Meeting Synopsis

VIII International Myeloma Workshop,Banff Springs Hotel, Banff, Alberta, Canada,4±8 May 2001

Reiman T, Keats J. VIII International Myeloma Workshop,Banff Springs Hotel, Banff, Alberta, Canada, 4±8 May 2001.Eur J Haematol 2001: 67: 199±202. # Munksgaard 2001.

Tony Reiman., Jonathan Keats.Department of Oncology, University of Alberta and

Cross Cancer Institute, Edmonton, Alberta, Canada

Correspondence: Tony Reiman or Jonathan Keats,

Department of Oncology, University of Alberta & Cross

Cancer Institute, 11560 University Avenue, Edmonton,

Alberta T6G 1Z2, Canada

Tel: + (780) 432 8924

Fax:+(780) 432 8928

e-mail: treiman13@hotmail.com or jkeats@ualberta.ca

Accepted for publication 11 July 2001

The VIII International Myeloma Workshop washeld on 4±8 May 2001 in Banff, Alberta, Canada.At this meeting, held every two years, the worldleaders in multiple myeloma research present thestate of the art in the biology and management ofthis disease. This year's meeting was attended by685 registrants and was cochaired by Linda M.Pilarski and Andrew R. Belch of the Cross CancerInstitute, Edmonton, Alberta, Canada. The follow-ing is a summary of the presentations at this year'sworkshop.

Discussion

Autologous transplantation

The ®rst results from the British MRC MyelomaVII trial were presented by Dr J.A. Child (UK),comparing high-dose melphalan with autologousstem cell support (n=204) to standard-dose chemo-therapy (n=203) in patients under 60 yr of age. Themedian OS was 52 months in the high-dose arm and42 months in the conventional therapy arm; stat-istical signi®cance was not presented. However, ahigh-dose arm is planned as the control arm forsubsequent MRC trials in myeloma. These resultswere consistent with the IFM 90 trial, which wasupdated at seven years and continued to showimproved survival with autologous transplantation

compared to standard chemotherapy presented byDr M. Attal (France).

Early results from three randomized trials oftandem vs. single autologous transplantation formyeloma were presented, suggesting that the bene-®ts of a second transplant are modest at best. In theFrench IFM 94 trial, 403 untreated patients under60 yr of age were randomized to receive either asingle autologous transplant (melphalan 140 mg/m2

plus 8 Gy TBI, arm A) or a tandem transplant (armB), with melphalan 140 mg/m2 conditioning in the®rst transplant and melphalan plus TBI as in arm Ain the second transplant. Three hundred and forty-four eligible patients underwent a second random-ization, to peripheral blood (PBSC) vs. bone marrow(BM) stem cell support. The patients receivingtandem transplantation with PBSC support werefound to have superior response rate (P<0.05),5-yr EFS (P<0.01) and OS (P<0.05). However,there was no signi®cant advantage to tandemtransplantation when arms A and B were comparedirrespective of the mode of stem cell support. Twoother trials of tandem vs. single autologous trans-plant were presented: the Bologna 96 trial, byDr H.E. Jernberg Wiklund (Sweden) (n=178), andthe French group `Myelome-autogreffe' trial, byDr J.P. Fermand (France) (n=193). Bologna 96reported a superior EFS for patients actuallyreceiving the tandem transplant, a result which

Eur J Haematol 2001: 67: 199±202Printed in UK. All rights reserved

Copyright # Munksgaard 2001

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ISSN 0902-4441

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disappeared using intention-to-treat analysis.Neither of these trials reported an OS difference.In the `Myelome-autogreffe' trial, a second random-ization showed no bene®t to CD34+ selection ofthe autograft. In a related trial presented byDr C.M. Segeren (Netherlands), the Dutch±BelgianHOVON group presented a phase III study usingdose-intense melphalan with or without myelo-ablative cyclophosphamide therapy and autologousstem cell rescue. No advantage in EFS or OS wasseen for either group.

Allogeneic transplantation

Dr G. Gahrton (Sweden) discussed that allogeneictransplant-related mortality (TRM) has decreasedsince 1994. In the EBMT myeloma series of over1000 patients, overall survival with peripheral bloodstem cells was inferior to that seen with marrowtransplantation, possibly due to an increase inchronic graft-vs.-host disease. The Seattle experi-ence with nonmyeloablative allogeneic transplanta-tion was presented by Dr W. Bensinger (USA).Following autologous transplant, conditioning withvery low dose (200 cGy) TBI, mycophenolate, andcyclosporine were administered prior to donor stemcell infusion. Fludarabine was added to the regimenfor patients having failed a prior autologoustransplant, due to a high graft rejection rate inthis group. Preliminary results suggest clinicallythat CR can be achieved in up to 50% of patients.TRM was 17%. The protocol is being expandedto other centres. In the Netherlands, high res-ponse rates were seen in Dr H.M. Lokhorst's(Netherlands) experience with donor lymphocyteinfusions post-allogeneic transplant (52% RR,22% CR).

