COMy 2019 | DEBATE: Should smoldering myeloma be treated very early? 

On Saturday 18 May 2019, in Paris, FR, Sundar Jagannath, Icahn School of Medicine at Mount Sinai, New York, NY and our steering committee member, Mario Boccadoro, University of Torino, Torino, IT, debated the controversial topic of whether smoldering multiple myeloma (SMM) should be treated early. The debate took place at the 5^th World Congress on Controversies in Multiple Myeloma (COMy).¹

FOR

Prof. Jagannath began by stating, that yes, early intervention is necessary in SMM. Firstly, Prof. Jagannath described how SMM progresses into multiple myeloma (MM) through the acquisition of currently unknown driver mutations and interplay with the microenvironment. Prof. Jagannath also highlighted SMM is a heterogeneous disease and that since a higher mutational burden is correlated with a higher risk of progression to MM, a patient’s risk increases over time.

Risk stratification

Defining SMM is complex, and constantly evolving. Prof. Jagannath stated that the issue with the current stratification system is that it is based on tumor burden at the time of sampling. He added that reassessing a patient a month after initial diagnosis may better define the treatment plan, based on the evolution of disease.

In the near future, he indicated that there may be a new distinction between benign monoclonal gammopathy (an incidental finding that does not require treatment) and malignant monoclonal gammopathy (that requires treatment).

Patients with high-risk features have a shorter time to progression (TTP)

Data were presented showing that patients with high-risk features have a shorter TTP, from Shaji Kumar, Mayo Clinic:²

• High risk features; bone marrow plasma cell (BMPC) percentage of >20%, free light chain ratio (FLCr) of >20 and the presence of high-risk cytogenetics (del[17p], t[4;14] or hyperdiploidy)
• High-risk (≥2 features), intermediate risk (1 feature), low risk (none)
• TTP (high vs intermediate vs low): 14.5 months (95% CI, 10.7–25.4) vs 63 months (95% CI, 29.8–not reached [NR]) vs NR, P <0.0001

Concepts for treatment

Moving on to discuss the aims of early treatment Prof. Jagannath described trials can either;

1. Aim to eradicate all clones to cure the disease or
2. Aim to delay clonal evolution by modifying the microenvironment and control the disease

There are two main patterns of progression in SMM, the first is natural tumor evolution (~20% of cases) and the second is Darwinian clonal selection (~80% of cases). The latter is more common, as additional mutations are acquired during progression and over time. Prof. Jagannath argued these patients should be candidates for preventative therapy since treating patients before clonal development is a viable strategy to improve the patient’s prognosis.

Modification of the tumor microenvironment can be done with immunomodulatory drugs such as lenalidomide, the use of monoclonal antibodies, immune checkpoint inhibitors, antibody-drug conjugates, BiTE antibodies against B-cell maturation antigen (BCMA) or vaccines.

• Trials involving monoclonal antibodies in SMM have begun, including elotuzumab, which, in a phase II trial with a minimum follow-up of 28 months, had a 2-year progression-free survival (PFS) of 69% ³

What treatment?

Prof. Jagannath indicated that the treatment choice, if SMM is treated intensively, depends whether we aim to cure or control the disease. He used the example of the GEM-CESAR study, which used an intensive approach, early, in patients with high-risk SMM.

• GEM-CESAR study:⁴
  • N = 90
  • Treatment pathway:
    • Induction: 6x 28-day cycles carfilzomib + lenalidomide + dexamethasone (KRd, n = 71)
    • High dose melphalan (HDM) + autologous stem cell transplant (ASCT, n = 42)
    • Consolidation: 2 x 28-day cycles KRd
    • Maintenance: Rd for 24x 28-day cycles
  • Overall response rate (ORR) post-induction: 98%
  • ORR post-HDM+ASCT, post-consolidation and post-maintenance: 100%
  • Treating early is a viable option for these patients

Prof. Jagannath concluded his argument by stating it was important to treat early, to eradicate the disease and delay clonal evolution.

AGAINST

Firstly, using data from a study of 276 patients with SMM who were monitored over a 26-year period, Prof. Boccadoro demonstrated that the risk of progression, whilst 10% during the first 5-years, decreased significantly to 3% per year for the following 5-years and 1% per year for the last 10-years, indicating risk of progression decreases over time.⁵

However, in order to treat these high-risk SMM candidates early prior to progression, three criteria would need to be in place:

1. A uniform, consensus definition of high-risk SMM agreed by the International Myeloma Working Group (IMWG)

• Current lack of consensus definition, which Prof. Boccadoro demonstrated by showing an exhaustive list of risk models used in different studies
• Risk models are regularly updated and revised
  • No agreement on which should be adopted

2. Results from randomized phase III trials comparing early treatment to observation, in relation to TTP and overall survival

• There are limitations and restrictions with the current studies that have been conducted
  • QUIREDEX study treated high-risk SMM (n = 100) with lenalidomide + dexamethasone (Rd) or no treatment⁴
    • Skeletal survey used for stratification, likely some of the patients with high-risk SMM had active MM
    • Under-treated with Rd alone: 18%
      • Potentially had active MM
    • Over-treated with Rd: 15%
      • Did not progress within 7 years despite not receiving treatment
    • Boccadoro believes >30% of patients were treated inappropriately
  • In a trial of siltuximab vs placebo in high-risk SMM, no significant PFS benefit was observed (NR vs5 months, P = 0.0597)⁶

3. An effective treatment strategy

• Defined aim of treatment: to cure, or control disease?
• Balance between cytoreduction and toxicity
• Aim to cure: increased cytoreduction, increased toxicity
• Aim to control: reduced cytoreduction, reduced toxicity
• A higher intensity treatment achieves higher ORR and CR rates, but also higher rates of secondary primary malignancies and toxicity and these risks must be weighed

To conclude, Prof. Boccadoro argued that we do not yet have a consensus definition of high-risk SMM, we have not identified the optimal treatment strategy for these patients, and we only have conflicting data from phase III studies. In his final statement, Prof. Boccadoro stated that the answer to the debate, in his opinion, is “not yet”, rather than a straight “no”.

In a poll conducted by the Multiple Myeloma Hub on Twitter shortly after the debate, voters marginally agreed that SMM should be treated early (53%).