Research Article|Articles in Press, 103649

Intermediate-dose cyclophosphamide and bortezomib for PBSC mobilization in multiple myeloma

Published:January 31, 2023DOI:


      • The addition of bortezomib to intermediate-dose cyclophosphamide in PBSC mobilization did not impact the stem cell yield.
      • All patients with mobilization failure in both groups had t(11;14).
      • In the bortezomib^intermediate-dose-cyclophosphamide group, response status in MM was upgraded after PBSC mobilization.


      Although the incorporation of bortezomib into induction regimens has improved, response rates in patients with multiple myeloma (MM), the role of bortezomib in the, peripheral blood stem cell (PBSC) mobilization remains unclear. We assessed the, PBSC mobilization efficacy, safety, and disease response of intermediate-dose, cyclophosphamide and bortezomib in the PBSC mobilization. Twenty-one patients with, newly diagnosed MM were enrolled in a phase II, non-randomized study that used, bortezomib (1.3 mg/m2/day on days 1, 4, 8, and 11) and intermediate-dose, cyclophosphamide (2 g/m2/day on days 2, 3) (Bor-ID-CY). The data from 15 patients, who received intermediate-dose cyclophosphamide (ID-CY) were used as a historical, control group. The total CD34 + cell yield of Bor-ID-CY and ID-CY groups were not, significantly different (median 6.3 ×106/kg vs. 6.5 ×106/kg, p = 0.19). All three patients, with mobilization failure of two groups had t(11;14). Six patients in Bor-ID-CY group, were upgraded from a status that was less than a very good partial response (VGPR), at the time of PBSC mobilization to a VGPR or better after PBSC mobilization, (p = 0.014). Four patients in Bor-ID-CY group developed sepsis. The time to, engraftment was similar in the two groups. The addition of bortezomib to ID-CY did not, impact the stem cell yield or quality.


