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Smoldering multiple myeloma (SMM): an introduction to this month’s educational theme on the multiple myeloma (MM) Hub

Starting July 2019, the Multiple Myeloma (MM) Hub will be featuring articles centered around an educational theme. This article on smoldering MM (SMM) represents the first in this series providing an introduction to the theme and an overview of information already available on the MM Hub.

Active MM progresses from two precursor conditions; the first is a biological premalignancy called monoclonal gammopathy of undetermined significance (MGUS), and the second is smoldering multiple myeloma (SMM). The latter is distinguished by a higher risk of progression to active MM compared to MGUS, at 10% per year in SMM compared to 1% per year in MGUS.1

SMM is biologically heterogenous comprising a group of patients with MGUS and a group with MM, who have not yet developed CRAB symptoms (hypercalcemia [C], renal failure [R], anemia [A] and lytic bone lesions [B]) or other myeloma defining events (MDEs) that are characteristic of active MM disease.

Over recent years there have been many discussions concerning the definition of high-risk SMM, predicting risk of progression to active disease, and when/whether to intervene.

Trials in high-risk SMM

There are many ongoing trials in the SMM field, notably those investigating whether early intervention for patients at high-risk of progression provides a survival advantage compared to observation.

Recently, during the 2019 American Society of Clinical Oncology (ASCO) meeting, Sagar Lonial presented the E3A06 study of lenalidomide in high-risk SMM, which supported the use of early intervention.

Phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk SMM

Further study results from 2019, reported at the European Society of Hematology (EHA) meeting, were from the GEM-CESAR study as presented by Maria-Victoria Mateos. The GEM-CESAR study used induction therapy with carfilzomib, lenalidomide and dexamethasone (KRd) followed by high-dose melphalan (HDM), autologous stem cell transplant (ASCT) and subsequent consolidation and maintenance with KRd. This study showed 85% of patients with SMM maintained complete responses (CR), with a minimal residual disease (MRD) negativity rate of 68% at the KRd maintenance stage.

Results from two other clinical trials in high-risk SMM were presented during the American Society of Hematology (ASH) meeting in 2018. The first, a phase II trial, was presented by Irene Ghobrial, and discussed the use of elotuzumab, lenalidomide and dexamethasone to treat high-risk SMM. The study investigators found the triplet regimen to be well-tolerated, with a 95% progression-free survival (PFS) at 36 months post-treatment. The other trial was a phase II trial using ixazomib, lenalidomide and dexamethasone. Again, this study found the triplet regimen to have minimal toxicity and high response rates, with further studies ongoing.

The use of a PVX-410 vaccine, a human leukocyte antigen A2 multi-peptide cancer vaccine, has also been investigated in SMM, with results published in August 2018. The phase I/IIa study investigated PVX-410 with, and without, lenalidomide in a high-risk SMM population. The results indicated the vaccine can increase immunogenicity in a specific patient population, though larger trials are required.


Whilst the study results reported above show promise for early intervention methods in high-risk SMM, there is still much discussion ongoing regarding;

  • When to intervene?
  • Should intervention be intensive?
  • Is observation sufficient in certain patients?
  • How do we define patients at high-risk of progression?

When to intervene

These questions have been debated at recent meetings, including the 5th World Congress on Controversies in Multiple Myeloma (COMy) meeting, 2019, where Sundar Jagannath and Mario Boccadoro discussed the pros and cons of treating SMM early. Sundar Jagannath began by presenting the argument FOR early intervention, stating that it is important to treat early, to eradicate the disease and delay clonal evolution. Mario Boccadoro then presented the argument AGAINST treating early, saying that we need a consensus definition of high-risk SMM first, and that we need to identify the optimal treatment strategy as current trial results are contradictory. In a poll conducted by the MM Hub on Twitter following the debate, 53% of users agreed that SMM should be treated early.

The MM Hub also conducted its first ever expert discussion during the 2019 ASCO meeting, with Maria Victoria-Mateos and Francesca Gay debating when intensive treatment strategies should be used in SMM and NDMM. Both speakers are heavily involved in trials in the high-risk SMM population, and the newly diagnosed MM population, respectively, leading to an excellent debate addressing many important questions. Both concluded that intensive treatment strategies are feasible in both SMM and NDMM patient populations. They also agreed that treatment should be modified according to risk factors, to ensure treatment is optimal for each patient. This could form the beginning of personalized medicine in SMM and is likely to grow in coming years.

Intensive treatment strategies: at what stage should these be deployed in SMM and NDMM?

Predicting SMM progression and defining high-risk

Defining high-risk SMM, and the risk of progression is another ongoing issue in the field. There are multiple risk stratification models; notably the Mayo Clinic model2 and the Spanish Myeloma Group model3. Both have been well validated in trials, though are often updated and utilized differently, meaning a lack of consensus. In order to make clinical trials more comparable and allow decision-making to be well-informed, many believe consensus criteria should be developed, incorporating all the variables used in these models.

The 2014 International Myeloma Working Group (IMWG) criteria for high-risk SMM include; bone marrow plasma cell percentage of >60, free light chain ratio of ≥100 and >1 focal lesion detected by magnetic resonance imaging. A further study by Vernon Wu and Ajai Chari evaluated biomarkers to identify if this was an accurate definition. They found four additional biomarkers to predict ultra-high-risk patients.

Another study evaluated whether pre-existing SMM or MGUS had an impact on patient outcome with the authors concluding that patients with pre-existing precursor conditions had a superior outcome, particularly SMM patients who had an improved overall survival compared to patients with MGUS.

Finally, predicting progression from SMM to active MM is difficult. The MM Hub previously published an article summarizing several abstracts from ASH 2017 which attempted to identify genetic markers that indicate a risk of progression. One of these abstracts, presented by Niamh Keane identified that MYC translocations were a genetic marker for progression to MM, whilst Irene Ghobrial showed specific genetic alterations are associated with high-risk SMM and had the potential to predict risk.

Impact of NGS in the management of smoldering MM

The patient focus

Another consideration for treating SMM patients is the patient’s quality of life (QoL) and treatment experience. A recent study found that psychological distress and mental health-related QoL is similar between patients with precursor disease and those with active MM. Particularly, the anticipation of cancer in those with SMM can cause a similar psychological burden to those with active disease. Therefore, there is a distinct need to psychosocial support in this group of patients.

The Multiple Myeloma Hub will be generating a series of articles within the SMM area, aiming to address these important questions. Make sure you check back for the next in the series!

  1. Rajkumar S.V. Langdren O. Mateos M-V. Smoldering multiple myeloma. Blood. 2015 Apr 02. DOI: 10.1182/blood-2014-09-568899.
  2. Lakshman A. et al., Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018 Jun 12. DOI: 10.1038/s41408-018-0077-4
  3. San Miguel J. et al., Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria. American Society of Clinical Oncology (ASCO) Annual Meeting. 2019 Jun 02. [accessed 2019 Jul 10]