Thalidomide

Thalidomide has become a standard therapy forpatients with otherwise refractory myeloma. Theinitial idea that the drug is primarily antiangiogenicin its activity has expanded as evidence of directeffects on the tumour and microenvironment hasmounted. Dr B. Barlogie (USA) updated his ori-ginal series, with a total of 169 patients treated withthalidomide for refractory relapse, indicating sim-ilar results compared with the time of ®rstpublication. Presentations at this meeting focusedon the use of thalidomide alone and in combinationas ®rst-line therapy in myeloma. Dr D. Weber(USA) reported a 36% response rate with single-agent thalidomide ®rst-line, with a 72% responserate in combination with dexamethasone. DrB. Durie (USA) reported response rates of 44%with up-front thalidomide, including durable

responses in patients using doses as low as 50 mgevery 2 d. Dr S. Rajkumar (USA) reported that77% obtained a response with the combination ofthalidomide and dexamethasone. Thrombotic eventswere seen in 8%. The Sloan±Kettering experiencewith thalidomide, doxorubicin and dexamethasoneas ®rst-line therapy was presented by Dr. K. Osman(USA) and was marked by venous thrombosis in4/15 patients. Dr M. Coleman (USA) obtained a74% overall response rate in 40 patients withclarithromycin, low-dose thalidomide and dexa-methasone in combination; once again, thromboticphenomena were seen, including three fatal events(two pulmonary emboli, one stroke). In addition,an interaction among the drugs was seen, suchthat Cushingoid effects were seen in 25% andthe tolerated doses of each individual drug wererelatively low. Dr B. Barlogie (USA) has beenincorporating thalidomide into intensive multi-agent protocols, and has noted an increase invenous thrombosis as well as hypothyroidism.Dr M. Hussein (USA) reported other side-effects of thalidomide alone or in combination,including folate/B12 de®ciencies, ®ne tremors, bra-dycardia, skin rashes, toxic epidermal necrolysisand neuropathy.

Bisphosphonates

Interesting evidence was presented that bispho-sphonates have direct antitumour activity. Todate, clinical trials have focused on the preven-tion of skeletal events, both in myeloma and othertumours. At an industry-sponsored (Novartis) sym-posium, the ®rst results of three protocols involvingzoledronate were presented by Dr R. Vescio (USA).In the ®rst trial, 1640 patients with myeloma orbreast cancer and lytic bony disease were random-ized to monthly infusions of zoledronate (4 mg,15 min infusions) or pamidronate (90 mg, 2 hinfusions), the current standard. With 12 monthsof follow-up, the two drugs displayed equal ef®cacyin prevention of skeletal events. Two protocolscomparing zoledronate to placebo for the preven-tion of skeletal events in prostate cancer (n=639)and lung or other cancers (n=763) revealed asigni®cant reduction in bony complications withzoledronate. The results with prostate cancer wereinteresting given the predominantly osteoblasticnature of the bony lesions seen in that disease.

New therapies

Many new compounds were discussed regardingmechanisms of action and potential antitumouref®cacy in multiple myeloma. Promising preclinicaland/or early phase I clinical trials data were

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presented. Potentially useful agents include theproteosome/NF-kB inhibitor PS-341, immuno-modulatory drugs (IMiDs), antiangiogenic agents,2-methoxyestradiol, VEGF receptor inhibitors,TRAIL, arsenic trioxide, inhibitors of the RANK±RANK ligand interaction, newer bisphosphon-ates and anti-HM1.24 monoclonal antibody. Inautologous transplantation, new ideas included166Ho-DOTMP for conditioning and novel purgingstrategies. The paradigm of high-dose, cytotoxicchemotherapy in myeloma may in the future giveway to the use of newer agents speci®cally targetingpathways involving the tumour microenvironment,angiogenesis, apoptosis, and tumour cell signaling.

The myeloma clone

Controversy continues to surround the origin of themyeloma clone, as evident in the ®rst session of themeeting. Dr L. Pilarski (Canada) presented newdata indicating the presence of multiple Ig heavychain isotypes within individual patients linkedto the unique patient-speci®c VDJ signature. Ofparticular interest was the correlation between thepresence of non-clinical, pre-switch IgM express-ing clonal MM cells and worsened prognosis.Furthermore, in the NOD-SCID xenograft model,the pre-switch clonal cells exhibited the ability toself-renew, as they could be transferred to asecondary mouse recipient. Dr F. Stevenson (UK)presented a possible mechanism for the existence ofpre-switch isotypes as being either cis- or trans-RNA splicing. This was supported by the detectionof multiple Ig heavy chain isotypes within singlehairy cell leukemia cells. Finally, Dr M. Bakkus(Belgium) presented data accumulated using the 5Tmouse model, indicating a trans-switching origin ofpreswitch IgM cells. This phenomenon was onlyevident in the in vivo model and not the in vitro cellline, in contrast to the existence of a pre-switchprecursor cell.

