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recommended as initial therapy. Various combinations of drugs are now available with high RR. Recent data suggest that the upfront combination of a PI plus one IMiD or an alkylating agent is highly effective. Bortezomib–, thalidomide– and dexamethasone (VTD) has proved to be highly effective as a frontline treatment and is significantly superior to VAD or Thal-Dex before and after ASCT with a very manageable pattern of toxicity. VTD is widely used and recommended as induction and/or consolidation therapies in ASCT eligible patients, based on three Phase III trials. The IFM 2013 04 study comparing VTD and VCD (bortezomib, cyclophosphamide and dexamethasone) as induction before HDT is ongoing. The most promising three-drug association might be bortezomib, lenalidomide and dexamethasone (RVD). RVD is the current combination studied within the IFM 2009 trial. Addition of a fourth drug has not proved to be more efficient in the EVOLUTION trial as this is generally more toxic.

In patients not eligible for ASCT, the combinations melphalan–prednisone– thalidomide (MPT), bortezomib– melphalan–prednisone (VMP) and, very recently, lenalidomide–dexamethasone (RD) have shown improved PFS and OS. Following this induction/consolidation phase, some controversy remains as to whether patients should stay on treatment (continuous or maintenance therapies) or discontinue therapy for a ‘treatment-free interval’.19

In the setting

of HDT, lenalidomide maintenance resulted in a markedly prolonged PFS that did not translate into a prolonged OS. Similarly in elderly patients, continuous RD was superior to fixed 18-cycle RD in terms of PFS but with only a slight difference regarding OS.20

Supportive care

Supportive care is very important and includes management of anaemia, pain, hypercalcaemia, skeletal complications, infections, and adequate nutrition.

Relapse 4

Despite improvements in survival, all patients will ultimately relapse and the treatment of patients with relapsed or refractory MM remains a challenge. This is discussed in detail in a later article. The remission duration in relapsed myeloma decreases with each regimen. On the molecular level, while one dominant clone may be eliminated with

induction/consolidation therapies, residual minor clones are likely to expand with this resetting of the clonal dynamics and hence herald a clinical relapse.

Relapse therapy

A number of drugs are approved and many combinations can be used as relapse therapy, carfilzomib (Kyprolis®


pomalidomide, and panobinostat (HDAC inhibitor) having been recently registered by the US Food and Drug Administration. In Europe, only pomalidomide received European Medicine Agency approval. Unfortunately, the duration of responses is limited and all patients will develop progressive disease.

In patients with relapsed MM, the choice of salvage therapy should take into account the age as well as other co- morbidities such as renal failure and diabetes. It should be individualised and must depend on the following considerations: did the initial therapy comprise novel agents and/or ASCT? What was the degree and duration of response to last therapy? What were the previous toxicities? What is the type of relapse and performance status? Do we have any clinical trial data available? Once again, the three-drug

combination of a PI and an IMiD in Phase III trials demonstrated high response rates and prolonged survivals. The ASPIRE trial, published in the New England Journal of Medicine, showed an eight-month PFS improvement with the KRD regimen over the standard RD until progression or intolerance (26.3 vs 17.6 months).21 Results of the combination of ixazomib (PI) to RD are awaited and should be reported during the 2015 ASCO meeting. Monoclonal antibodies such as anti-CD38 (daratumumab, SAR650984 and MOR202)/anti SLAMF7 (elotuzumab) and small inhibitor molecules, such as Filanesib or Selinexor, have shown promise in the relapsed-refractory setting and could potentially change the future of relapsed MM. ●

References 1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860–73.

2. Ferlay J et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374–403.

3. Kyle RA. Multiple myeloma: how did it begin? Mayo Clin Proc 1994;69:680–3.

4. Kuehl WM, Bergsagel PL. Early genetic events provide the basis for a clinical classification of multiple myeloma. Hematology Am Soc Hematol

Educ Program 2005;346–52.

5. Walker BA et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood 2013;121:3413–9.

6. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer 2012;12:335–48.

7. Bahlis NJ. Darwinian evolution and tiding clones in multiple myeloma. Blood 2012; 120:927–8.

8. Keats JJ et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120:1067–76.

9. Landgren O et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009;113:5412–7.

10. Rajkumar SV, Lacy MQ, Kyle RA. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood Rev 2007;21:255–65.

11. Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–48.

12. Greipp PR et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412–20.

13. Avet-Loiseau H et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia 2013;27(3):711–7.

14. Hebraud B et al. Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood 2015;125:2095–100.

15. Ludwig H et al. European perspective on multiple myeloma treatment strategies in 2014. Oncologist 2014;19:829–44.

16. Engelhardt M et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica 2014;99: 232–42.

17. Mikhael JR et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 2013;88:360–76.

18. Anguiano A et al. Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma. J Clin Oncol 2009;27:4197–203.

19. Attal M, Roussel M. Maintenance therapy for myeloma: how much, how long, and at what cost? Am Soc Clin Oncol Educ Book 2012;515–22.

20. Benboubker L et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014;371:906–17.

21. Stewart AK et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142–52.

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