Correspondence Paul Greaves T. Andrew Lister John G. Gribben

Keywords: late effects of therapy, fertility, lymphomas First published online 2 April 2014

Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The

doi: 10.1111/bjh.12874

London Medical School, Queen Mary University of London, London, UK E-mail: [email protected]

References Greaves, P., Sarker, S., Chowdhury, K., Johnson, R., Matthews, J., Matthews, R., Smith, M., Korszun, A., Gribben, J.G. & Lister, T.A. (2013) Fertility and sexual function in longterm survivors of haematological malignancy:

using patient-reported outcome measures to assess a neglected area of need in the late effects clinic. British Journal of Haematology, 164, 526–535. Pryzant, R.M., Meistrich, M.L., Wilson, G., Brown, B. & McLaughlin, P. (1993) Long-term reduction in sperm count after chemotherapy with

and without radiation therapy for non-Hodgkin’s lymphomas. Journal of Clinical Oncology, 11, 239–247. Watson, A.R., Rance, C.P. & Bain, J. (1985) Long term effects of cyclophosphamide on testicular function. British Medical Journal (Clinical Research Ed.), 291, 1457–1460.

Long-term survival after allogeneic stem cell transplantation for advanced stage multiple myeloma

Despite the use of novel drugs and autologous stem cell transplantation (SCT), multiple myeloma (MM) is still considered to be an incurable disease. Both autologous and allogeneic SCT (allo-SCT) improve long-term survival. Allo-SCT can result in long-term disease control and remains a potentially curative therapeutic modality, related in part to the immune anti-myeloma effect of the allograft, but it is hampered by high transplant-related toxicities. Reduced intensity conditioning (RIC) allo-SCT has been developed in order to reduce transplant-related mortality while maintaining a graftversus-myeloma (GVM) effect. Few studies have reported long-term outcomes in MM after allo-SCT, with a median follow-up typically ranging from 2 to 5 years. Recently, Sahebi et al (2013) reported an overall survival (OS) of 60%, progression-free survival (PFS) of 31% and relapse incidence of 59% at 7 years in 60 MM patients undergoing allo-SCT after RIC, with a median follow-up of 98 years. Very late relapses occurred in 10% of patients, even as late as 115 years after transplantation (Sahebi et al, 2013). We report on the long-term follow-up (median 682 years) of 42 consecutive MM patients who underwent myeloablative conditioned (MAC) or RIC allo-SCT at a single centre between 1988 and 2011. Baseline characteristics of the patients are detailed in Table I. Most of the patients had advanced stage and standard risk cytogenetic abnormalities. Conventional chemotherapy was given as induction in all but two. At the time of transplantation, 28 patients had chemosensitive disease in complete (CR, n = 4) or partial remission (PR, n = 24) whereas 14 were in relapse or progression 616

(PD). Using bone marrow (n = 16) or peripheral stem cells (n = 26) from a familial (n = 37) or an alternative (n = 5) matched donor, the allografting procedure was either scheduled as part of upfront treatment (n = 21), as a planned tandem auto-allo-transplant (n = 7), or as salvage therapy for relapsed disease (n = 21) or after failure of auto-SCT (n = 7). Thirteen patients received donor lymphocyte infusions (DLI). Outcomes are listed in Table II. Acute graft-versus-host disease (GVHD) grade II-IV occurred in 18 patients, and 3 had grade III-IV. Seven patients died early and could not be evaluated for chronic GVHD (cGVHD). Extensive cGVHD was observed in 7 of 35 patients (20%); 8 displayed cGVHD (23%) and 20 had no cGVHD (57%). Best responses achieved post-transplant were CR (50%) and PR (38%). Six patients achieved CR after an allograft performed in PD. Three out of 13 patients achieved a PR after DLI. At the time of analysis, 16 patients are alive, 7 of them in CR. OS was 50%, 45% and 26%, and PFS 50%, 43% and 7% at 5, 10 and 20 years, respectively. There were no significant differences in outcome between RIC and MAC, or between allografts performed in first-line or as salvage therapy, early (1 year) after diagnosis. Chronic GVHD and achievement of CR after SCT were not significantly associated with better OS or PFS. At the time of analysis, 26 patients have progressed/ relapsed. Twenty-six have died, 13 from disease progression or relapse and 13 from transplant-related complications. Non-relapse mortality (NRM) was 24%, 29% and 29% at 1, ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 612–628