Genetic instability

Dr H. Avet-Loiseau (France) presented dataaccrued from nearly 700 patients with plasma cellmalignancies. Within this cohort 75% have chromo-somal abnormalities at the 14q32 region. Trans-locations involving 4p16 (FGFR3) and 16q23(c-maf ) were rare in MGUS and SMM, suggestingthey may be more indicative of true MM. Trans-locations involving 4p16 were most common in IgAMM, while involvement of 16q23 associated withPCL. Translocations involving 11q13 (cyclin D1/myeov) were most common in BJ MM; however,this abnormality was found in all stages of MM.

Moreover, the 25% of patients lacking 14q32abnormalities are most often IgG MM caseswithin the good prognosis group [low B2m andno del(13)]. A subsequent correlation between13q14 deletions and decreased response rate toconventional chemotherapy and overall shortersurvival was presented by Dr Johannes Drach(Austria). 13q14 status was independent ofresponse rates to HDT; however, patients with13q14 deletions had a shorter progression-freeand overall survival. Moreover, deletion of 22qappears to be an independent prognostic indicatoridentifying a subset of patients with poor out-come. Patients with t(11; 14) appear to have near-diploid DNA content, unlike the majority ofMM patients with hyperdiploid cells. Furthermore,the incidence of t(4; 14) appears to correlate withchromosome 13 deletions [Dr R. Fonseca (USA)].

Bone marrow microenviroment and osteoclasts

Dr J. Epstein (USA) presented data gathered usingthe SCID-hu mouse model, where human bonefragments are implanted into the mice to provide ahuman microenvironment for the human myelomacells. Utilizing this system they found that zole-dronic acid prevented the accumulation of osteo-clasts to the transplanted bones, while, pamidronateprevented osteoclast activity. Furthermore, preven-tative treatment of mice with pamidronate, zole-dronic acid, or TRANCE-Fc (RANKL antagonist)prior to myeloma cell engraftment preventedmyeloma growth, suggesting that osteoclast activityis essential for the survival and proliferation ofsome ex vivo human MM cells in this model.Utilizing the in vivo 5T mouse model Dr G. Mundy(USA) presented data indicating and antimyelomaeffect of RANK-Fc (RANKL antagonist) alongwith its expected inhibition of bone disease. Further-more, neutralizing antibodies against alpha5/beta1integrin found on MM PC and its ligand VCAM1found on BM stromal cells prevented the increasedproduction of cytokines associated with boneresorption. The expression of RANKL within thebone marrow of MM patients remains controver-sial, as the cells expressing RANKL and the level ofexpression vary between different groups.

Myelomagenesis

The marker of choice at this meeting for MM PCwas syndecan-1 (CD138) as a majority of pre-sentations denoted MM cells with this marker.The importance of syndecan-1 was highlighted byDr R. Sanderson (USA). He found syndecan-1localizes to the uropod, trailing edge of motile cells,

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and the site of initial cell±cell interactions. Thelocalization of syndecan-1 appears to be mediatedby the extracellular domain of syndecan-1, throughheparin mediated interactions.

The importance of genetic instability in regardsto myelomagenesis was presented in two talks.Dr M. Kuehl (USA) highlighted the high incidence,60±70%, of IgH translocations in MM cells andhypothesized on the likely role such translocationsplay in the initiation of myeloma. The incidenceof multiple IgH switch translocations was stated tobe around 17%. However, the importance of switchtranslocations was overshadowed by the level ofgross chromosomal gains and losses observed inalmost every MM patient. The importance of switchtranslocations in the pathogenesis of MM wasquestioned by Dr J. Ho (Australia). Althoughswitch translocations are common within myeloma

patients, not all patients have detectable 14q32abnormalities, suggesting a likely involvement inthe progression of MM and not the initiation ofMM. Furthermore, the level of target gene expres-sion appears to be dependent on the breakpoints.For instance, the level of cyclin D1 and myeovexpression was assayed in a panel of patients witht(11; 14) by quantitative real-time RT-PCR. In thispanel each possible pro®le was observed, from over-expression of both cyclin D1 and myeov to the lackof expression of both genes. Furthermore, in someinstances only cyclin D1 was overexpressed, orconversely only myeov was overexpressed. Thishighlights the importance of studying beyond thechromosomal abnormalities, as not all similarabnormalities will provide identical phenotypesbecause the gene expression pro®les will varybetween the breakpoints.

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