Gordon Cook

Guidelines for the diagnosis and management of multiple myeloma 2011.

653. Spencer, A., Prince, H.M., Roberts, A.W., Prosser, I.W., Bradstock, K.F., Coyle, L., Gill, D.S., Horvath, N., Reynolds, J. & Kennedy, N. (2009) Consolidation therapy with low-dose thalido- mide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. Journal of Clinical Oncology, 27, 1788–1793. Srkalovic, G., Cameron, M.G., Rybicki, L., Deitcher, S.R., Kattke-Marchant, K. & Hussein, M.A. (2004) Monoclonal gammopathy of undeter- mined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer, 101, 558– 666. Stadtmauer, E.A., Weber, D.M., Niesvizky, R., Belch, A., Prince, M.H., San Miguel, J.F., Facon, T., Olesnyckyj, M., Yu, Z., Zeldis, J.B., Knight, R.D. Guideline 74 a 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 32–75 & Dimopoulos, M.A. (2009) Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. European Journal of Haematology, 82, 426–432. Stewart, A.K., Vescio, R., Schiller, G., Ballester, O., Noga, S., Rugo, H., Freytes, C., Stadtmauer, E., Tarantolo, S., Sahebi, F., Stiff, P., Meharchard, J., Schlossman, R., Brown, R., Tully, H., Benyunes, M., Jacobs, C., Berenson, R., White, M., DiPersio, J., Anderson, K.C. & Berenson, J. (2001) Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemo- therapy for multiple myeloma: results of a multicenter randomized controlled trial. Journal of Clinical Oncology, 19, 3771–3779. Stewart, A.K., Chen, C.I., Howson-Jan, K., White, D., Roy, J., Kovacs, M.J., Shustik, C., Sadura, A., Shepherd, L., Ding, K., Meyer, R.M. & Belch, A.R. (2004) Results of a multicenter randomized phase II trial of thalidomide and prednisone mainte- nance therapy for multiple myeloma after autol- ogous stem cell transplant. Clinical Cancer Research, 10, 8170–8176. Stewart, A.K., Bergsagel, P.L., Greipp, P.R., Dis- penzieri, A., Gertz, M.A., Hayman, S.R., Kumar, S., Lacy, M.Q., Lust, J.A., Russell, S.J., Witzig, T.E., Zeldenrust, S.R., Dingli, D., Reeder, C.B., Roy, V., Kyle, R.A., Rajkumar, S.V. & Fonseca, R. (2007) A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia, 21, 529–534. Terpos, E. & Dimopoulos, M.A. (2005) Myeloma bone disease: pathophysiology and management. Annals of Oncology, 16, 1223–1231. Terpos, E. & Rahemtulla, A. (2004) Bisphosphonate treatment for multiple myeloma. Drugs of today (Barcelona, Spain: 1998), 40, 29–40. Terpos, E., Sezer, O., Croucher, P.I., Garcia-Sanz, R., Boccadoro, M., San Miguel, J., Ashcroft, J., Blade, J., Cavo, M., Delforge, M., Dimopoulos, M.A., Facon, T., Macro, M., Waage, A. & Son- neveld, P. (2009) The use of bisphosphonates in multiple myeloma: recommendations of an ex- pert panel on behalf of the European Myeloma Network. Annals of Oncology, 20, 1303–1317. Tosi, P., Zamagni, E., Cellini, C., Cangini, D., Tac- chetti, P., Tura, S., Baccarani, M. & Cavo, M. (2004) Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. European Journal of Haematology, 73, 98–103. Tosi, P., Zamagni, E., Cellini, C., Plasmati, R., Cangini, D., Tacchetti, P., Perrone, G., Pastorelli, F., Tura, S., Baccarani, M. & Cavo, M. (2005) Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma. European Journal of Haematology, 74, 212–216. Vela-Ojeda, J., Garcia-Ruiz-Esparza, M.A., Padilla- Gonzalez, Y., Gomez-Almaguer, D., Gutierrez- Aguirre, C.H., Gomez-Rangel, D., Morales- Toquero, A., Ruiz-Delgado, G.J., Delgado-Lamas, J.L. & Ruiz-Arguelles, G.J. (2007) Autologous peripheral blood stem