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Multiple Myeloma working group


1. Composition
2. Description of the field of work
3. Trials
4. Developments
5. Treatment guidelines (if applicable)
6. Publications


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1. Composition



Prof. dr. P. Sonneveld (Erasmus MC)



Prof. dr. S. Zweegman (VUmc)



Dr. N. W.C.J. van de Donk (VUmc)


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2. Description of the field of work

The key objectives of this working group are:

to draw up guidelines for the treatment and diagnosis of multiple myeloma and related disorders including AL amyloidosis and M. Waldenström;
initiation and implementation of multicentre phase II and phase III clinical trials amongst younger and older patients;
the related standardisation of modern methods for determining risk profiles including cytogenetics and gene expression profiling;
the further elaboration of collaboration with international study groups including the IFM, GIMEMA, GMMG and the Nordic group;
maintaining and further expanding an internationally-competitive position in respect of research into new medicines in clinical trials.


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3. Trials

For the various indication areas that fall within the responsibility of the working group, a minimum package of trials is formulated, that must always be activated. Trial-free periods are avoided as far as possible or filled in with short phase II trials or collaboration with industry-initiated trials. In addition, trials can be put forward that can be implemented on the basis of prioritisation or current interests.

The permanent package of trials consists of:

Trial for first-line treatment amongst younger patients with Multiple Myeloma (currently HOVON 95);
Trial for first-line treatment of older patients with Multiple Myeloma (currently HOVON 87);
Trial for recurrent treatment amongst older patients with Multiple Myeloma;

Trial into Allogeneic transplantation amongst patients with Multiple Myeloma (currently HOVON 108).

Depending on the developments, initiatives may be taken for trials with other indications, such as:

M. Waldenström;
Supportive Care.


All phase I/II MM studies can be found in the overview below (these are HOVON-associated studies):


MM phase I/II trials (HOVON associated)




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4. Developments

The working group is investing heavily in implementing 'correlative studies' with the clinical trials. In particular, focus will be placed on obtaining additional biological information about the tumour and the 'host' by means of Gene Expression Profiling (GEP) and mutation analysis (SNPs) and making use of large-scaled CHIP-based analyses. For this purpose, financing will have to be generated within HOVON;
Preparation for new trials (follow-up to HOVON 65) etc. HOVON 86 and 87 are in start-up phase;
The working group is investing in expanding collaboration with other trial groups with a view to increasing the scale and impact of the trials. Examples are long-term cooperation with the German GMMG group in the H50 and H65 trials and recent collaboration with Scandinavian groups for Hovon 87;
The working group is placing the emphasis on the optimisation of clinical information made available in the trials through investing in 'minimal data sets' necessary for the CRFs. The intention is to keep the trial logistically compact and to restrict the burden for the HDC;
The working group was the first to implement a trial according to the European GCP Directive, and expects further development in this field;
The working group is placing the emphasis on obtaining and maintaining an internationally-competitive position in respect of studies into new medicines in clinical trials;
The working group will cooperate in improving the slow and incomplete process of trial management and trial analysis by the HOVON Data Center over the past few years.

The analyses implemented in 2008 are:

HOVON 50 (MM < 65 years);
HOVON 54 (donor versus no donor, Allo SCT);
HOVON 65 an initial analysis required for response.


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5. Treatment guidelines (if applicable)

For patients unable or unwilling to be treated in part of a trial, the HOVON myeloma working group has revised the guidelines for treatment as drawn up in 2005. Here click on to the section on Guidelines

The most important alterations are that:

In the first line, Thalidomide is recommended;
For older patients in combination with melphalan/ prednison (MP-T);
For younger patients in combination with dexamethasone (Thal/Dex (+/- adriamycine, TAD);
In the second line, both bortezomib/dexamethasone, lenalidomide/dexamethasone and thalidomide/dexamethasone can be administered. As necessary, a low dosage of cyclophosphamide can be added to the combination thalidomide/dexamethasone;
Given the absence of random studies between the above forms of therapy, the choice will be made on an individual basis, according to previous treatment and the side effects profile.

The combinations referred to above are also eligible for treatment for the following relapses:



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6. Publications

H.M. Lokhorst, P. Sonneveld, A.W. Dekker, M. van Marwijk Kooy,
O.J.A.Th. Meuwissen, R.H.J. van Oers, P.W. Wijermans, R.J. van der Griend:
- A phase II study of double or triple intermediate dose melphalan (IDM) and filgrastim for previously untreated multiple myeloma.
Br. J Haematol, 92, 44-48, (1995).

