Kim HC, et al. Plasma cell malignancy in the acquired immune deficiency syndrome : association with Epstein-Barr virus. Am J Clin Pathol. 1989;92(2):222–8. doi: 10.1093/ajcp/92.2.222.
  13. Karnad AB, Martin AW, Koh HK, et al. Nonsecretory multiple myeloma in a 26-year-old man with acquired immunodeficiency syndrome, presenting with multiple extramedullary plasmacytomas and osteolytic bone disease. Am J Hematol. 1989;32(4):305–10. doi: 10.1002/ajh.2830320412.
  14. Gold JE, Schwam L, Castella A, et al. Malignant plasma cell tumors in human immunodeficiency virus-infected patients. Cancer. 1990;66(2):363–8. doi: 10.1002/1097-0142(19900715)66:2<363::aid-cncr2820660227>3.0.co;2-j.
  15. von Keyserlingk H, Baur R, Stein H, et al. Multiple myeloma in a patient at risk for AIDS. Cancer Detect Prev. 1990;14(3):403–4.
  16. Kumar S, Kumar D, Schnadig VJ, et al. Plasma cell myeloma in patients who are HIV-positive. Am J Clin Pathol .1994;102(5):633–69. doi: 10.1093/ajcp/102.5.633.
  17. Pizarro A, Gamallo C, Sanchez-Munoz JF, et al. Extramedullary plasmacytoma and AIDS-related Kaposi’s sarcoma. J Am Acad Dermatol. 1994;30(5):797–800. doi: 10.1016/s0190-9622(08)81519-8.
  18. Ventura G, Lucia MB, Damiano F, et al. Multiple myeloma associated with Epstein–Barr virus in an AIDS patient: A case report. Eur J Haematol. 1995;55(5):332–4. doi: 10.1111/j.1600-0609.1995.tb00706.x.
  19. Yee TT, Murphy K, Johnson M, et al. Multiple myeloma and human immunodeficiency virus-1 (HIV-1) infection. Am J Hematol. 2001;66(2):123–5. doi: 10.1002/1096-8652(200102)66:2<123::aid-ajh1028>3.3.co;2-g.
  20. Kentos A, Vekemans M, van Vooren JP, et al. High-dose chemotherapy and autologous CD34-positive blood stem cell transplantation for multiple myeloma in an HIV carrier. Bone Marrow Transplant. 2002;29(3):273–5. doi: 10.1038/sj.bmt.1703348.
  21. Aboulafia DM. Thalidomide-based treatment for HIV-associated multiple myeloma: a case report. AIDS. 2003;13(8):383–9.
  22. Amara S, Dezube BJ, Cooley TP, et al. HIV-Associated Monoclonal Gammopathy: A Retrospective Analysis of 25 Patients. Clin Infect Dis. 2006;43(9):1198. doi: 10.1086/508351.
  23. Gimeno E, Sorli L, Abella E, et al. Сomplete remission of smoldering myeloma in an HIV patient after highly antiretroviral therapy. Haematologica. 2007;92(Suppl 2):485, abstract 1348.
  24. Feller L, White J, Wood NH, et al. Extramedullary myeloma in an HIV-seropositive subject. Literature review and report of an unusual case. Head Face Med. 2009;5(1):4. doi: 10.1186/1746-160X-5-4.
  25. Muzaffar J, Usmani S, Abdallah AO, et al. High-dose chemotherapy and autologous stem cell transplantation for multiple myeloma in HIV-positive patients in the highly active antiretroviral therapy era: the myeloma institute of research and therapy experience. Clin Lymph Myel Leuk. 2013;13(2):171–4. doi: 10.1016/j.clml.2012.12.004.
  26. Agrawal S, Deshpande A. A unique presentation of multiple myeloma in an HIV patient. Indian J Med Res. 2013;137(4):815–6.
  27. Coker WJ, Jeter A, Schade H. Plasma cell disorders in HIV-infected patients: epidemiology and molecular mechanisms. Biomark Res. 2013;1(1):8. doi: 10.1186/2050-7771-1-8.
  28. Li G, Lewis RD, Mishra N, Axiotis CA. A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: a potential therapeutic effect of HAART in multiple myeloma. Leuk Res. 2014;38(9):1079–84. doi: 10.1016/j.leukres.2014.07.001.
  29. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962–72. doi: 10.1182/blood-2007-10-078022.
  30. Dezube BJ, Aboulafia DM, Pantanowitz L. Plasma cell disorders in HIV infected patients: from benign gammopathy to multiple myeloma. AIDS. 2004;14(7):372–4.
  31. Глинщикова О.А., Февралева И.С., Макарик Т.В. и др. Определение генетических полиморфизмов CCR5-∆32 и CCR2-64I у доноров и ВИЧ-1 инфицированных пациентов. Гематология и трансфузиология. 2014;59(приложение 1):39.[Glinshchikova OA, Fevraleva IS, Makarik TV, et al. Analysis of genetic polymorphisms CCR5-∆32 and CCR2-64I in donors and HIV-1 patients. Gematologiya i transfuziologiya. 2014;59(Suppl 1):39. (In Russ)]
  32. Heiko J, Todd AM, Streeck H. How a Single Patient Influenced HIV Research–15-Year Follow-up. N Engl J Med. 2014;370(7):682–3. doi: 10.1056/NEJMc1308413.
  33. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21–33. doi: 10.4065/78.1.21.
  34. Blade J, Kyle RA. Multiple myeloma in young patients: clinical presentation and treatment approach. Leuk Lymphoma. 1998;30(5–6):493–501. doi: 10.3109/10428199809057562.

