General MM

Treatment-responsive biology observed in high-risk smoldering myeloma

Multiple Myeloma (MM) is almost always preceded by the precursor state of monoclonal gammopathy of undetermined significance (MGUS), and subsequently smoldering myeloma (SM). A subset of patients with smoldering myeloma carry an increased risk of developing MM, and are classified as high-risk. Currently, standard practice is careful monitoring of these patients until signs of myeloma defining end organ damage are observed, and only at this point is treatment initiated. With such an array of novel agents now available and with tolerable safety profiles, there is a strong argument for earlier intervention, although this remains a matter of fierce debate. Both sides of the argument were presented at the European Society of Hematology (EHA) 22nd Congress in June 2017 and were reported by the MM Hub.  One of the main arguments against intervention is that not everyone with SM progresses to MM. Therefore, identifying the patients that are at high-risk of progression is key and several models have been established in order to define this patient subset.

In order to examine the effect of early intervention, a previous study compared patients with either SM or newly diagnosed MM (NDMM) treated with a triplet regimen of carfilzomib, lenalidomide and dexamethasone, followed by lenalidomide maintenance. The result was a high response rate in both cohorts and minimal residual disease (MRD) negativity in patients with high-risk SM. In order to better understand the mechanisms at play in the two cohorts, this trial was expanded with further recruitment of patients with high-risk SM, and patients were followed for a longer period of time. The findings of this trial, along with an analysis of the baseline mutational landscape of both patient sets, was published in Blood Advances in September 2017. The study was conducted by Sham Mailankody from the Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, USA, and Dickran Kazandijan from the Center for Cancer Research, National Cancer Institute, MD, USA, and led by Ola Landgren.

Key Highlights:
  • Patients (pts) with high-risk smoldering myeloma (SM) or newly diagnosed MM (NDMM) were enrolled in 2 studies initiated by the NCI: NCT01402284 and NCT01572480
  • A further 18 pts with SM were enrolled between 29 May 2012, and 14 January 2014
  • SM was defined using the International Myeloma Working Group (IMWG) 2003 guidelines and high risk of progression was defined using either the Mayo Clinic or Spanish PETHEMA risk model, or both
  • Pts were treated with carfilzomib, lenalidomide and dexamethasone, followed by lenalidomide maintenance
  • Baseline BM biopsy samples were analyzed from both sets of pts: SM = 18 pts and NDMM = 40 pts
  • Median follow-up = 43.3 months (cut-off = October 20, 2016)
  • Best response rates: partial response (PR) or better = 18 pts (100%); complete response (CR) or a stringent CR = 16/18 pts; MRD negativity or CR as best response = 15/18 pts
  • After 2 years of maintenance: PR = 18 pts (100%); CR or stringent CR = 16/18 pts (89%); MRD-negative CR = 10/16 pts (63%)
  • Estimated PFS for ITT: 36-month = 94.1% (95% CI, 65.0%-99.2%) and 48-month = 70.6% (95% CI, 16.0%-93.6%)
  • Estimated OS for ITT: 36- and 48- month PFS = 100%
  • Grade 3-4 adverse events (AEs) in > 1 pt: lymphopenia = 39%, neutropenia = 28%, anemia = 22%, diarrhea = 17%, lung infection = 17%, hypophosphatemia = 11%, and thromboembolic event = 11%
  • Serious AEs: pulmonary infection = 2 pts (11%) and congestive heart failure = 1 pt (5.5%)
  • Discontinuation due to AEs: 2 pts
Genetic landscape and baseline mutational patterns in high-risk SM:
  • SM Samples from 13/18 were evaluable; NDMM = 40 samples
  • Copy number deletions and gains were typical of abnormal plasma cells, confirming high purity of the samples
  • Median number of single nucleotide variants per patient: SM =34 (interquartile range, 30-58); NDMM = 40 (interquartile range, 28-54) nonsynonymous
  • The frequency of mutations in at least 1/15 previously identified significantly mutated genes: NDMM = 18/40 pts (45%); SM = 1/15 pts (6.6%) and this patient would be regarded as having MM according to the revised IMWG 2014 criteria and had mutations in both FAM46C and TRAF3
  • Mutations in genes of the NFKB pathway: SM pts = 1/15 pts (6.6%) and NDMM = 10/40 (25%) of 40 pts
  • Mutations in histone modifying enzyme pathways: NDMM = 1 pt

 Conclusion

This study provides novel data showing a high response rate from high-risk SM patients, along with a differential baseline mutational pattern that indicates a lower mutational burden in the precursor state. This would be expected given that this state is often asymptomatic, but the strength of this study is that it was coupled with a strong MRD negative treatment response. However, the authors readily admit that the small sample size is a limitation: “the sample size precludes us from providing definitive conclusions”. Therefore, it will be interesting to follow the outcome of a larger trial set up by the Spanish PETHEMA group that is currently enrolling 90 patients with high-risk SM, and in addition, to see similar data for mutational analyses in this set. This could help expand on the concept of treatment-responsive biology, and potentially seal the debate regarding early intervention in certain patient subsets.

 
References
  1. Mailankody S., Kazandjian D. et al. Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma. Submitted 16 February 2017; accepted 14 August 2017. DOI 10.1182/ bloodadvances.2017005934.
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