Abstract
High-risk (HR) multiple myeloma (MM) has poor outcomes with conventional therapy. Tandem autologous-non-myeloablative (NMA) allogeneic stem cell transplantation (autologous stem cell transplantation (ASCT)-NMA allogeneic SCT) is potentially curative secondary to graft-versus-myeloma effect. We retrospectively analysed ASCT-NMA allogeneic SCT outcomes of 59 HR and relapsed MM patients. At a median follow-up of 35.8 months, the outcomes for HR-MM upfront tandem ASCT-NMA allogeneic SCT and standard-risk (SR) MM upfront ASCT alone were comparable (median PFS 1166 days versus 1465 days, P=0.36; median overall survival (OS) not reached in both cohorts, P=0.31). The 5-year PFS and OS of patients who had ASCT-NMA allogeneic SCT after relapsing from previous ASCT were 30% and 48% respectively. High CD3+ cell dose (>3 × 108/kg) infusion was associated with more acute GvHD (grade 2–4) (47% vs 17.5%; P=0.03), extensive chronic GvHD (80% vs 50%; P=0.04), increased transplant-related mortality (26.3% vs 5%; P=0.009) and inferior OS (median OS 752 days vs not reached; P=0.002). On multivariate analysis, response achieved with tandem transplant (<CR vs CR vs stringent CR; hazard ratio=5.54, confidence interval=2.67–11.5; P<0.0001) and CD3+ cell dose infused (hazard ratio=1.42; confidence interval=1.21–1.67; P<0.0001) emerged as factors influencing OS. We conclude that tandem ASCT-NMA allogeneic SCT is an effective therapy for HR or relapsed MM and that higher CD3+ doses have an adverse impact on transplant outcome.
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References
Mahindra A, Hideshima T, Anderson KC . Multiple myeloma: biology of the disease. Blood Rev 2010; 24 (Suppl 1): S5–11.
Boyd KD, Pawlyn C, Morgan GJ, Davies FE . Understanding the molecular biology of myeloma and its therapeutic implications. Expert Rev Hematol 2012; 5: 603–617.
Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF . New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol 2008; 9: 1157–1165.
Bianchi G, Richardson PG, Anderson KC . Promising therapies in multiple myeloma. Blood 2015; 126: 300–310.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J 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: 149–157.
Majithia N, Rajkumar VS, Lacy MQ, Buadi FK, Dispenzieri A, Gertz MA et al. Outcomes of primary refractory multiple myeloma and the impact of novel therapies. Am J Hematol 2015; 90: 981–985.
Avet-Loiseau H . Ultra high-risk myeloma. Hematology Am Soc Hematol Educ Program 2010; 2010: 489–493.
Avert-Loiseau H, Durie BG, Cavo M, Attal M, Gutierrez N, Haessler J et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia 2013; 27: 711–717.
Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant 2015; 21: 2039–2051.
Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B . Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.
Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 77–84.
Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL et al. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant 2014; 20: 1211–1216.
Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88: 2787–2793.
Björkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: 4711–4718.
Björkstrand B . European Group for Blood and Marrow Transplantation Registry studies in multiple myeloma. Semin Hematol 2001; 38: 219–225.
Lokhorst HM, Segeren CM, Verdonck LF, van der Holt B, Raymakers R, van Oers MH et al. Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 2003; 21: 1728–1733.
Crawley C, Iacobelli S, Björkstrand B, Apperley JF, Niederwieser D, Gahrton G . Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109: 3588–3594.
Kumar S, Zhang M-J, Li P, Dispenzieri A, Milone GA, Lonial S et al. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. Blood 2011; 118: 1979–1988.
Thiede C, Florek M, Bornhauser M, Ritter M, Mohr B, Brendel C et al. Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplant 1999; 23: 1055–1060.
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.
Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbera H et al. Report of the European Myeloma Network on Multiparametric Flow Cytometry in Multiple Myeloma and Related Disorders. Haematologica 2008; 93: 431–438.
van Dongen JJ, Lhermitte L, Bottcher S, Almeida J, van der Velden VH, Flores-Montro J et al. Euroflow Consortium (EU-FP6, LSHB-CT-2006-018708). Euroflow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 2012; 26: 1908–1975.
Ludwig H, Durie B, Bolejack V, Turesson I, Kyle RA, Blade J et al. Myeloma in patients under age 50 presents with more favorable features and shows better survival: an analysis of 10,549 patients from the International Myeloma Working Group. Blood 2008; 111: 4039–4047.
Ludwig H, Bolejack V, Crowley J, Blade J, San Miguel J, Kyle RA et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol 2010; 28: 1599–1605.
Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101: 4569–4575.
Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 2004; 125: 64–68.
Chang H, Qi C, Yi QL, Reece D, Stewart AK . p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 2005; 105: 358–360.
Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106: 2837–2840.
Avet-Loiseau H, Attal M, Campion L, Caillot D, Hulin C, Marit G et al. Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol 2012; 30: 1949–1952.
Durie BG, Salmon SE . A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842–854.
Bataille R, Boccadoro M, Klein B, Durie B, Pileri A . C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system. Blood 1992; 80: 733–737.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.
Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Gertz MA, Lacy MQ et al. Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood 2005; 106: 2276–2279.
Terpos E, Katodritou E, Roussou M, Pouli A, Michalis E, Delimpasi S et al. High serum lactate dehydrogenase adds prognostic value to the international myeloma staging system even in the era of novel agents. Eur J Haematol 2010; 85: 114.
Boyd KD, Ross FM, Chiecchio L, Dagrada GP, Konn ZJ, Tapper WJ et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia 2012; 26: 349–355.
Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica 2010; 95: 1150–1157.
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol A et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol 2015; 33: 2863–2869.
Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE et al. minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol 2013; 31: 2540–2547.
Paiva B, van Dongen J, Orfao A . New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood 2015; 125: 3059–3068.
Kröger N, Badbaran A, Zabelina T, Ayuk F, Wolschke C, Alchalby H et al. Impact of high-risk cytogenetics and achievement of molecular remission on long-term freedom from disease after autologous-allogeneic tandem transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2013; 19: 398–404.
Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.
Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: 3474–3480.
Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E III et al. Tandem autologous versus single autologous transplantation followed by allogeneic hematopoietic cell transplantation for patients with multiple myeloma: results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial. Lancet Oncol 2011; 12: 1195–1203.
Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R et al. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 2012; 119: 6219–6225.
Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al. Tandem autologous/reduced-intensity conditioning allogenic stem cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29: 3016–3022.
Einsele H, Schafer HJ, Hebart H, Bader P, Meisner C, Plasswilm L et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121: 411–418.
Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H et al. Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36: 963–969.
Qazilbach MH, Saliba R, De Lima M, Hosing C, Couriel D, Aleman A et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106: 1084–1089.
De Lavallade H, El-Cheikh J, Faucher C, Furst S, Stoppa AM, Coso D et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008; 41: 953–960.
Shimoni A, Hardan I, Ayuk F, Schilling G, Atanackovic D, Zeller W et al. Allogenic hematopoietic stem cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long term follow up. Cancer 2010; 116: 3621–3630.
Freytes CO, Vesole DH, LeRademacher J, Zhong X, Gale RP, Kyle RA et al. Second transplants for multiple myeloma relapsing after a previous autotransplant-reduced-intensity allogeneic vs autologous transplantation. Bone Marrow Transplant 2014; 49: 416–421.
Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Basinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447–3454.
Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabeline T et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100: 755–760.
Sahebi F, Lacobelli S, Bienzen AV, Volin L, Dreger P, Michallet M et al. Comparison of upfront tandem autologous-allogeneic transplantation versus reduced intensity allogeneic transplantation for multiple myeloma. Bone Marrow Transplant 2015; 50: 802–807.
Kapoor P, Kumar SK, Dispenzieri A, Lacy MQ, Buadi F, Dingli D et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol 2013; 31: 4529–4535.
Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 2005; 29: 961–966.
Lahuerta JJ, Mateos MV, Martínez-López J, Rosinol L, Sureda A, de la Rubia J et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 2008; 26: 5775–5782.
Ladetto M, Ferrero S, Drandi D, Festuccia M, Patriarca F, Mordini N et al. Prospective molecular monitoring of minimal residual disease after non-myeloablative allografting in newly diagnosed multiple myeloma. Leukemia 2016; 30: 1211–1214.
Lee CK, Badros A, Barlogie B, Morris C, Zangari M, Fassas A et al. Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after after reduced intensity conditioning. Exp Hematol 2003; 31: 73–80.
Roos-Weil D, Moreau P, Avet-Loiseau H, Golmard JL, Kuentz M, Vigouroux S et al. Impact of genetic abnormalities after allogeneic stem cell transplantation in multiple myeloma: a report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Haematologica 2011; 96: 1504–1511.
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Nair, A., Walker, P., Kalff, A. et al. Adverse impact of high donor CD3+ cell dose on outcome following tandem auto-NMA allogeneic transplantation for high-risk myeloma. Bone Marrow Transplant 52, 839–845 (2017). https://doi.org/10.1038/bmt.2017.37
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DOI: https://doi.org/10.1038/bmt.2017.37
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