Jennifer M. Bird

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

Guidelines for supportive care in multiple myeloma 2011

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate‐induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.

The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation

In this study, we retrospectively analysed the clinical features, risk factors and outcome of 22 patients with thrombotic thrombocytopenic purpura (TTP) occurring after allogeneic stem cell transplantation. All but two of these patients received stem cells from unrelated donors (UDs), two‐thirds were female, three‐quarters were adults and leukaemia was the major reason for transplant. The incidence of TTP was 20 out of 332 patients (6%) with UD transplants and two out of 104 recipients (2%) of matched sibling allografts (P = 0·16). In order to ascertain basic demographic risk factors for the development of TTP, we compared the 22 patients with 434 patients who did not develop TTP. Compared with patients who did not develop TTP, patients with TTP were nearly three times older (P < 0·001) and were more than twice as likely to be female (P = 0·001). Because > 90% of patients were recipients of UD marrow, we then compared the 20 UD‐bone marrow transplantation (BMT) patients with 60 randomly selected UD‐BMT patients who did not develop TTP. On univariate analysis, age and female gender were again significant risk factors, as was grade II–IV acute graft‐versus‐host disease (GvHD) (P = 0·002), and there was a trend towards an association with chronic GvHD (P = 0·083). However, after logistic regression analysis, only age and sex remained significant (P < 0·001 and 0·009 respectively). We report an 86% mortality with only three survivors out of 22 patients, and one of these remains thrombocytopenic and red cell transfusion dependent, possibly in part because of graft hypoplasia. Six out of 17 patients responded to plasmapheresis, but the majority of them ultimately succumbed because of TTP, often in association with GvHD or fungal infection.

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.

The outcome of high‐dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty‐three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60–200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant‐related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6–54 months) and the median time to best response was 6·5 months. Four of 17 evaluable patients (24%) became dialysis‐independent at a median of 5 months post‐HDT/stem cell transplantation. At a median follow‐up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5‐year survival in about one‐third of patients.

T Cell-Depleted Unrelated Donor Bone Marrow Transplantation for Acute Myeloid Leukemia

The outcome for 39 patients with acute myeloid leukemia (AML) in remission who had CAMPATH 1M T cell-depleted unrelated donor bone marrow transplantations (BMTs) is described. Conditioning was mainly with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (14.4 Gy), but 5 patients received busulfan in place of TBI and 200 mg/kg cyclophosphamide. All patients received cyclosporin, and short-course methotrexate was given to recipients of mismatched grafts. The patient population was predominantly pediatric (median age, 10 years), but one third of the patients was aged 15 years or above. Twenty-five patients were in second complete remission (CR2), and 14 had high-risk CR1 disease (primarily failed remission induction or antecedent myelodysplastic syndrome, often with complex cytogenetic abnormalities). Both recipient and donor were cytomegalovirus seronegative in 15 of 37 cases (38%); 51% of patients were matched for HLA class I and II. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 24% of patients; chronic GVHD occurred in 5 of 31 evaluable patients (16%), 4 extensive and 1 limited. Relapse occurred in 5 cases (13%); 1 of these 5 patients survives, 24 months after a second unrelated donor transplantation. Two of these relapses were associated with secondary graft failure (incidence rate, 5%). All patients engrafted primarily. Severe viral infection was the major transplant-associated complication, with 12 episodes in 9 patients, 5 of them lethal. Twenty-five patients survive at a median follow-up of 44 months (range, 2-102 months), with estimated actuarial overall and disease-free survival rates at 44 months of 61% (SE 8%) and 57% (SE 8%), respectively. Nineteen patients are more than 2 years post-BMT and may be cured. The functional status of long-term survivors is excellent, with 19 of 21 patients who survive 6 months or more in full-time employment or full-time students. These encouraging results suggest that in patients lacking a sibling donor, unrelated donor BMT for AML in remission achieves survival figures as good as or better than those reported on patients with autologous stem cell transplantation, and that T-cell depletion of grafts is associated with a low relapse rate and an excellent functional status. However, only a randomized study comparing unrelated donor BMT and auto-grafting will resolve which of these treatment strategies is better for patients with AML.

Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23–46%) in the autologous group and 20% (95% CI, 10–34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48–72%) in the autologous group and 38% (95% CI, 25–53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52–75%) in the autologous group and 39% (95% CI, 26–54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1–11%) in the autologous group and 41% (95% CI, 28–56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

Thrombotic Thrombocytopenic Purpura Following Stem Cell Transplantation

Thrombotic thrombocytopenic purpura (TTP) occurring after stem cell transplantation is poorly understood. The literature is scant and heterogeneous; little is known about the conditions pathogenesis except that it appears to differ from that of classical or de novo TTP. There are no widely agreed diagnostic criteria hence, it is difficult to compare the major findings of the relatively small, single centre series that have been reported. The true incidence is disputed and risk factors have only recently been evaluated. Plasma exchange is commonly employed for the therapy of severe post-transplant TTP but there are no data that support its use. This review summarises the state of knowledge of post-transplant TTP in 2002, addressing all the aforementioned issues and aims to provide the basis for further systematic study of this problematic complication of transplant.