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        • Attal M.
        • Lauwers-Cances V.
        • Hulin C.
        • Leleu X.
        • Caillot D.
        • Escoffre M.
        • et al.
        Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.
        N Engl J Med. 2017; 376: 1311-1320
        • Cavo M.
        • Gay F.
        • Beksac M.
        • Pantani L.
        • Petrucci M.T.
        • Dimopoulos M.A.
        • et al.
        Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study.
        Lancet Haematol. 2020; 7: e456-e468
        • Koreth J.
        • Cutler C.S.
        • Djulbegovic B.
        • Behl R.
        • Schlossman R.L.
        • Munshi N.C.
        • 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 Transpl. 2007; 13: 183-196
        • Lahuerta J.J.
        • Mateos M.V.
        • Martínez-López J.
        • Rosiñol 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
        • Moreau P.
        • Attal M.
        • Pégourié B.
        • Planche L.
        • Hulin C.
        • Facon T.
        • et al.
        Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial.
        Blood. 2011; 117: 3041-3044
        • Dytfeld D.
        • Griffith K.A.
        • Friedman J.
        • Lebovic D.
        • Harvey C.
        • Kaminski M.S.
        • et al.
        Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial.
        Leuk Lymphoma. 2011; 52: 1271-1280
        • Bensinger W.
        • DiPersio J.F.
        • McCarty J.M.
        Improving stem cell mobilization strategies: future directions.
        Bone Marrow Transpl. 2009; 43: 181-195
        • Wood W.A.
        • Whitley J.
        • Moore D.
        • Sharf A.
        • Irons R.
        • Rao K.
        • et al.
        Chemomobilization with etoposide is highly effective in patients with multiple myeloma and overcomes the effects of age and prior therapy.
        Biol Blood Marrow Transpl. 2011; 17: 141-146
        • Olavarria E.
        • Kanfer E.J.
        Selection and use of chemotherapy with hematopoietic growth factors for mobilization of peripheral blood progenitor cells.
        Curr Opin Hematol. 2000; 7: 191-196
        • Alegre A.
        • Tomás J.F.
        • Martínez-Chamorro C.
        • Gil-Fernández J.J.
        • Fernández-Villalta M.J.
        • et al.
        Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone.
        Bone Marrow Transpl. 1997; 20: 211-217
        • Arora S.
        • Majhail N.S.
        • Liu H.
        Hematopoietic progenitor cell mobilization for autologous stem cell transplantation in multiple myeloma in contemporary era.
        Clin Lymphoma Myeloma Leuk. 2019; 19: 200-205
        • Kapoor P.
        • Ramakrishnan V.
        • Rajkumar S.V.
        Bortezomib combination therapy in multiple myeloma.
        Semin Hematol. 2012; 49: 228-242
        • Kumar S.
        • Flinn I.
        • Richardson P.G.
        • Hari P.
        • Callander N.
        • Noga S.J.
        • et al.
        Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.
        Blood. 2012; 119: 4375-4382
        • Reeder C.B.
        • Reece D.E.
        • Kukreti V.
        • Chen C.
        • Trudel S.
        • Hentz J.
        • et al.
        Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial.
        Leukemia. 2009; 23: 1337-1341
        • Einsele H.
        • Engelhardt M.
        • Tapprich C.
        • Müller J.
        • Liebisch P.
        • Langer C.
        • et al.
        Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial.
        Br J Haematol. 2017; 179: 586-597
        • Ghobadi A.
        • Fiala M.A.
        • Rettig M.
        • Schroeder M.
        • Uy G.L.
        • Stockerl-Goldstein K.
        • et al.
        A phase I study of the safety and feasibility of bortezomib in combination with G-CSF for stem cell mobilization in patients with multiple myeloma.
        Clin Lymphoma Myeloma Leuk. 2019; 19: e588-e593
        • Niesvizky R.
        • Mark T.M.
        • Ward M.
        • Jayabalan D.S.
        • Pearse R.N.
        • Manco M.
        • et al.
        Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.
        Clin Cancer Res. 2013; 19: 1534-1546
        • Japanese Society for Transplantation and Cellular Therapy
        Hematopoietic stem cell transplantation guideline, Hematopoietic stem cells collection (version 2).
        JSHCT Monogr. 2022; Vol.85
        • Durie B.G.
        • Harousseau J.H.
        • Miguel J.S.
        • Blade J.
        • Barlogie B.
        • Anderson K.
        • et al.
        International uniform response criteria for multiple myeloma.
        Leukemia. 2006; 20: 1467-1473
        • Bagal B.
        • Gokarn A.
        • Punatar S.
        • Das S.
        • Bonda A.
        • Nayak L.
        • et al.
        Bortezomib and cyclophosphamide based chemo-mobilization in multiple myeloma.
        Int J Hematol. 2020; 112: 835-840
        • Rettig M.P.
        • Ansstas G.
        • DiPersio J.F.
        Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4.
        Leukemia. 2012; 26: 34-53
        • Ghobadi A.
        • Rettig M.P.
        • Cooper M.L.
        • Holt M.S.
        • Ritchey J.K.
        • Eissenberg L.
        • et al.
        Bortezomib is a rapid mobilizer of hematopoietic stem cells in mice via modulation of the VCAM-1/VLA-4 axis.
        Blood. 2014; 124: 2752-2754
        • Ogawa Y.
        • Tobinai K.
        • Ogura M.
        • Ando K.
        • Tsuchiya T.
        • Kobayashi Y.
        • et al.
        Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma.
        Cancer Sci. 2008; 99: 140-144
        • Papandreou C.N.
        • Daliani D.D.
        • Nix D.
        • Yang H.
        • Madden T.
        • Wang X.
        • Pien C.S.
        • et al.
        Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer..
        J Clin Oncol. 2004; 22: 2108-2121
        • Perea G.
        • Sureda A.
        • Martino R.
        • Altés A.
        • Martínez C.
        • Cabezudo E.
        • et al.
        Predictive factors for a successful mobilization of peripheral blood CD34+ cells in multiple myeloma.