cell transplantation in multiple myeloma using oral versus I.V. melphalan. Annals of Hematology, 86, 277–282. van de Velde, H.J., Liu, X., Chen, G., Cakana, A., Deraedt, W. & Bayssas, M. (2007) Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica, 92, 1399–1406. Vigneau, C., Ardiet, C., Bret, M., Laville, M., Fiere, D., Tranchand, B. & Fouque, D. (2002) Inter- mediate-dose (25 mg/m) IV melphalan for multiple myeloma with renal failure. Journal of Nephrology, 15, 684–689. Vogel, C.L., Yanagihara, R.H., Wood, A.J., Schnell, F.M., Henderson, C., Kaplan, B.H., Purdy, M.H., Orlowski, R., Decker, J.L., Lacerna, L. & Hohneker, J.A. (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist, 9, 687–695. Waage, A., Gimsing, P., Juliusson, G., Turesson, I., Gulbrandsen, N., Eriksson, T., Hjorth, M., Niel- sen, J.L., Lenhoff, S., Westin, J. & Wisloff, F. (2004) Early response predicts thalidomide efficiency in patients with advanced multiple myeloma. British Journal of Haematology, 125, 149–155. Wang, M., Knight, R., Dimopoulos, M., Siegel, D., Rajkumar, S.V., Facon, T., Alexanian, R., Yu, Z., Zeldis, J., Olesnyckyj, M. & Weber, D. (2006) Lenalidomide in combination with dexametha- sone was more effective than dexamethasone in patients who have received prior thalidomide for relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts), 108, Abstract 3553. Weber, D.M., Gavino, M., Delasalle, K., Rankin, K., Giralt, S. & Alexanian, R. (1999) Thalidomide alone or with dexamethasone for multiple mye- loma. Blood, 94(Suppl. I), 604a. Weber, D., Wang, M., Chen, C., Belch, A., Stadt- mauer, E.A., Niesvisky, R., Yu, Z., Olesnyckyj, M., Zeldis, J., Knight, R.D. & Dimopoulos, M. (2006) Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of 2 Phase III Studies (MM-009, MM-010) and Subgroup Analysis of Patients with Impaired Renal Function. Blood (ASH Annual Meeting Abstracts), 108, 3547. Weber, D.M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E.A., Siegel, D., Borrello, I., Rajkumar, S.V., Chanan-Khan, A.A., Lonial, S., Yu, Z., Patin, J., Olesnyckyj, M., Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexa- methasone for relapsed multiple myeloma in North America. New England Journal of Medicine, 357, 2133–2142. Wechalekar, A., Amato, D., Chen, C., Stewart K., A. & Reece, D. (2005) IgD multiple myeloma–a clinical profile and outcome with chemotherapy and autologous stem cell transplantation. Annals of Hematology, 84, 115–117. Wijermans, P., Schaafsma, M., Norden, Y.v., Ammerlaan, R., Wittebol, S., Sinnige, H., Zweegman, S., Kooi, M.v.M., Griend, R.V.d., Lokhorst, H. & Sonneveld, P. (2008) Melphalan/ prednisone versus melphalan/prednisone/thalid- omide in induction therapy for multiple myelo- ma in elderly patients: final analysis of the dutch cooperative group HOVON 49 study. Blood (ASH Annual Meeting Abstracts), 112, Abstract 649. Zervas, K., Mihou, D., Katodritou, E., Pouli, A., Mitsouli, C.H., Anagnostopoulos, A., Delibasi, S., Kyrtsonis, M.C., Anagnostopoulos, N., Terpos, E., Zikos, P., Maniatis, A. & Dimopoulos, M.A. (2007) VAD-doxil versus VAD-doxil plus tha- lidomide as initial treatment for multiple mye- loma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Annals of Oncology, 18, 1369–1375. Zucchelli, P., Pasquali, S., Cagnoli, L. & Ferrari, G. (1988) Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney International, 33, 1175–1180. Guideline a 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 32–75 75

