EHA 22nd Congress Clinical Debate: Treatment should be started in every patient with high-risk smoldering multiple myeloma? 

The MM Hub team were pleased to attend the 22^nd congress of the European Hematology Association held in Madrid from 22^nd-25^th of June. On Saturday from 2.45 p.m. – 3.45 p.m. a Clinical Debate was held in order to examine both sides of the argument for early treatment of patients with high-risk smoldering multiple myeloma (high-risk SMM). The session was chaired by a member of the MM Hub steering committee, Professor Heinz Ludwig, from the Wilhelminen Cancer Research Institute, Vienna, Austria.

 YES

First to the podium, arguing in favor of early intervention, was a member of the MM Hub steering committee: Professor María-Victoria Mateos, from the University Hospital of Salamanca, Spain. She began her talk by explaining that routinely, treatment of smoldering MM is only initiated when the disease is active. However, she feels that treatment should be started immediately before progression to measurable, or so-called ‘active disease’, for which symptoms and organ damage can ensue.

The heterogeneous nature of SMM was highlighted, as this makes it important to consider cases on an individual basis. The audience were then asked to consider the treatment of MM from a more general oncology perspective, as there is early intervention in almost all malignancies, with the objective of curing/eradicating disease or delaying progression to active disease – and in all other cases we would not wait to treat until patients had progressed. Professor Mateos said she felt strongly that SMM should not be an exception to this, and that waiting for myeloma symptomology to develop cannot be the right approach.

However, in light of data from several studies of early treatment that showed no resultant benefit on time to progression (TTP) or overall survival (OS), and data which showed heterogeneity between risk of progression from MGUS and SMM, to active disease, it is clear that the first step should be to identify subgroups of patients with a high risk of progression. Indeed, there is now a proposal to develop an international staging system (ISS) in order to define risk of progression from high-risk SMM to MM in a homogeneous way.

However, in the absence of any ISS at present, Professor Mateos suggested that one of two different models could be used: The Spanish model - which uses detection of aberrant PCs by immunophenotype plus immunoparesis, but can only be utilized if flow cytometry is available, or, The Mayo Clinic model - which uses PC BM infiltration and serum M-component level, and is available in all centers. Although there appears to be disagreement between the two models (overall agreement = 22/77, 28.6%), she explained that this may not be truly reflective of the real data, since the outcome of patients with disagreement was never followed up, or indeed it was never noted whether they were low-, medium-, or high- risk to start off. Of note, both models resulted as independent prognostic factors in multivariate analysis, including large numbers of patients. In addition, concordance was found between The Mayo model and the Swedish registry, for which 29% of SMM patients will be considered for early treatment.

She then talked about how MGUS was underexplored, and that the biology of the disease and the transition to MM, was still little understood. It was also pointed out that the IMWG criteria for diagnosing MM does in fact support intervention for high-risk SMM patients that display certain features, such as clonal BM PC percentage ≥ 60%, serum-free light chain ratios ≥100 and ≥1 focal lesion on MRI studies.

The QuiRedex study was then described, in which high-risk patients were defined according to either the Mayo and/or Spanish models and given early treatment of lenalidomide plus dexamethasone, or left untreated. Patients were screened monthly for BM counts, biochemical analysis (creatine and calcium) and serum/urine levels of MC. Skeletal surveys wer performed during the screening phase, and thereafter if symptoms appeared. Significant benefits were observed for the treatment group versus the untreated group, with a median TTP not reached vs. 21 months; HR for progression = 0.18 (95% CI, 0.09 to 0.32; P<0.001) and a 3-year survival rate of 94% vs. 80%; HR for death = 0.31 (95% CI, 0.10 to 0.91; P=0.03). The data also demonstrated that early treatment did not induce more resistant relapses, although the treatment regime led to a higher risk of developing a secondary malignancy (12% vs. 3%).

In real practice, Professor Mateos proposed use of the Mayo model (until the ISS is released), as it is available in all centers, and the Spanish model where flow cytometry is available, as well as studying the evolving pattern of the M-spike, which gives dynamic information. Numerous clinical trials with several drugs are currently ongoing for high-risk SMM, both to delay the disease progression (Elo-Rd, daratumumab, KRd, ixazomib Rd, nivolumab-Rd, isatuximab etc.) and to cure the disease (CESAR, ASCENT). Patients enrolled in the CESAR trial will receive carfilzomib, lenalidomide and dexamethasone induction, followed by high-dose therapy and ASCT, then consolidation and maintenance. The ASCENT trial, an IMF/Black Swan initiative in which high-risk SMM patients with receive intense therapy over 2 years, with the end goal of reaching MRD-negativity. She hoped that the results of these trials, along with the development of new biomarkers, will hopefully mean that more SMM patients will be considered as having active disease, and will therefore receive treatment.