Impact of Pretransplant Therapy and Depth of Disease Response before Autologous Transplantation for Multiple Myeloma

Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (ASCT) typically receive a finite period of initial therapy before ASCT. It is not clear if patients with suboptimal (less than a partial) response to initial therapy benefit from additional alternative therapy with intent to maximize pretransplant response. We identified 539 patients with MM who had an ASCT after having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. These patients were then divided into 2 groups: those who received additional salvage chemotherapy before ASCT (n = 324) and those who had no additional salvage chemotherapy immediately before ASCT (n = 215). Additional pretransplant chemotherapy resulted in deepening responses in 68% (complete response in 8% and PR in 60%). On multivariate analysis there was no impact of pretransplant salvage chemotherapy on treatment-related mortality, risk for relapse, progression-free survival, or overall survival. In conclusion, for patients achieving less than a PR to initial induction therapy, including with novel agent combinations, additional pre-ASCT salvage chemotherapy improved the depth of response and pre-ASCT disease status but was not associated with survival benefit.

The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma

Summary.  We performed a retrospective analysis of outcome in 45 patients with multiple myeloma receiving unrelated donor stem cell transplants (UD‐SCT) in the UK between 1993 and 2002; 17 received myeloablative conditioning regimens and 28 received reduced intensity conditioning (RIC) protocols. Forty patients received pretransplant CAMPATH serotherapy. Forty‐two of 45 patients had detectable disease at transplant, but 33 of 45 were chemoresponsive. Sixty per cent of patients had received a previous autograft. Myeloid engraftment was seen in 95% of recipients and was significantly faster in recipients receiving peripheral blood stem cells (P = 0·07) and RIC (P = 0·001). The incidence of severe (grade 3/4) acute graft versus host disease (aGvHD) was 5% (2/40). The 100‐d non‐relapse mortality was 18% (5/38) following RIC and 53% (9/17) following myeloablative regimens. Twenty‐nine per cent of patients achieved a complete remission, 61% a partial remission, giving a 90% overall response rate. At median follow‐up (513 d), overall survival was 40%: 54% in the RIC group (median follow‐up: 489 d) and 18% in the myeloablative group (median follow‐up: 560 d). In recipients of UD‐SCT, RIC protocols that incorporated CAMPATH were associated with faster myeloid engraftment, less severe aGvHD and lower 100‐d non‐relapse mortality than myeloablative regimens, without a corresponding rise in relapse rate during the period of observation.

Updates to the guidelines for the diagnosis and management of multiple myeloma

Bastuji-Garin, S., Fouchard, N., Bertocchi, M., Roujeau, J.C., Revuz, J. & Wolkenstein, P. (2000) SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. The Journal of Investigative Dermatology, 115, 149–153. Ca~ namares Orbis, I., Garc ıa Mu~ noz, C., Cortijo Cascajares, S. & M endez Esteban, M.E. (2012) Desensitization to lenalidomide. Farmacia Hospitalaria, 36, 542–543. Spanish. McCarthy, P.L., Owzar, K., Hofmeister, C.C., Hurd, D.D., Hassoun, H., Richardson, P.G., Giralt, S., Stadtmauer, E.A., Weisdorf, D.J., Vij, R., Moreb, J.S., Callander, N.S., Van Besien, K., Gentile, T., Isola, L., Maziarz, R.T., Gabriel, D.A., Bashey, A., Landau, H., Martin, T., Qazilbash, M.H., Levitan, D., McClune, B., Schlossman, R., Hars, V., Postiglione, J., Jiang, C., Bennett, E., Barry, S., Bressler, L., Kelly, M., Seiler, M., Rosenbaum, C., Hari, P., Pasquini, M.C., Horowitz, M.M., Shea, T.C., Devine, S.M., Anderson, K.C. & Linker, C. (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. New England Journal of Medicine, 366, 1770–1781. Nardone, B., Wu, S., Garden, B.C., West, D.P., Reich, L.M. & Lacouture, M.E. (2013) Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis. Clinical Lymphoma Myeloma & Leukemia, 13, 424–429. Penna, G., Allegra, A., Romeo, G., Alonci, A., Cannav o, A., Russo, S., D’Angelo, A., Petrungaro, A. & Musolino, C. (2012) Severe dermatologic adverse reactions after exposure to lenalidomide in multiple myeloma patients with a positive HLA-DRB1*1501 and HLA-DQB1*0602. Acta Oncologica, 51, 944–947. Phillips, J., Kujawa, J., Davis-Lorton, M. & Hindenburg, A. (2007) Successful desensitization in a patient with lenalidomide hypersensitivity. American Journal of Hematology, 82, 1030. Rajkumar, S.V., Jacobus, S., Callander, N.S., Fonseca, R., Vesole, D.H., Williams, M.E., Abonour, R., Siegel, D.S., Katz, M. & Greipp, P.R., Eastern Cooperative Oncology Group. (2010) Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. The Lancet Oncology, 11, 29–37. Richardson, P., Jagannath, S., Hussein, M., Berenson, J., Singhal, S., Irwin, D., Williams, S.F., Bensinger, W., Badros, A.Z., Vescio, R., Kenvin, L., Yu, Z., Olesnyckyj, M., Zeldis, J., Knight, R. & Anderson, K.C. (2009) Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood, 114, 772–778. Seki, J.T., Banglawala, S., Lentz, E.M. & Reece, D.E. (2013) Desensitization to lenalidomide in a patient with relapsed multiple myeloma. Clinical Lymphoma Myeloma & Leukemia, 13, 162–165. Sviggum, H.P., Davis, M.D., Rajkumar, S.V. & Dispenzieri, A. (2006) Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Archives of Dermatology, 142, 1298–1302.