The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells

Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56(dim) NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patient-derived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression.

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial.

Summary Background Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events. Methods Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001). Interpretation The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline. Funding Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial

BACKGROUND Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. METHODS This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. FINDINGS Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). INTERPRETATION This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. FUNDING Cancer Research UK.

CD4+CD25+FoxP3+ regulatory T cells are increased whilst CD3+CD4−CD8−αβTCR+ Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden

Increased levels of naturally occurring regulatory T cells (TReg cells) have been found in a variety of solid tumours and haematological malignancies. In multiple myeloma (MM), evidence suggests that TReg cells are increased though controversy exists with regards to their function and no relationship to disease stage and treatment has been demonstrated. Here, we demonstrate significantly elevated levels of functional CD4+CD25+FoxP3+ TReg cells in a large cohort of patients with MM as well as monoclonal gammopathy of uncertain significance (MGUS) in comparison to age‐matched, healthy controls. The frequency of Double Negative TReg cells was also evaluated, demonstrating that these cells were reduced in patients with MM. Furthermore, a characteristic profile of immunomodulatory cytokines in the peripheral blood and bone marrow of patients with MM and MGUS was demonstrated, compared with healthy controls. This data adds further evidence to the understanding of the role of TReg cell subsets in tumour immunology and the fundamentals of the host/tumour immune conflict.

A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42–51%). Therapy‐related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22–31%), constipation (37%, 95% CI 32–42%) and peripheral neuropathy (27%, 95% CI 23–32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3–8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.

The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study

Fifty-one patients with primary myelofibrosis (PMF) received allogeneic haematopoietic stem cell transplants from related (n=33) or unrelated (n=18) donors. Twenty-seven patients, 19–54 years old, were prepared with myeloablative regimens including CY plus BU (n=4) or TBI (n=23). Twenty-four patients, 40–64 years old, received reduced-intensity conditioning (RIC) regimens. All RIC regimens contained fludarabine, combined with melphalan (n=19) or BU (n=5), and alemtuzumab or anti-thymocyte globulin (ATG) in the majority (n=19). Four patients (17%) in the RIC group had primary graft failure. Previous splenectomy reduced time to engraftment in the RIC group (13 versus 20 days; P=0.008). For MA and RIC groups, respectively, at 3 years, overall survival rates were 44 and 31% (P=0.67), progression-free survival 44 and 24% (P=0.87), and actuarial relapse rates 15 and 46% (P=0.06). Non-relapse mortality at 3 years was 41% for the myeloablative and 32% for the RIC group. Acute GVHD occurred in 29 and 38% of patients in the myeloablative and RIC groups, respectively. Extensive chronic GVHD developed in 30 and 35% of evaluable patients, respectively.

Tumour Cell Generation of Inducible Regulatory T-Cells in Multiple Myeloma Is Contact-Dependent and Antigen-Presenting Cell-Independent

Regulatory T-cells (TReg cells) are increased in patients with multiple myeloma (MM). We investigated whether MM cells could generate and/or expand TReg cells as a method of immuno-surveillance avoidance. In an in vitro model, CD4+CD25- FoxP3 - T-cells co-cultured with malignant plasma cells (primary MM cells and cell lines) induced a significant generation of CD4+CD25+ FoxP3 + inducible TReg cells (tTReg cells; p<0.0001), in a contact-dependent manner. tTReg cells were polyclonal, demonstrated a suppressive phenotype and phenotypically, demonstrated increased FoxP3 (p = 0.0001), increased GITR (p<0.0001), increased PD1 (p = 0.003) and decreased CD62L (p = 0.007) expression compared with naturally occurring TReg cells. FACS-sorted tTReg cells differentiated into FoxP +IL-17+ and FoxP3 -IL-17+ CD4+ cells upon TCR-mediated stimulation. Blocking experiments with anti-ICOS-L MoAb resulted in a significant inhibition of tTReg cell generation whereas both IL-10 & TGFβ blockade did not. MM tumour cells can directly generate functional TReg cells in a contact-dependent manner, mediated by ICOS/ICOS-L. These features suggest that tumour generation of TReg cells may contribute to evasion of immune surveillance by the host.

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: Clinical features, viral load correlates and prognostic factors in the rituximab era

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50–65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had ⩽10 000 and ⩽40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12–0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12–2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.