Correspondence Table I. Patients characteristics Variable Age at transplant (years) < 50 >50 Gender Male Female Disease stage at diagnosis Stage I Stage II Stage III Cytogenetic risk stratification Standard risk* High risk† Unknown Time from diagnosis to transplant 1 year Treatment regimen First line Salvage therapy Prior therapy Conventional chemotherapy Novel agents Nothing Disease status prior allo-SCT Complete remission Partial remission Stable/progressive disease Stem cell source Bone marrow Peripheral blood stem cell Donor type Sibling donor Matched unrelated donor Gender match: donor recipient Female donor male recipient Other Transplant regimen Myeloablative conditioning Reduced intensity conditioning

Table II. Patient outcomes N (%), median (range) 51 (36–67) 3 (7) 39 (93) 25 (60) 17 (40) 6 (14) 12 (29) 24 (57) 20 (48) 8 (19) 14 (33) 21 (50) 21 (50) 21 (50) 21 (50) 32 (76) 8 (19) 2 (5) 4 (10) 24 (57) 14 (33) 16 (38) 26 (62) 37 5 8 (19) 34 (81) 25 (60) 17 (40)

Outcome

N (%), median (range)

Best response to transplant Complete response 21 Partial response 16 Stable disease 0 Progressive disease/relapse 0 Not evaluable 5 Relapse Yes 26 No 7 Vital status Alive 16 Dead 26 Cause of death Disease progression 13 Organ failure 6 aGVHD 1 cGVHD 1 Infection 3 Neoplasm 2 Median survival (days) All patients 2490 (209–9642) Alive 4366 (2749–9642) Dead 1517 (209–6490) Overall survival At 5 years 50% At 10 years 45% At 20 years 7% Progression-free-survival At 5 years 50% At 10 years 43% At 20 years 7% Cumulative incidence of NRM 1 year NRM 24% 2 years NRM 26% 5 years NRM 29% 20 years NRM 29% Cumulative incidence of RM 1 year RM 25% 2 years RM 40% 5 years RM 69% 20 years RM 86%

SE

95% CI

007 007 010

025–056 029–060 006–045

007 007 006

032–062 028–059 000–019

006 006 007 007

013–041 015–044 018–047 018–047

007 008 008 007

014–044 026–060 055–088 072–100

allo-SCT, allogeneic stem cell transplantation. *Standard risk: lack of high-risk abnormalities. †High risk: t(14;16)(q32;q23), del(17p) by conventional cytogenetic analysis or fluorescence in-situ hybridization (FISH); when available t(4;14)(p16;q32), del(13q) by conventional cytogenetic analysis.

aGVHD, acute graft-versus-host disease; cGVHD, chronic graftversus-host disease; NRM, non-relapse mortality; RM, relapse mortality; SE, standard error; 95% CI, 95% confidence interval.

5 and 20 years, respectively. The 1-year incidence of NRM was not significantly different between MAC and RIC. Cumulative incidence of progression/relapse was 25%, 69% and 86%, at 1, 5 and 20 years, respectively, without significant difference between RIC and MAC, or between an allograft performed first-line or as salvage therapy. Six patients suffered a late relapse, which occurred between 6 and 105 years after the procedure. None of these six patients

had high-risk features at diagnosis. Only two were transplanted within 1 year from diagnosis and four received a MAC regimen. All experienced an acute GVHD grade I-II. None of them displayed cGVHD nor received consolidation or maintenance therapy after the procedure. One died of refractory MM 125 years after transplantation, and two died of metastatic cancers (angiosarcoma and pancreatic adenocarcinoma) at 10 and 15 years after allo-SCT, respectively.

ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 612–628

617

Correspondence Two further patients experienced malignancies. One patient was diagnosed with prostate carcinoma while under lenalidomide maintenance therapy. The other patient developed an acute myeloid leukaemia in donor cells, 4 years after transplantation, and has been in CR for both diseases for 9 years (Havelange et al, 2006). Based on the long-term follow-up of this cohort, we confirm the previous observation that more than 10% of myeloma patients experienced late progression/relapse after allo-SCT (Sahebi et al, 2013). Neither cGVHD nor achievement of CR after allo-SCT were significantly associated with improved OS or longer PFS in our series. In agreement with previous studies emphasizing that toxicity remains a major drawback of the procedure, we observed a 29% incidence of toxic death that was mainly related to organ failure or infection. RIC has been proposed to reduce transplant-related mortality while maintaining a GVM effect (Bruno et al, 2007). However, RIC is associated with a higher risk of relapse (Crawley et al, 2007). Adding novel drugs as part of conditioning and maintenance treatment might also prevent relapse. The use of bortezomib with conditioning might limit the risk of relapse after RIC (Caballero-Velazquez et al, 2013). As it selectively eliminates alloreactive T-cells, it could also be of value in preventing GVHD (Koreth et al, 2009) and avoiding toxicities. Maintenance with lenalidomide reduces relapses, as it potentiates Natural Killer cell activity (Danylesko et al, 2012), but exposes patients to more GVHD (Kneppers et al, 2011). Lowdose lenalidomide (5 mg/day) might be an alternative option (Wolschke et al, 2013). Future studies should explore the integration of novel agents and cellular therapies with RIC in an attempt to reduce the incidence of disease recurrence.

