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Should smoldering multiple myeloma be treated?

Nov 3, 2020
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During the eighth annual meeting of the Society of Hematologic Oncology (SOHO), Angela Dispenzieri and Multiple Myeloma Hub Co-Chair, María-Victoria Mateos, debated whether smoldering multiple myeloma (SMM) should be treated early.1,2 

Currently, SMM is not treated in clinical practice because it is an asymptomatic disease. Treatment is usually given when SMM progresses to active multiple myeloma (MM) and symptoms of the disease appear, such as the presence of bone pain, lytic bone lesions, frequent infections and fever, anemia, and fatigue, all of which impact the quality of life of patients.1 

For1

María-Victoria Mateos began the debate by showing data from historical clinical trials conducted in patients with SMM using conventional agents, such as melphalan and prednisone, thalidomide, zoledronic acid, and bisphosphonates. Although there may have been improvements in overall response rates, none of the trials to date showed any benefit in terms of time to progression or overall survival.  However, SMM is now known to be a heterogeneous disease, and the reported trials did not differentiate between the different risk groups: i.e., high, intermediate, and low. Mateos proposes that patients in the high-risk SMM group should be treated.

The revised International Myeloma Working Group (IMWG) 2019 diagnostic criteria for high-risk SMM include:

  • serum M spike > 2 g/dL,
  • free light chain ratio > 20, and
  • bone marrow plasma cell infiltration > 20%.

The risk of progression at 2 years for patients in this high-risk category is 50%.

Considering the molecular pathogenesis of the disease, from monoclonal gammopathy of undetermined significance (MGUS) to SMM to MM, the initial transition involves mostly two non-overlapping pathways associated with dysregulated cyclin D expression, but further change requires additional genetic abnormalities. Therefore, it may be easier to manage a less complex disease with an early treatment plan.  

María-Victoria Mateos discussed two potential reasons to treat SMM:

  1. To prevent the development of MM.
  2. To cure the disease before the development of MM.

In terms of prevention, several phase II trials have investigated the use of lenalidomide + dexamethasone as a backbone for treating patients with intermediate- to high-risk SMM. Although the sample sizes are small, the results encourage combination treatments with elotuzumab, ixazomib, or carfilzomib, with overall response rates of 84–100% (Table 1). Phase II studies using monotherapies with monoclonal antibodies, isatuximab or daratumumab, are also demonstrating positive results for the treatment of high-risk SMM, but again the studies are small. Additional ongoing phase III randomized registration studies in this setting compare the use of daratumumab vs observation, or lenalidomide + dexamethasone vs isatuximab + lenalidomide + dexamethasone, which, if proven positive, will support the role of new standards of care for high-risk SMM.      

Table 1. Phase II trials using lenalidomide + dexamethasone as a backbone for the treatment of high-risk SMM1

*Different techniques and thresholds were used in each trial to assess MRD status.
CR, complete response; Elo, elotuzumab; Ixa, ixazomib; KRd, carfilzomib + lenalidomide + dexamethasone; MRD, measurable residual disease; NE, not evaluable; ORR, overall response rate; Rd, lenalidomide + dexamethasone.

Response, %

NCT02279394
Elo-Rd
(n = 50)

NCT02916771
Ixa-Rd
(n = 26)

NCT01572480
KRd
(n = 12)

ORR

84

89

100

CR

7

19

100

MRD negative*

NE

12

92

Considering a curative approach, the GEM-CESAR trial (NCT02415413), a multicenter phase II study investigating the use of carfilzomib + lenalidomide + dexamethasone induction, followed by HSCT, consolidation, and maintenance for up to 2 years. In the high-risk SMM subgroup, 60% of patients achieved MRD-negativity assessed by next-generation flow cytometry after maintenance. This translated to encouraging progression-free survival (92%) and overall survival (96%) at 35 months; however, a longer follow-up is needed to see how sustained these responses are. The ASCENT trial (NCT03289299), an International Myeloma Foundation/Black Swan Research Initiative®, is also investigating a curative approach with the combination of carfilzomib + lenalidomide + dexamethasone, in which high-risk SMM patients will receive intense therapy over 2 years, with the end goal of reaching MRD negativity by next-generation flow cytometry.

Therefore, Mateos argues that high-risk SMM should be treated early to prevent progression to MM: it is possible to easily identify this subgroup of patients using the IMWG 2019 criteria, and the results of the phase II and III trials discussed here are encouraging.

Which patients with smoldering multiple myeloma would you enrol in a clinical trial?

Against2

Angela Dispenzieri began her argument by discussing the heterogeneity of SMM patients and their characterization by the IMWG as low (34% of patients), intermediate (29% of patients), and high risk (37% of patients). She demonstrated that the progression rates from this risk classification model are significantly different between groups and that 50% of intermediate- and low-risk patients will not progress to MM by 10 years.