        Ann Hematol. 2001; 80: 592-597
        • Fitoussi O.
        • Perreau V.
        • Boiron J.M.
        • Bouzigon E.
        • Cony-Makhoul P.
        • Pigneux A.
        • Agape P.
        • et al.
        A comparison of toxicity following two different doses of cyclophosphamide for mobilization of peripheral blood progenitor cells in 116 multiple myeloma patients.
        Bone Marrow Transpl. 2001; 27: 837-842
        • Hamadani M.
        • Kochuparambil S.T.
        • Osman S.
        • Cumpston A.
        • Leadmon S.
        • Bunner P.
        • 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 Transpl. 2012; 18: 1128-1135
        • Hiwase D.K.
        • Bollard G.
        • Hiwase S.
        • Bailey M.
        • Muirhead J.
        • Schwarer A.P.
        Intermediate-dose CY and G-CSF more efficiently mobilize adequate numbers of PBSC for tandem autologous PBSC transplantation compared with low-dose CY in patients with multiple myeloma.
        Cytotherapy. 2007; 9: 539-547
        • Zannetti B.A.
        • Saraceni F.
        • Cellini C.
        • Fabbri E.
        • Monaco F.
        • Guarini A.
        • et al.
        Low-dose cyclophosphamide versus intermediate-high-dose cyclophosphamide versus granulocyte colony-stimulating factor alone for stem cell mobilization in multiple myeloma in the era of novel agents: a multicenter retrospective study.
        Biol Bone Marrow Transplatnation. 2021; 27 (e1-244.e8)
        • Broxmeyer H.E.
        • Orschell C.M.
        • Clapp D.W.
        • Hangoc G.
        • Cooper S.
        • Plett P.A.
        • et al.
        Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.
        J Exp Med. 2005; 201: 1307-1318
        • Mohty M.
        • Hübel K.
        • Kröger N.
        • Aljurf M.
        • Apperley J.
        • Basak G.W.
        • et al.
        Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the european group for blood and marrow transplantation.
        Bone Marrow Transpl. 2014; 49: 865-872
        • Lanza F.
        • Saraceni F.
        • Pezzi A.
        • Martino M.
        • Bosi A.
        • Cascavilla N.
        • et al.
        A comparative analysis of biosimilar vs. originator filgrastim in combination with plerixafor for stem cell mobilization in lymphoma and multiple myeloma: a propensity-score weighted multicenter approach.
        Am J Hematol. 2017; 92: E557-E559
        • Lanza F.
        • Lemoli R.M.
        • Olivieri A.
        • Laszlo D.
        • Martino M.
        • Specchia G.
        • et al.
        Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma.
        Transfusion. 2014; 54: 331-339
        • Tsukuda N.
        • Nishikori M.
        • Goto H.
        • Kanamori R.
        • Nishina S.
        • Seto T.
        • Iida S.
        Safety and effectiveness of plerixafor for peripheral blood stem cell mobilization in autologous stem cell transplantation: Results of a post-marketing surveillance study.
        Drugs Real World Outcomes. 2022; 9: 63-78
        • Kostopoulos I.V.
        • Eleutherakis-Papaiakovou E.
        • Rousakis P.
        • Ntanasis-Stathopoulos I.
        • Panteli C.
        • Orologas-Stavrou N.
        • et al.
        Aberrant plasma cell contamination of peripheral blood stem cell autografts, assessed by next-generation flow cytometry, is a negative predictor for deep response post autologous transplantation in multiple myeloma; a prospective study in 199 patients.
        Cancers. 2021; 13: 4047-4051
        • Olivieri A.
        • Marchetti M.
        • Lemoli R.
        • Tarella C.
        • Iacone A.
        • Lanza F.
        • et al.
        Proposd definition of ‘poor mobilizer’ in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo Italiano Trapianto di Midollo Osseo.
        Bone Marrow Transpl. 2012; 47: 342-351
        • Olivieri J.
        • Attolico I.
        • Nuccorini R.
        • Pascale S.P.
        • Chiarucci M.
        • Poiani M.
        • et al.
        Predicting failure of hematopoietic stem cell mobilization before it starts: the predicted poor mobilizer (pPM) score.
        Bone Marrow Transpl. 2018; 53: 461-473
        • Bhutani D.
        • Zonder J.
        • Valent J.
        • Tageja N.
        • Ayash L.
        • Deol A.
        • et al.
        Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma.
        Support Care Cancer. 2013; 21: 2437-2442
        • Kumar S.
        • Giralt S.
        • Stadtmauer E.A.
        • Harousseau J.H.
        • Palumbo A.
        • Bensinger W.
        • et al.
        Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens.
        Blood. 2009; 114 (International Myeloma Working Group): 1729-1735
        • Gasparetto C.
        • Jagannath S.
        • Rifkin R.M.
        • Durie B.G.M.
        • Narang M.
        • Terebelo H.R.
        • et al.
        Effect of t(11;14) abnormality on outcomes of patients with newly diagnosed multiple myeloma in the Connect MM Registry.
        Clin Lymphoma Myeloma Leuk. 2022; 22: 149-157
        • Lakshman A.
        • Alhaj Moustafa M.
        • Rajkumar S.V.
        • Dispenzieri A.
        • Gertz M.A.
        • Buadi F.K.
        • et al.
        Natural history of t(11;14) multiple myeloma.
        Leukemia. 2018; 32: 131-138
        • Jung S.H.
        • Yang D.H.
        • Ahn J.S.
        • Kim Y.K.
        • Kim H.J.
        • Lee J.J.
        Advanced lytic lesion is a poor mobilization factor in peripheral blood stem cell collection in patients with multiple myeloma.
        J Clin Apher. 2014; 29: 305-310
        • Giuliani N.
        • Ferretti M.
        • Bolzoni M.
        • Storti P.
        • Lazzaretti M.
        • Dalla Palma B.
        • et al.
        Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation.
        Leukemia. 2012; 26: 1391-1401
        • Asada N.
        • Katayama Y.
        • Sato M.
        • Minagawa K.
        • Wakahashi K.
        • Kawano H.
        • et al.
        Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells.
        Cell Stem Cell. 2013; 12: 737-747