Multiple myeloma is characterized by recurrent
relapses5
While outcomes have improved with the recent availability of targeted agents and
combination therapies, most patients with multiple myeloma (MM) inevitably
relapse.14,15 With each subsequent line of
therapy, the duration and quality of response deteriorates, and the risk of another
relapse increases.14,16,17
With each successive relapse, time to progression and depth
of response decrease16
A heterogeneic disease
At the time of diagnosis, the cellular and genetic architecture of multiple myeloma is
highly complex and heterogeneous across patients.8,18 Many patients
harbor anywhere from
three to seven detectable subclones.19 Within each
patient clonal diversity continuously evolves throughout the treatment continuum.8 Somatic mutations, chromosomal
translocations and deletions, and epigenetic modifications accumulate over time within
myeloma clones as the disease advances. This evolution may occur through branching
pathways, where mutations create different clones that may drive disease evolution and
treatment resistance.6 Genetic heterogeneity of these myeloma
cells highlight the need for simultaneously targeting multiple mechanisms of disease,
including protein degradation.20,21
Myeloma cell heterogeneity can evolve over time8
High-risk patients5
High-risk (such as patients who relapsed after < 1 year from primary therapy) multiple
myeloma patients have poorer survival outcomes.5,22,23 Several
chromosomal mutations
can occur in the genes responsible for normal antibody development in multiple
myeloma. These mutations include deletion of 17p, translocation t(4:14) and/or
translocation t(14:16).5 Risk factor classification,
including cytogenetic factors, can change as multiple myeloma progresses and
patients can develop high-risk features at relapse or progression. Evaluation of
cytogenetic and other risk factors at relapse is important for staging and treatment
designation.24
| Cytogenetic
Abnormalities |
Clinical/Disease
features |
Quality of
response |
Not all chromosomal abnormalities are viewed as having equally poor
prognosis25,26
Having > 1 abnormality is associated with poorer
prognosis25
IgH translocations25,27,28
- t(4;14)
- t(14;16)
- t(14;20)
Genomic imbalance25,27
|
- R-ISS (stage II/III)26,27
- High serum β2-microglobulin (≥ 5.5 mg/L)26,27
- Renal insufficiency25,27
- Low serum albumin27
- Elevated LDH: (LDH > Upper Limit of Normal)26,27
- Presence of extramedullary disease or plasma cell leukemia25,27,28
|
Primary resistant MM/inadequate response to frontline therapy28
Early relapse after first line of therapy is associated with poor
prognosis29
Relapse occurring within ≤ 12 months of autologous stem cell
transplantation and/or primary therapy22,29
|
| Cytogenetic Abnormalities |
Not all
chromosomal abnormalities are viewed as having equally poor
prognosis25,26
Having > 1 abnormality is associated with poorer
prognosis25
IgH translocations25,27,28
- t(4;14)
- t(14;16)
- t(14;20)
Genomic imbalance25,27
|
| Clinical/Disease features |
- R-ISS (stage II/III)26,27
- High serum β2-microglobulin (≥ 5.5 mg/L)26,27
- Renal insufficiency25,27
- Low serum albumin27
- Elevated LDH: (LDH > Upper Limit of Normal)26,27
- Presence of extramedullary disease or plasma cell leukemia25,27,28
|
| Quality of response |
Primary resistant MM/inadequate response to frontline therapy28
Early relapse after first line of therapy is associated with poor
prognosis29
Relapse occurring within ≤ 12 months of autologous stem cell
transplantation and/or primary therapy22,29
|
LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, Revised International Staging
System.
| Unmet need & challenges23 |
- Lack of upfront testing in newly diagnosed multiple myeloma
- Lack of common ways to categorize high-risk disease
- Lack of consensus or standardized treatment
|
| Investigational therapies
aim to
overcome high-risk status and produce outcomes that more closely match those
of standard-risk patients23 |