General MM

COMy 2019 | DEBATE: Are we ready to personalize therapy in multiple myeloma?

During the 5th World Congress on Controversies in Multiple Myeloma (COMy), Saad Usmani, Levine Cancer Institute, Charlotte, NC, had the difficult challenge of presenting both sides of the argument around the personalization of therapy in multiple myeloma (MM).1

FOR

Dr Usmani began by stating that, in his opinion, we are already personalizing therapy. Treatment decisions already take into consideration the patient’s age, co-morbidities, insurance issues, disease-related factors such as renal status, high-risk features and previous treatment history.

MM is not one disease.

  • It progresses from monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM)
  • Treatment decisions need to consider the tumor burden at the time of presentation
  • Clonal heterogeneity means that at any one time there are multiple myeloma clones present in each patient
  • These clones evolve over time, acquiring further mutations and increasing heterogeneity

‘One-size-fits-all’ approach does not work.

  • MMRF CoMMpassSM study (NCT01454297) study identified that a high mutation load was correlated with an increased risk of disease progression and that the outcomes of each genetic subgroup were different2
    • Dr Usmani provided an example of two patients whose time to progression was significantly different, with one molecular subtype (TP53mut) progressing within 1 month, versus >18 months for TP53wt1
  • Cytogenetics can be used for prognostication and may predict treatment response, for example, translocation (11;14) has been associated with response to venetoclax, which is a Bcl-2 inhibitor:
    • In a phase I study in relapsed/refractory MM (n=66) where 67% of patients treated with venetoclax + bortezomib + dexamethasone responded, the OS rate in patients with t[11;14] vs no t[11;14]) was 78% vs 65%3
  • Some patients, particularly the older population, do not receive a full course of therapy
    • Treatment/dose is often adjusted, based on their performance status, transplant eligibility and frailty index scores

Dr Usmani drew the attention to an ongoing master protocols trial (NCT02884102) using genetic profiling to determine a high-risk alterations and analyze survival rates and disease recurrence.

He concluded that we are already using personalized therapy in the treatment of MM, and that further personalization may become a key feature of future trials.

AGAINST

Dr Usmani argued against personalized therapy in MM, beginning by describing the main challenges, including:

  • A lack of uniformity; no consensus or full understanding of:
    • How to define high risk and standard risk
      • Fluorescence in situ hybridization is an option, but there is no confirmed cut-off
    • The interplay between the microenvironment and MM cells
    • How to utilize the information that we obtain on cytogenetic profiles in clinical practice
      • The risks associated with seven cytogenetic subgroups have been known for nearly 14 years, but not yet adapted into clinical practice
  • MM is a heterogeneous disease with differing predominant clones throughout the course of the disease.
    • Subclonal expansion paradigm needs to be fully understood before treatment can be personalized
  • There is no current evidence to support personalized treatment of MM:
    • Every study that has improved progression-free survival (PFS) and overall survival (OS) has been conducted based on a ‘one-size-fits-all’ approach
    • Existing knowledge in MM exists because we treat the disease the same in different patient populations e.g. SWOG S0777, ALYCONE and ASPIRE

Concluding his argument, Dr Usmani stated there is no prospective randomized data to support personalized therapy in MM at present and we need to understand the disease more fully, before moving into an era of personalized medicine.

The MM Hub ran a Twitter poll shortly after this debate concluded, with a small majority of 55% agreeing that we are not ready to personalize therapy today.

References
  1. Usmani S. Session 14: Debate: Are we ready to personalize therapy today? The 5th World Congress on Controversies in Multiple Myeloma, Paris, France. Oral debate. 2019 May 18.
  2. Miller A. et al. High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma. Blood Cancer J. 2017 Sep 7. DOI: 10.1038/bcj.2017.94
  3. Moreau P. et al. A PHASE 1B STUDY OF VENETOCLAX COMBINED WITH BORTEZOMIB AND DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA. Haematologica. 2017 Jun 24. EHA Learning Centre. Abstract #S460 and oral presentation.
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