New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review

REVIEWS , , ,

OM Votyakova

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Ol’ga Mikhailovna Votyakova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-92-09; e-mail: omvtk@yandex.ru 24

For citation: Votyakova OM. New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review. Clinical oncohematology. 2017;10(4):425–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-425-434

ABSTRACT

Despite improvements in the treatment of patients with newly diagnosed multiple myeloma (MM) through the introduction of new drugs and high-dose chemotherapy with autologous hematopoietic stem cell transplantation, relapses are still inevitable in all patients. The use of immunomodulatory agents (thalidomide, lenalidomide) and proteasome inhibitor bortezomib has improved the treatment of relapses. However, the disease progression lead to repeated relapses and eventually refractory MM. For these patients new therapeutic strategies are needed, including the development of more effective drugs within the existing classes and the study of new combinations, as well as searching new targets for the treatment of MM. We present the key clinical data on the efficacy and safety of the most promising proteasome inhibitors (carfilzomib, ixazomib), new generation immunomodulatory drug pomalidomide, and monoclonal antibodies (daratumumab and elotuzumab).

Keywords: proteasome inhibitors, immunomodulatory medication, monoclonal antibodies, multiple myeloma.

Received: March 14, 2017

Accepted: June 20, 2017

Read in PDF

REFERENCES

  1. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–5. doi: 10.1038/leu.2013.313.
  2. Ludwig H, Sonneveld P, Davies F, et al. European Perspective on Multiple Myeloma Treatment Strategies in 2014. Oncologist. 2014;19(8):829–44. doi: 10.1634/theoncologist.2014-0042.
  3. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691–5. doi: 10.1182/blood-2010-10-299487.
  4. Richardson PG, Sonnefeld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(11):3557–60. doi: 10.1182/blood-2006-08-036947.
  5. Dimopoulos MA, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32. doi: 10.1056/NEJMoa070594.
  6. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133–42. doi: 10.1056/NEJMoa070596.
  7. Weber D, Knight R, Chen C, et al. Prolonged overall survival with lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2007;110(11): Abstract 412.
  8. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867–74.
  9. Usmani S, Ahmadi T, Ng Y, et al. Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥ 3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. Oncologist. 2016;21:1355–61. doi: 10.1634/theoncologist.2016-0104.
  10. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study. Leukemia. 2012;26(1):149–57. doi: 10.1038/leu.2011.196.
  11. Bolli N, Avert-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997. doi: 10.1038/ncomms3997.
  12. Lohr JG, Stojanov P, Carter SL, et al. Multiple Myeloma Research Consortium. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91–101. doi: 10.1016/j.ccr.2013.12.015.
  13. Egan JB, Shi CH, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060–6. doi: 10.1182/blood-2012-01-405977.
  14. Yee AJ, Raje NS. Sequencing of nontransplant treatments in multiple myeloma patients with active disease. Hematology Am Soc Hematol Educ Program. 2016(1):495–503. doi: 10.1182/asheducation-2016.1.495.
  15. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52. doi: 10.1056/NEJMoa1411321.
  16. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621–34. doi: 10.1056/NEJMoa1516282.