References Bruno, B., Rotta, M., Patriarca, F., Mordini, N., Allione, B., Carnevale-Schianca, F., Giaccone, L., Sorasio, R., Omede, P., Baldi, I., Bringhen, S., Massaia, M., Aglietta, M., Levis, A., Gallamini, A., Fanin, R., Palumbo, A., Storb, R., Ciccone, G. & Boccadoro, M. (2007) A comparison of allografting with autografting for newly diagnosed myeloma. New England Journal of Medicine, 356, 1110–1120. Caballero-Velazquez, T., Lopez-Corral, L., Encinas, C., Castilla-Llorente, C., Martino, R., Rosinol, L., Sampol, A., Caballero, D., Serrano, D. & Heras, I. (2013) San Miguel J, Perez-Simon JA. Phase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post)-allogeneic transplantation for high-risk myeloma patients. British Journal of Haematology, 162, 474–482. Crawley, C., Iacobelli, S., Bjorkstrand, B., Apperley, J.F., Niederwieser, D. & Gahrton, G. (2007) Reduced-intensity conditioning for myeloma:

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Twenty patients were long-term survivors (more than 3000 days after diagnosis), possibly because of the use of novel agents at relapse and the achievement of PR after DLI in 3 out of 13 cases. In addition, at the date of final analysis, 16 patients are alive, 7 of whom are in CR. The present data underscores that long-term disease control can be achieved in a subset of MM patients undergoing allo-SCT, even when performed in heavily pre-treated, advanced stage, refractory MM.

Conflict of interest The authors declare no conflict of interest.

Author contributions MCV, LM, EV and AF designed the study, MCV collected the data, MCV and AF analysed the data, MCV, LM, EV and AF co-wrote the paper. Marie-Christiane Vekemans Lucienne Michaux Eric Van Den Neste Augustin Ferrant Department of Haematology, Cliniques universitaires Saint-Luc, UCL, Brussels, Belgium E-mail: [email protected]

Keywords: multiple myeloma, transplantation, graft-versus-host disease, toxicity, outcome First published online 4 April 2014 doi: 10.1111/bjh.12881

lower nonrelapse mortality but higher relapse ratescompared with myeloablative conditioning. Blood, 109, 3588–3594. Danylesko, I., Beider, K. & Shimoni, A. (2012) Nagler. Novel strategies for immunotherapy in multiple myeloma: previous experience and future directions. Clinical & Developmental Immunology, 2012, 753407. Havelange, V., Antoine-Poirel, H., Saussoy, P., Van Den Neste, E. & Ferrant, A. (2006) Donor cell leukemia developing after haematopoietic stem cell transplantation for multiple myeloma. Acta Clinica Belgica, 61, 82–86. Kneppers, E., Van der Holt, B., Kersten, M.J., Zweegman, S., Meijer, E., Huls, G., Cornelissen, J.J., Janssen, J.J., Huisman, C., Cornelisee, P.B., Bruijnen, C.P., Emmelot, M., Sonneveld, P., Lokhorst, H.M., Mutis, T. & Minnema, M.C. (2011) Lenalidomide maintenance after myeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood, 118, 2413–2419.

Koreth, J., Alyea, E.P., Murphy, W.J. & Welniak, L.A. (2009) Proteasome inhibition and allogeneic haematopoietic stem cell transplantation: a review. Biology of Blood and Marrow Transplantation, 15, 1502–1512. Sahebi, F., Shen, Y., Somlo, G., Thomas, S.H., Htut, M., Karanes, C., Krishnan, A.Y., MurataCollins, J., Palmer, J., Rincon, A. & Forman, S.J. (2013) Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study. British Journal of Haematology., 160, 199–206. Wolschke, C., St€ ubig, T., Hegenbart, U., Sch€ onland, S., Heinzelmann, M., Hildebrandt, Y., Ayuk, F., Atanackovic, D., Dreger, P., Zander, A. & Kr€ oger, N. (2013) Post-allograft lenalidomide induces strong NK cell-mediated anti-myeloma activity and risk for T-cell mediated GvHD. Results from a phase I/II Dosefinding study. Experimental Hematology, 41, 134–142.

ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 612–628

Long-term survival after allogeneic stem cell transplantation for advanced stage multiple myeloma.

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