BSH 2017: How I treat molecular high-risk myeloma – what can we do, what should we do?

High-risk multiple myeloma (MM) continues to pose a challenge to haematologists both in terms of diagnostics and therapy. Opening the UK Myeloma Forum at the 2017 BSH annual meeting, Professor Thierry Facon from Lille in France reviewed the available treatment options from the point of view of patients’ transplant eligibility and level of fitness.

Professor Gordon Cook (Leeds Teaching Hospitals), who chaired the UKMF session, discusses the key elements from Professor Facon’s presentation.

High-risk multiple myeloma (MM) continues to pose a challenge to haematologists both in terms of diagnostics and therapy. Opening the UK Myeloma Forum session at this year’s BSH annual meeting, Professor Thierry Facon from Lille in France reviewed the available treatment options from the point of view of patients’ transplant eligibility and level of fitness.

A consensus panel at this year’s International Myeloma Workshop in New Delhi, India defined high-risk disease as MM showing any of the genetic markers revised ISS stage III, high-risk gene expression profiling (GEP) using any panel, or karyotypic or metaphase-based cytogenetic abnormalities. There is also emerging data on 1p deletions and from technologies such as RNA sequencing and circulating DNA which may convey high-risk disease. Whilst there is clear evidence that patients with R-ISS stage III MM have poorer survival outcomes than stage I and II,¹ subtle differences in the definition of high-risk disease with respect to the importance of t(4; 14) and gain 1q lesions as well as a lack of consensus on the HR definition of del17p may affect the clinical outcome to an as yet unknown extent. In addition to genetic markers, high-risk MM may also be defined in terms of clinical presentation such as plasma cell leukaemia or extramedullary or CNS disease, or in terms of response characteristics such as lack of response to imid/proteasome inhibitor (PI) induction or early relapse post-autologous stem cell transplantation (ASCT).

In younger fit patients who are eligible for transplantation, ASCT has been shown to significantly improve progression-free survival (PFS) and overall survival (OS) compared with lenalidomide, bortezomib and dexamethasone (RVd)² and bortezomib, melphalan and prednisone (VMP)³ in patients with high-risk cytogenetics at screening. The benefit of ASCT over RVd was less pronounced in high-risk patients compared with standard-risk patients,² which according to Professor Facon is a common finding with innovative therapies for MM. A retrospective analysis published at ASH in 2013 suggested that PFS and OS are longer after double ASCT compared with single ASCT in high-risk patients who failed to achieve complete remission after bortezomib-based induction.⁴ This finding was confirmed in the EMN02/HO95 study, a large randomised prospective study from the European Myeloma Network which included nearly 1,200 patients and which showed that double ASCT resulted in a median PFS of 46.8 months in patients with high-risk cytogenetics, compared with 26.5 months after single ASCT (HR 0.49; 95% CI 0.24, 0.99; p=0.046).⁵ The EMN02/HO95 study also suggests that high-risk patients may benefit from VRd consolidation therapy (HR 0.78; 95% CI 0.61, 1.00), although this benefit is less clear than with double ASCT.⁵ Last but not least, the recently reported Myeloma XI study shows a clear improvement in PFS with lenalidomide maintenance therapy following ASCT both in standard-risk patients and high-risk patients – in fact, HR patients on lenalidomide maintenance therapy had better PFS outcomes than standard-risk patients on observation only.⁶

In Professor Facon’s opinion, high-risk MM patients should definitely be considered for treatment with new drugs. Recent updates from the pivotal studies with carfilzomib, ixazomib and elotuzumab all show that high-risk patients benefit from these therapies in terms of PFS and OS^7-9 – especially in the TOURMALINE study with ixazomib where patients with high-risk cytogenetics did as well as the standard-risk patients.⁸ Likewise it is expected that the impressive overall treatment benefit of daratumumab in the POLLUX study will be reflected in the high-risk group.¹⁰

The choice of therapy for non-transplant eligible patients should be based not merely on the age of the patient age but on whether he/she is fit or frail. Fit elderly patients generally do better and can be treated very effectively with regimens such as VRd¹¹ or KRd.¹² Clinical studies are in progress to determine the PFS benefit of elotuzumab, ixazomib and daratumumab in this patient population.

In contrast, elderly frail patients have very few options available beyond Rd and Vd and focus should be on reducing early mortality due to side effects or disease progression – for elderly frail patients who relapse, palliative therapy very soon becomes the only alternative.

 

References

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2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med 2017;376:1311-1320.
3. Cavo M, Beksac M, Dimopoulos MA, et al. Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial). Blood 2016;128:673-673.
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8. Richardson PG, Avet-Loiseau H, Palumbo A, et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III Tourmaline-MM1 study. J Clin Oncol 2016;34.
9. Lonial S, Richardson PG, Mateos M-V, et al. ELOQUENT-2 update: Phase III study of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM)—Identifying responders by subset analysis. J Clin Oncol 2016;34.
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