The utility of maintenance treatment remains controversial

Less toxic and more effective, many molecules are being developed and new management strategies appear to better fight myeloma. Head of the department of hematology and blood diseases at the CHRU in Lille, Professor Thierry Facon gives an update on this extremely dynamic research.

Against myeloma, new drugs under development

The treatment of multiple myeloma depends on the stage of the disease, the patient's age and general condition. Symptom-free forms (asymptomatic myeloma) receive careful follow-up but no treatment. In case of symptoms, the treatment combines chemotherapy, corticotherapy and new molecules. In patients under the age of 65, initial treatment usually involves intensive chemotherapy supported by an autograft of hematopoietic stem cells. New therapeutic strategies, new molecules and a better knowledge of the biology of this cancer now offer new hopes against myeloma. we takes stock with Prof. Thierry Facon, head of the department of hematology and blood diseases at the CHRU in Lille.

The special case of patients with poor prognosis

In patients under the age of 65, treatment is based on intensive chemotherapy (a high dose of melphalan - Alkeran ®) supported by an autograft of blood - derived hematopoietic stem cells (so - called peripheral blood stem cell autograft). For these patients, several studies advocate the introduction of a maintenance treatment to be taken continuously after this autograft. The challenge is to be able to delay the resumption of the course of the disease without reducing the quality of life of the patient by side effects.

Will the concept of intratumoral heterogeneity overturn care?

"Today the question is whether autograft should be associated with consolidation and maintenance treatment." Three publications in the New England Journal of Medicine 1,2,3 in 2012 address the At the time of their publication, studies are contradictory on the results in terms of survival and the long-term tolerance of the treatment also debates with in particular the appearance of cancers Secondary, "says Prof. Thierry Facon.

Today there is no Authorization to place on the market (AMM) in the United States or at European level of medicines to treat myeloma in this indication. "The European Medicines Agency (EMA) has estimated in 2012 that the data are not sufficient to ensure that the majority of Europeans remain skeptical, Such a strategy could lead to a marketing authorization, "Prof. Facon explains. "Beyond the current controversy, it remains nevertheless probable that we will see, in the years to come, appear maintenance treatments or continuous treatments of the myeloma, with the medicines which we have at present or with another one, Other innovative medicines ". And in this area, the prospects are many.

Progress is expected in different classes of molecules involved in the treatment of multiple myeloma.

Among the immunomodulators (such as thalidomide and lenalidomide), a new molecule appears: pomalidomide. One-third of patients who fail with lenalidomide respond to pomalidomide. This third-generation immunomodulator has been approved by the Food and Drug Administration (FDA) for patients with multiple myeloma who have received at least two previous treatments, including lenalidomide and bortezomib 4.
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Among the proteasome inhibitors (such as bortezomib), carfilzomib was approved by the FDA in 2012. It appears to be more effective and better tolerated, in particular by inducing less peripheral neuropathies, the main side effect of bortezomib 5. The ixazomib Development course in phase III, may be the first oral proteasome inhibitor 6. Another oral proteasome inhibitor, oprozomib is also the subject of several studies 7.
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Two monoclonal antibodies are particularly promising and are currently under development. Elotuzumab specifically targets the CS1 protein, a protein that is present on the surface of abnormal plasma cells and is not found on normal cells. This targeted effect therefore causes little toxicity. Daratumumab targets a small molecule on the surface of normal plasma cells called CD38. It is also administered intravenously. Daratumumab appears to be very promising, with very low toxicity, and results in monotherapy in patients with relapsed myeloma 10.

It is now known that certain genetic abnormalities (in detail, the translocation t (4.14) found in 10 to 15% of patients and the deletion (17p) found in 7 to 10% of patients) seriously aggravate the prognosis. The average survival of these patients is about one year. "11 But if these genetic abnormalities can now be found from bone marrow sampling performed at diagnosis, To offer these patients treatment different from the standard treatments, for lack of study carried out specifically in this subgroup of bad prognosis which represents 10 to 20% of the cases "confesses Pr. Facon.
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A track would be to combine innovative molecules to improve the prognosis of these particularly severe patients, but these therapeutic trials remain difficult to initiate

For a long time, the vision of a myeloma consisting of a group of uniform cancer cells has long been favored: cells (plasmocytes) that have become abnormal will all begin to produce durably and in excessive quantity a single type of antibody, called monoclonal immunoglobulin. Today, for myeloma but also for other cancers, the vision of a tumor made of identical cancer cells now gives way to that of a more heterogeneous tumor made of several subtypes (or subclones) Of cancer cells in constant evolution 12. This is the concept of intratumoral heterogeneity. "It can be hypothesized that in the case of a good response to treatment, at least in some patients, we will mainly reduce the dominant clone, the main group of cancer cells. From these assumptions, it can be assumed that tomorrow a genetic analysis of the cancer cells will better guide the treatment either through a combination of treatment from the outset (aiming at To attack several subpopulations of cancer cells), or by more precisely guiding second-line treatments, "says Professor Facon, who specifies that for the time being these hypotheses have not given rise to clinical applications In the face of myeloma.

The arrival of new molecules and new strategies (maintenance treatment and / or based on the genetic characteristics of individuals and tumors) is now translated into additional weapons against myeloma. The hope is to be able tomorrow, thanks to less binding treatments, to control myeloma to the point of transforming it into a chronic disease.

1 - Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. - Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC , Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL, IFM Investigators. - N Engl J Med. 2012 May 10,366 (19): 1782-91. (Study available online) 2 - Lenalidomide after stem-cell transplantation for multiple myeloma. - McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH 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 MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. - Engl J Med. 2012 May 10,366 (19): 1770-81. (Study available online) 3 - Continuous lenalidomide treatment for newly diagnosed multiple myeloma. - Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J , Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA, MM-015 Investigators. - N Engl J Med. 2012 May 10,366 (19): 1759-69. (Available online) 4 - FDA Communiqué - February 2013 (available online) 5 - Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. - Thompson JL - Ann Pharmacother. 2013 Jan, 47 (1): 56-62. Doi: 10.1345 / aph.1R561. Epub 2013 Jan 8. (abstract online) 6 - Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and / or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose- Escalation Study. - Paul G. Richardson et al. - 2011 ASH Annual Meeting oral poster / abstract 301. (abstract available online); 7 - Proteasome inhibitors in the treatment of multiple myeloma. - McBride A, Ryan PY. Expert Rev Anticancer Ther. 2013 Mar, 13 (3): 339-58. Doi: 10.1586 / era.13.9. (Available on-line) 8 - Phase I / II Study of Elotuzumab More Lenalidomide / Dexamethasone in Relapsed / RefractoryMultiple Myeloma: LongTerm Safety - Asco 2013 - Phase III Study of Lenalidomide and Dexamethasone with or Without Elotuzumab to Treat Relapsed or Refractory Multiple Myeloma (ELOQUENT - 2) - ClinicalTrials.gov (available online) 10 - Daratumumab, CD38 Monoclonal Antibody in Patients with Multiple Myeloma 11 - Genetic abnormalities in multiple myeloma: prognostic aspect - B.Hebraud - Eurocancer 2013 - June 26, 2013 - (slides available on line) Dose-Escalation Phase I / II Study - 12 - Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing, New England Journal of Medicine, Vol. 366, p. 883-892, 2012 (study available online)