  17. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373(7):621–31. doi: 10.1056/NEJMoa1505654.
  18. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319–31. doi: 10.1056/NEJMoa1607751.
  19. Kuhn DJ, Orlowski RZ, Bjorklund CC. Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs). Curr Cancer Drug Targets. 2011;11(3):285–95. doi: 10.2174/156800911794519725.
  20. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817–25. doi: 10.1182/blood-2012-05-425934.
  21. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2015;17(1):27–38. doi: 10.1016/S1470-2045(15)00464-7.
  22. Avet-Loiseau H, Fonseca R, Siegel D, et al. Efficacy and Safety of Carfilzomib, Lenalidomide, and Dexamethasone Vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Aspire (NCT01080391). Blood. 2015;126(23):731.
  23. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70(5):1970–80. doi: 10.1158/0008-5472.CAN-09-2766.
  24. Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res. 2011;17(23):7313–23. doi: 10.1158/1078-0432.CCR-11-0636.
  25. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, Phase III trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.
  26. Dimopoulos MA, Weisel KC, Song KW, et al. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015;100(10):1327–33. doi: 10.3324/haematol.2014.117077.
  27. Dimopoulos MA, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573–85. doi: 10.1038/leu.2014.60.
  28. ИМНОВИД® (IMNOVID®) инструкция по применению [электронный документ]. Доступно по: https://www.vidal.ru/drugs/imnovid__44356. Ссылка активна на 31.07.2017.[IMNOVID® instruction for medical use [Internet]. Available from: https://www.vidal.ru/drugs/imnovid__44356. (accessed 31.07.17) (In Russ)]
  29. Baz RC, Martin TG, Lin H-Y, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127(21):2561–8. doi: 10.1182/blood-2015-11-682518.
  30. Lacy MQ, LaPlant BR, Laumann KM, et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM). Blood. 2014;124(21):304.
  31. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841–9. doi: 10.1007/s00262-013-1493-8.
  32. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013;88(1):168–77. doi: 10.1016/j.critrevonc.2013.04.003.
  33. Lonial S, Richardson P, Mateos M-V, et al. ELOQUENT-2 update: Phase III study of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM)—Identifying responders by subset analysis. 2016 ASCO Annual Meeting. Poster 8037. Available from: http://meetinglibrary.asco.org/record/126339/abstract (accessed 31.07.17).
  34. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121(4):482–8. doi: 10.1309/74r4-tb90-buwh-27jx.
  35. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. 2011;186(3):1840–8. doi: 10.4049/jimmunol.1003032.
  36. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124(21):3474.
  37. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. mAbs. 2015;7(2):311–21. doi: 10.1080/19420862.2015.1007813.
  38. Jansen JHM, Boross P, Overdijk MB, et al. Daratumumab, a human CD38 antibody induces apoptosis of myeloma tumor cells via Fc receptor-mediated crosslinking. Blood. 2012;120(21): Abstract 2974.
  39. Krejcik J, Casneuf T, Nijhof I, et al. Immunomodulatory effects and adaptive immune response to daratumumab in multiple myeloma. Blood. 2015:126(23): Abstract 3037.
  40. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–19. doi: 10.1056/NEJMoa1506348.
  41. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551–60. doi: 10.1016/S0140-6736(15)01120-4.
  42. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37–44. doi: 10.1182/blood-2016-03-705210.
  43. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375:754–66. doi: 10.1056/NEJMoa1606038.