Editorial theme | What you need to know about high-risk multiple myeloma

In the following weeks, the Multiple Myeloma Hub will be reviewing the current clinical landscape of high-risk multiple myeloma (MM). Crucial advances have been made, which help to better identify and treat patients with a poor prognosis. However, despite the available new therapies and combinations, this subset of patients still presents with poor survival outcomes.

In this article, you will find about what has already been covered on the hub and what topics we will focus on during this new Editorial Theme. Stay tuned!

Biological and clinical features – How to identify patients with high-risk MM?

 The term “high-risk MM” is broadly used to define a group of adverse biological and clinical features that define a disease with earlier progression and death. There have been several attempts to identify patients with high-risk MM, but one staging system alone cannot fit all cases, and moreover, the aggressiveness and prognosis can significantly change in later stages of the disease.¹

The consensus of the International Myeloma Working Group (IMWG) is to stratify patients by risk following the Revised-International Score System (R-ISS) (Table 1).² This system incorporates some clinical aspects evaluated at diagnosis, but mainly relies on the presence of determined cytogenetic abnormalities (CAs), i.e. del(17p), t(4;14), and t(14;16). According to the R-ISS, 10% of newly diagnosed patients can be classified as high-risk MM (R-ISS-III).¹

Since the R-ISS was defined, there has been an open discussion about additional mutations that may be necessary for risk assessment, and the re-evaluation of other mutations that might not have the impact that was once thought, such as t(14;16). Soon after the publication of the 2015 consensus, the IMWG reviewed their definition of high-risk cytogenetics, and included t(14;20) and any nonhyperdiploid karyotype. Additionally, patients carrying more than three cited CAs are now automatically classified in the ultra-high-risk cytogenetics subgroup, with less than 1–2 years of median overall survival.³

One of the topics that we will cover during this Editorial Theme is the urgent need to update the IMWG criteria again to include important CAs, like del(1p32) and amp(1q) in routine testing (see the cytogenetic prognostic index survival developed by the Intergroupe Francophone du Myélome). Additionally, recent studies have demonstrated the benefit of using next-generation sequencing, instead of fluorescence in situ hybridization, for a more comprehensive approach to identifying patients with a higher risk of aggressive disease.⁴

Table 1. R-ISS and associated survival outcomes in newly diagnosed MM²

iFISH, interphase fluorescence in situ hybridization; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; R-ISS, revised-International Staging System; ULN, upper limit of normal
Risk group		5-year PFS rates, %	5-year OS rates, %
R-ISS-I	ISS-1 (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL) No high-risk cytogenetic abnormalities by iFISH [such as del(17p) and/or t(4;14) and/or t(14;16)] Normal LDH levels < ULN	55	82
R-ISS-II	Not ISS-1 or ISS-3	36	62
R-ISS-III	ISS-3 (serum β2-microglobulin level ≥ 5.5 mg/L) and either: - high-risk cytogenetic abnormalities by iFISH - and/or LDH levels > ULN	24	40

As shown in Table 1, patients with high-risk cytogenetics have shorter progression-free survival and overall survival outcomes.¹ So far, no treatment strategy has been able to successfully overcome this poor prognosis, despite patients achieving complete hematological responses. However, crucial advances have been made in measurable residual disease (MRD), with several studies having shown that achieving MRD-negativity has a greater impact on patients with high-risk cytogenetics and significantly improves their risk of progression and/or death.⁵

In the following weeks, we will review the impact of achieving deep responses in high-risk MM, and why MRD negativity (assessed by next-generation sequencing and/or next-generation flow cytometry) should be the goal of treatment when evaluating new therapies for this difficult-to-treat subset of patients.

Clinical management – How to treat high-risk MM?

After establishing MRD-negativity as a clear endpoint of treating patients with high-risk cytogenetics, the suitable treatment strategy should prioritize the therapies demonstrating higher rates of negative MRD at the maximum sensitivity available (logarithmic range of 10⁵–10⁶). The treatment selection will vary in transplant-eligible or ineligible patients, and newly diagnosed or relapsed/refractory patients. Recent large randomized trials have reported positive results in high-risk cytogenetics when combining a proteasome inhibitor with an immunomodulator and a monoclonal antibody, followed by maintenance treatment. However, most trials in MM are underpowered to evaluate new agents’ efficacy in this subgroup of patients.⁴

Below, you will find a summary by Pieter Sonneveld, outlining the current clinical recommendations for high-risk patients discussed at the 25th European Hematology Association (EHA) Annual Meeting. As a part of this Editorial Theme, we will publish more detailed analyses on transplantation, triplet, and quadruplet combinations in MM with high-risk cytogenetics.

 The majority of clinical trials studying the efficacy of new regimens for high-risk patients, only analyze the results according to the R-ISS stratification. Nevertheless, there are other biological and clinical characteristics that confer a higher risk of progression and/or death to patients with MM. The subgroups of patients listed below are usually underrepresented in current clinical trials, and there is a substantial medical need to investigate new treatment strategies for them further ¹:

• Primary refractory MM
• Presence of extramedullary disease
• Higher levels of circulating plasma cells and evolution to secondary plasma cell leukemia
• Early relapse after autologous stem cell transplantation

Although we have already covered some of these data in previous articles, we will also review the latest results and recommendations in some of these subgroups.

Related articles

• Can you identify high-risk MM more effectively?
  
• The clinical significance of chromosome 1 abnormalities in newly diagnosed multiple myeloma
• How to use MRD status to treat high-risk multiple myeloma
• Tandem stem cell transplantation for newly diagnosed high-risk multiple myeloma
• Primary refractory multiple myeloma: Real-world experience and recommendations
• How to achieve the best results in patients with high-risk MM