The role of the bone marrow niche in MM pathogenesis is becoming more evident. SMM cells are not yet discernible from MM cells using fluorescence in situ hybridization, gene expression programming, or whole-genome sequencing. This emphasizes that the microenvironment is playing a role in the progression of SMM. Therefore, targeting the SMM cells may not be the best approach to preventing progression. A better understanding of the transcriptome and epigenome of the progression of SMM may help identify biomarkers or give biological insight into the patients that are truly at risk of progressing to MM and would benefit from treatment, though this is a long way off. Alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single-nucleotide variants), the DNA repair pathway (deletion 17p, TP53, and ATM single-nucleotide variants), and MYC aberrations (translocations or copy number variations) were all identified as independent risk factors of progression in a next-generation sequencing study. However, these findings require further validation.

Therefore, Angela Dispenzieri argues that, at this moment, patients diagnosed with SMM should not be treated as most cases will not progress to MM, and the tools that will help identify those who will are not widely validated for use in clinical practice just yet.

Key evidence: QUIREDEX and E3A06 trials

Both Mateos and Dispenzieri used the trials QUIREDEX (NCT00480363) and E3A06 (NCT01169337) to illustrate their respective arguments. The key points are summarized in Table 2.

Table 2. Arguments for and against the treatment of SMM based on the QUIREDEX and E3A06 trials1,2

*Trial was carried out prior to the update to myeloma-defining event criteria in 2014.
CI, confidence interval; dex, dexamethasone; HR, hazard ratio; IMWG, International Myeloma Working Group; len, lenalidomide; Mayo 2018, Mayo Clinic 2018 risk stratification model; MM, multiple myeloma; NR, not reached; obs, observation; PFS, progression-free survival; QoL, quality of life; SMM, smoldering MM; TTP, time to progression.

 

QUIREDEX

(NCT00480363)

E3A06

(NCT01169337)

Intro

 

One of the first randomized, phase III trials in patients with high-risk SMM

Investigated the use of len + dex (9 induction cycles followed by 2 years maintenance) vs obs

Median follow-up: 10.8 years

Previously reported on the Multiple Myeloma Hub

Len monotherapy compared to observation

Phase II median follow-up: 82 months

Phase III median follow-up: 35 months

Arguments for SMM treatment

Significant difference in median TTP between cohorts: 9 years for len + dex vs 2 years for obs

HR, 0.27; 95% CI, 0.16–0.42; p < 0.001

Significant benefit in median OS: NR vs 7.8 years

HR, 0.54; 95% CI, 0.30–0.90; p < 0.034

QoL assessment: no difference between the treated and obs groups

PFS HR of 0.28 (95% CI, 0.12–0.63; p = 0.0005) in the whole trial population

Greater benefit reported for those classified as high-risk by the Mayo 2018 risk classification model (HR, 0.15; 95% CI, 0.04–0.55)

Also seen in high-risk category of IMWG 2019 risk classification model

QoL assessment: no difference between the treated and obs groups

Arguments against SMM treatment with the available data

High-risk population likely to be diagnosed with active MM nowadays*

QoL: more adverse events occurred in treatment arm, and more secondary malignancies occurred at 7 years for len + dex vs obs (12% vs 3%) 
→ unethical to routinely treat those with only 50% chance of developing MM at 10 years, as the treatment itself can lead to secondary malignancies

30-month PFS almost double that of QUIRIDEX (66% vs 35%), demonstrating patient heterogeneity

Mayo 2018 subanalysis:  

- No PFS benefit at 2 years with len vs obs for the intermediate- and low-risk groups. > 80% of obs group did not progress by 2 years
- The 2-year risk of progression of the high-risk SMM in the obs group was 31%, lower than the expected 50%
→ majority of patients with SMM will not benefit from early treatment

QoL: more adverse events occurred in treatment arm, and more secondary malignancies occurred at 3 years for len vs obs (11% vs 4%) 
→ unethical to routinely treat those with only 50% chance of developing MM at 10 years, as the treatment itself can lead to secondary malignancies

Conclusion

Only those patients with high-risk SMM should be treated early. However, more evidence is needed to determine precisely which patients are classified in this subgroup. Future transcriptomic and epigenomic data may provide a better understanding of which patients are indeed at risk of progressing sooner to overt MM and, therefore, could benefit from early intervention.

  1. Mateos MV. Smoldering MM should be treated early. Session V. Eighth annual meeting of the Society of Hematologic Oncology (SOHO). Sep 10, 2020; Virtual.
  2. Dispenzieri A. Smoldering MM should NOT be treated early. Session V. Eighth annual meeting of the Society of Hematologic Oncology (SOHO). Sep 10, 2020; Virtual.

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