The treatment schedule proposed is as follows:

When asked about practical recommendations for these patients, Professor Mateos suggested that the best option is to include them in a clinical trial, and added that in Spain, a recommendation for early treatment has been published and issued to all treatment centers.

NO

The counter argument was presented by Professor Kristinsson from the University of Iceland. He began by explaining that survival in MM is improving due to several reasons: high-dose therapy with stem cell support, novel drugs, improved supportive care and prognostic factors. He questioned whether earlier treatment was also a reason, as there is currently no evidence to suggest it is. He then described the IMWG diagnostic criteria for MM, pointing out that these guidelines allow us to identify MM, and that smoldering myeloma should not be treated, otherwise we are simply changing the guidelines. He then looked at the two risk models described by Professor Mateos, and was keen to point out that 28.6% overall agreement wasn’t good enough. Data from Robert Kyle’s study - which showed that the risk of progression is significantly affected by the level of monoclonal protein, the proportion of bone marrow plasma cells, or both, was also discussed.

He then presented data from one of his own studies, in which it was shown that prior knowledge of MGUS had limited impact on patient survival. He also collated data from numerous clinical trials to treat smoldering myeloma, for which again limited impact was observed on overall patient PFS or response rates. He then commented on the study published by Professor Mateos in NEJM in 2013, in which patients with high-risk SMM were treated. Although significant benefit was observed following the early treatment of these patients, in his opinion it had several limitations that prevent the results from being generally applicable. Firstly, two separate methods for identifying high-risk patients were used, and the control arm was not screened for bone disease. In addition, there was an age difference between the treatment and observation group (63 vs. 69 years, respectively) there were different treatment options at progression and the free light-chain analysis was not included. The control arm was also assessed by end-organ damage, while treatment arm was assessed according to biological progression. Most importantly, all the patients were asymptomatic until they received treatment and had only been identified due to comorbidities which led them to have either a blood test or a bone scan. Such comorbidities are relatively prevalent in MM patients – in a study led by Kristensson’s group, they found that 22% of patients had at least one comorbidity, and that 23% had more than two comorbidities, and indeed that the number of comorbidities directly correlated with a worse prognosis and lower percentage survival.

Professor Kristensson asked the question: 'Who decides if we should treat High-risk MM or not?', and was of the opinion that the patient must decide. He proposed that treatment options and expectations must be discussed with the patient, and that this decision must not be taken at diagnosis, as 23% of cases will not progress for 10 years. He recommended following the patient closely, as well as discussing treatment options and expectations, and emphasized that close monitoring of patients would be sufficient in many cases.

He finished by describing the iStopMM program (Iceland Screens, Treats or Prevents Multiple Myeloma) and IMF-funded large-scale screening study aimed at preventing myeloma before it develops. As the project leader, Professor Kristinsson and his team are aiming to recruit 148,000 Icelanders, who will then be screened via blood samples for the precursors to myeloma – MGUS (monoclonal gammopathy of undetermined significance) and SMM. Those individuals diagnosed as being in a precursor state (predicted to be in the range of 4500-5000), will be invited to participate in a randomized clinical trial to identify the best strategy for treatment, and to create a new risk model for disease progression. It has now screened more than 74,457 participants, and will be the basis for a population-based nationwide trial with early intervention.

He concluded by stating that early treatment of these patients would probably better, but he felt that more evidence and better predictors are needed at this stage. He then referred to a statement written by Professor Mateos in a recent publication: “The standard of care is observation for MGUS patients and this also applies to SMM”, which he feels should hold true until better predictors for progression can be routinely applied. He was then asked about practical recommendations for high-risk SMM patients, and answered that in Iceland they are not treated until progression, and said that he feels that the disease must be redefined, as there is a fine line between active and high-risk disease.

Conclusion

This Clinical Debate illustrates that even with the same evidence to hand there can be two completely different treatment strategies, depending on the point of view. Consequently, such topics must be constantly reviewed in light of new diagnostics, new therapies and clinical trial data, as well as clinical case studies. Importantly, it highlights the need for clinicians to keep asking the all-important question: ‘Why?’, and if that can be answered then there is no real right or wrong.