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Introduction
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for multiple myeloma (MM) but its role is controversial. The first clinical experi- ence with myeloablative regimens proved to be curative for a small proportion of patients but was accompanied by unacceptably high non-relapse mortality (NRM) rates.1,2 The introduction of less intensive conditioning regimens for allogeneic HCT, which relied on graft-versus-tumor (GvT) effects for tumor eradication, lowered NRM but at the expense of higher disease relapse rates.3,4 In the late 1990s, combining cytoreductive high-dose chemotherapy before autologous HCT with subsequent minimal intensi- ty conditioning allogeneic HCT, an approach aimed at inducing GvT effects, proved to be less toxic than mye- loablative allogeneic HCT and was well tolerated.5,6 Seven prospective trials compared clinical outcomes of autolo- gous HCT versus tandem autologous/minimal intensity allogeneic HCT in newly diagnosed MM patients and yielded discordant results regarding depth of response, overall survival (OS), and progression-free survival (PFS). Differences in conditioning regimens, as well as graft-versus-host disease (GvHD) prophylaxis, including ATG use, patient selection, definition of MM risk profiles, and duration of follow up, made meaningful comparisons between trials difficult.7-15 We previously reported initial results in 102 MM patients given tandem high-dose mel- phalan and autologous HCT followed by 200 cGy total body irradiation (TBI) with or without fludarabine 90mg/m2 and HLA-matched HCT from related or unrelat- ed donors.16 Here we update the early observations and add results from 142 additional patients treated with the same approach for a total of 244 patients with a median follow up of 8.3 years (range, 1.0-18.1).
Methods
Patients
From August 1998 to January 2016, 244 MM patients complet- ed sequential treatment with high-dose melphalan and autolo- gous HCT followed by 200 cGy TBI ± fludarabine and allogeneic, granulocyte colony stimulating factor (G-CSF)-mobilized periph- eral blood mononuclear cell (PBMC) infusion. One hundred and sixty-four (67%) patients were transplanted at the Fred Hutchinson Cancer Research Center (Fred Hutch), Seattle, WA, USA, and 80 (33%) patients received their transplant at eight other institutions. All patients included in the analysis were treat- ed under eighteen clinical trials that were co-ordinated by Fred Hutch, approved by each institution’s review board, and regis- tered at “clinicaltrials.gov”. All patients and donors signed written informed consent in accordance with the Declaration of Helsinki. The nature of the analysis is retrospective, and we present clini- cal data for those 244 patients who received both autologous and allogeneic HCT. Patients' characteristics are detailed in Table 1. Median age at diagnosis was 51 years (range, 25-67). Ninety- seven (42%) patients had high-risk cytogenetics. Fifty-seven (25%) had high-risk disease according to International Staging System (ISS) stage III and 36 (16%) according to Revised ISS (R- ISS) stage. Ninety-one (37%) had received more than one induc- tion therapy line for unresponsive disease. A total of 209 patients (86%) received tandem autologous-allogeneic upfront while 35 patients (14%) had failed a previous autologous HCT before the planned autologous-allogeneic HCT.
Definitions and risk assessment
haematologica | 2019; 104(2)
Tandem transplantation for multiple myeloma
Beta-2 (β2)-microglobulin and serum albumin values at diagno- sis were available for 225 (92%) patients and were used to calcu- late risk according to the ISS.17 The R-ISS was introduced in 2015,18 and we calculated it retrospectively for 217 (89%) patients. Lactate dehydrogenase (LDH) serum levels19 at diagnosis were available in 216 patients. Conventional cytogenetics and/or fluo- rescence in situ hybridization (FISH) studies at diagnosis and at any time before allogeneic HCT were available for 232 patients. High- risk cytogenetics were defined as follows: t(4;14);20 t(14;16);21 t(14;20)22 by FISH; del (17/17p),23 1q21 amplifications24 both by FISH and conventional karyotyping; and non-hyperdiploid kary- otype25 by conventional cytogenetics. Plasma cell leukemia includ- ed circulating plasma cells ≥ 20% of complete blood count or ≥2000 plasma cells per microliter.26 Extramedullary disease at diag- nosis was defined as extramedullary plasmacytomas.27 Patients were considered high risk if they had one of the following: ISS stage III, high-risk genetic lesions, extramedullary disease presen- tation, plasma cell leukemia, LDH levels ≥ 2 upper normal limits or failed previous autologous HCT. Ultra-high-risk was defined as having ≥ 2 adverse factors.23,28 All patients not meeting previous criteria were considered standard risk.
HLA-typing
Patients and donors were matched for HLA-A, HLA-B and HLA-C by at least intermediate resolution DNA typing and for HLA-DRB1 and DQB1 by high-resolution techniques, as previous- ly described.29 Donors were HLA-identical siblings in 179 cases and HLA-matched unrelated in 65 cases; 11 unrelated donors were mismatched with their recipients for a single HLA allele (n=7) or antigen (n=4).
Autologous hematopoietic cell transplantation
After induction treatment, patients proceeded to mobilization and collection of PBMC. Mobilization regimens included: cyclophosphamide plus dexamethasone (35% of patients), cyclophosphamide plus etoposide and dexamethasone (CED) (24%), cyclophosphamide plus paclitaxel (16%), VTD-PACE (bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin- cyclophosphamide-etoposide) (8%), VRD-PACE (bortezomib- lenalidomide-dexamethasone-cisplatin-doxorubicin-cyclophos- phamide-etoposide) (5%), carfilzomib plus RD-PACE (lenalido- mide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide- etoposide) (1%), cyclophosphamide plus etoposide and carboplat- inum (CEP) (2%), bendamustine plus etoposide and dexametha- sone (BED) (1%), Hyper-CVAD (cyclophosphamide-vincristine- doxorubicine-dexamethasone-adenosine arabinoside-mesna- methotrexate) (1%), or G-CSF (10 mg/kg) alone in 7% of the patients. After PBMC collection, patients received melphalan at 200 mg/m2 intravenously (N.B. 3 patients received melphalan 140 mg/m2 because of impaired renal function) before autologous PBMC infusion, with a median of 7.8 (range, 2.1-30.4) × 106 CD34+ cells/kg actual body weight.
Allogeneic hematopoietic cell transplantation
After complete recovery from autologous HCT, patients pro- ceeded to allogeneic HCT at a median of 75 days (range, 40-281). No further therapy was given between autologous and allogeneic HCT. The conditioning regimen for allogeneic HCT consisted of 200 cGy TBI at 7 cGy/minute from a linear accelerator (n=163) or two opposing Cobalt-60 sources (n=81). Recipients of unrelated grafts (n=65) received in addition three daily doses of fludarabine for a total of 90 mg/m2. PBMC grafts contained a median of 9.0 (range, 1.7-24.0) x 106 CD34+ cells/kg actual body weight. Post- grafting immunosuppression included mycophenolate mofetil
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