H.M. Lokhorst, P. Sonneveld ,C.M. Segeren, P. Weijermans:
- Multipel myeloom; behandeling anno 1998.
Ned Tijdschrift Geneesk, 42, 1596-1602, (1998)

H.M. Lokhorst, P. Sonneveld, J.J. Cornelissen, P. Joosten, M. Van Marwijk Kooy, H.K. Nieuwenhuis, M.H.J. van Oers, D.J. Richel, C.M. Segeren, G. Veth, L.F. Verdonck, P.W. Weyermans:
- Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma.
Bone Marrow Transplantation, 23, 317-322, (1999)

H.M. Lokhorst, L. Verdonck and P. Sonneveld:
- Intensive therapy in multiple myeloma : where do we stand? (Review)
Br J Haematol., 106, 18-27, (1999)

C.M. Segeren, P. Sonneveld , B. van der Holt, J.W. Baars, D.H. Biesma, J.J. Cornelissen, A.J. Croockewit, A.W. Dekker, W.E. Fibbe, B. Löwenberg, M. van Marwijk Kooy, M.H. J. van Oers, D.J. Richel, H.C. Schouten, E. Vellenga, G.E.G. Verhoef, P. Weijermans, S. Wittebol, H.M. Lokhorst:
- Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous pushinfusion for first-line treatment in untreated multiple myeloma.
Br J Haematol. 105, 127-130, (1999)

P.W.M. Willems, R.A.P. Raymakers, C.M. Segeren, C.E. van der Schoot, O.J.H.M. Verhagen, E. Wiemer, E.J.B.M. Mensink, A. Bloem, L.J. Groothuis, E. Vellenga, H.M. Lokhorst, P. Sonneveld:
- A Consensus protocol to quantitate malignant cells in multiple myeloma patients validated in a multicenter study.
Blood, 96, 63-70, (2000)

P. Sonneveld, S. Suciu, P. Wijermans, M. Beksac, R. Neuwirtova, G. Solbu, H. Lokhorst, J. van der Lelie, H. Dohner, H. Gerhartz, C.M. Segeren, R. Willemze and B. Löwenberg:
- Cyclosporin a combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914).
British Journal of Haematology, 115, 895-902, (2001).

K.L. Wu, H.H. Helgason, M.R. Schaafsma, H.M. Lokhorst, P.W. Wijermans, B. van der Holt en P. Sonneveld:
- Thalidomide als behandeling voor het refractaire multipel myeloom: een Nederlandse studie in 72 patiënten.
Ned T Geneesk, 146, 1445-1448, (2002)

H. Goldschmidt, P. Sonneveld, F.W. Cremer, B. van der Holt, P. Westveer, I. Breitkreuz, A. Benner, A. Glasmacher, I. Schmidt-Wolf, H. Martin, D. Hoelzer, A. Ho, H. Lokhorst:
- The joint HOVON-50/GMMG-HD3 randomized trial on the effect of Thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients.
Ann Hematol, 82(10):654-659 (2003).

C.M. Segeren, P. Sonneveld, B. van der Holt, E.Vellenga, A.J. Croockewit, G.E.Verhoef, J.J. Cornelissen, M.R.Schaafsma, M.H. van Oers, P.W. Wijermans, W.E. Fibbe, S. Wittebol, H.C. Schouten, M. van Marwijk Kooy, D.H. Biesma, J.W. Baars, R. Slater, M.M. Steijaert, I. Buijt, H.M. Lokhorst:
- Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study.
Blood, 101(6):2144-51, (2003).

H.M. Lokhorst, C.M. Segeren, B. van der Holt, L.F. Verdonck, R. Raymakers, M.H.J. Oers, R. Barge, H.C. Schouten, P.H.M. Westveer, M.M.C. Steijaert, J.J. Cornelissen, P. Sonneveld, for the Dutch-Belgian Haemato-Oncology Group (HOVON):
- Partial T-cell depleted allogeneic stem cell transplantation as part of first line treatment of multiple myeloma is inferior to intensive treatment alone. Results from a prospective comparison of patients treated in the phase III study HOVON 24.
J Clin Oncol , 21, 1728-1733 (2003)

M. van Agthoven, C.M. Segeren, I Buijt, C.A. Uyl-de Groot, B.van der Holt, H.M. Lokhorst, P. Sonneveld:
- A cost-utility analysis comparing intensive chemotherapy alone to intensive chemotherapy followed by myeloablative chemotherapy aith autologous stem-cell rescue in newly diagnosed patients with stage II/III multiple myeloma; a prospective randomised phase III study.
Eur. J. Cancer.5; 40(8):1159-69 (2004).

K.L. Wu, W. van Wieringen, E. Vellenga, S. Zweegman, H.M. Lokhorst, P. Sonneveld:
- Analysis of the efficacy and toxicity of bortezomib for treatment of relapsed or refractory multiple myeloma in community practice.
Haematologica 90(7);996-997, 2005

H. Lokhorst, P.C. Huijgens, R. Raymakers, G.M. Bos, E. Vellenga, P.W. Wijermans, P. Sonneveld; Myeloomwerkgroep van de Stichting Hemato-Oncologie voor Volwassenen Nederland:
- Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON).
Ned Tijdschr Geneeskd. 2005 Apr 9;149(15):808-13. Review. Dutch.
Erratum in: Ned Tijdsch Geneeskd. 2005 Dec 24;149(52):2948.

I. Breitkreuz, H.M. Lokhorst, M.S. Raab, B.V. Holt, F.W. Cremer, D. Herrmann, A. Glasmacher, I.G. Schmidt-Wolf, I.W. Blau, H. Martin, H. Salwender, A. Haenel, P. Sonneveld, H. Goldschmidt:
- Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield.
Leukemia, 2007 Mar. 22, (Epud ahead of print)

C. Schilthuizen, A. Broyl, B. van der Holt, Y. de Knegt, H. Lokhorst, P. Sonneveld:
- Influence of genetic polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 genes on survival and therapy-related toxicity in multiple myeloma.
Haematologica. 2007 Feb;92(2);277-8.

K.L. Wu, B. Beverloo, H.M. Lokhorst, C.M. Segeren, B. van der Holt, M.M. Steijaert, P.H. Westveer, P.J. Poddighe, G.E. Verhoef, P. Sonneveld; Dutch-Belgian Haemato-Onocology Cooperative Study Group (HOVON); Dutch Working Party on Cancer Genetics and Cytogenetics (NWCGC):
- Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma.
Br J Haematol. 2007 Feb;136(4):615-23.

K.L. Wu, P. Sonneveld:
- Zijn orale bisfosfonaten bij morbus Kahler even effectief als intraveneus (APD 90 mg à 6 weken)?
Internisten Vademecum, 11 (11), juli 2006.

P. Sonneveld, B.van der Holt, C.M. Segeren, E. Vellenga, A.J. Croockewit, G.E.G. Verhoef, J.J. Cornelissen, M.R. Schaafsma, M.H.J. van Oers, P.W. Wijermans, P.H.M. Westveer, and H.M. Lokhorst:
- Intermediate-dose Melphalan compared with myelo-ablative treatment in multiple myeloma: long term follow-up of the Dutch cooperative group HOVON 24 trial
Haematologica. 2007 Jul;92(7):928-35

Van Marion AM, Auwerda JJ, Lisman T, Sonneveld P, de Maat MP, Lokhorst HM, Leebeek FW.:

- Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens. Leuk Res. 2008 Jan 30; [Epub ahead of print]

Lokhorst HM, Hazenberg BP, Croockewit A.:

- High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.
N Engl J Med. 2008 Jan 3;358(1):92; author reply 92-3.

Lokhorst HM, Schmidt-Wolf I, Sonneveld P, van der Holt B, Martin H, Barge R, Bertsch U, Schlenzka J, Bos GM, Croockewit S, Zweegman S, Breitkreuz I, Joosten P, Scheid C, van Marwijk-Kooy M, Salwender HJ, van Oers MH, Schaafsma R, Naumann R, Sinnige H, Blau I, Verhoef G, de Weerdt O, Wijermans P, Wittebol S, Duersen U, Vellenga E, Goldschmidt H; Dutch-Belgian HOVON; German GMMG.:

- Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma.
Haematologica. 2008 Jan;93(1):124-7.


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