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Are all risk factors created equal in multiple myeloma?
by Sina A. Beer and Martin F. Kaiser
Received: September 2, 2026.
Accepted: September 9, 2026.
Citation: Sina A. Beer and Martin F. Kaiser. Are all risk factors created equal in multiple myeloma?
Haematologica. 2026 Sept 17. doi: 10.3324/haematol.2026.301908 [Epub ahead of print]
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Are all risk factors created equal in multiple myeloma?
Sina A. Beer and Martin F. Kaiser1,2
1 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
2 Department of Haematology, The Royal Marsden Hospital, London, United Kingdom.
Correspondence
Martin F. Kaiser, martin.kaiser@icr.ac.uk
Disclosures
MFK: Consultancy fees from AbbVie, Adaptive, BMS/Celgene, Johnson & Johnson, GSK,
Karyopharm, Kite, Pfizer, Poolbeg, Regeneron, Roche, Sanofi, and Takeda. Honoraria from
AbbVie, Adaptive, BMS/Celgene, Johnson & Johnson, GSK, Sanofi, SkylineDx, and Takeda.
Research support from BMS/Celgene. Travel support from BMS/Celgene, Johnson &
Johnson, and Takeda.
Contributions
MFK and SAB wrote this editorial. SAB created the figure.
Editorial
In this issue of Haematologica, Chung et al 1 assessed whether additional molecular markers
could improve on the 2025 IMS/IMWG high-risk multiple myeloma (MM) criteria, using an
integrated mutational and transcriptional analysis of the CoMMpass dataset.
The 2025 International Myeloma Society (IMS) – International Myeloma Working Group
(IMWG) updated definition of high-risk MM provided an important improvement for pre-
emptively identifying patients at high-risk of early relapse. High-risk cytogenetic aberrations
(HRCA) recommended to be tested in all patients at diagnosis now include gain(1q), del(1p),
del(17p) and high -risk immunoglobulin translocations (t(4;14), t (14;16), t(14;20)), enabling
the detection of disease harboring two or more HRCA - a well -established ultra -high-risk
group 2,3. In addition to HRCA, testing for TP53 single nucleotide variants (SNV),
preferentially by next-generation sequencing (NGS) , is now required as well. Operationally,
this means myeloma diagnostic lab oratories need workflows that enable DNA extraction
from highly purified C D138-positive tumour cells, either alongside traditional FISH or as
part of an NGS-based tumour genetic analysis . As a consequence, myeloma diagnostics are
finally getting integrated into modern molecular diagnostic workflows, which have
accelerated and expanded vastly for solid oncology over the past decade . Larg e oncology
diagnostic laboratories such as the UK National Health Service’s (NHS) Genomic Laboratory
Hubs (GLH) have established protocols to extract DNA and RNA from the same sample and
deliver highly specialised tumour genetic testing on a daily basis and at high volume ,
including DNA NGS mutational calling, as well as RNA-based transcriptional, or gene
expression profiling (GEP) , tests. The latter are reimbursed by the NHS and other public
healthcare systems; an example are thousands of breast cancer patients each year receiving
GEP testing, as the added prognostic value has been found to be beneficial and cost-effective
by the UK National Institute for Health and Care Excellence (NICE) and other healthcare
systems 4.
An analysis like that by Chung et al , which evaluates the added prognostic value of DNA
mutational signatures, as well as RNA -based GEP signatures in context of the updated IMS-
IMWG HR criteria is therefore timely and of potential clinical relevance. The team
specifically evaluated the APOBEC mutational signature and chromotripsis, both common in
cancer and found in myeloma . Both can be detected by NGS, ideally whole genome
sequencing (WGS), which is increasingly available but incurs additional cost . However ,
analysis pipelines for calling these signatures in line with ISO accredited diagnostics
standards are not yet universally established. The RNA GEP signature s evaluated in the
article include EMC92, which has been developed as a n accredited in-vitro diagnostic (IVD)
test (MMProfiler/SKY92) 5, as well as the research-only proliferation (PR) signature 6,7.
All tested signatures partially overlapped with IMS -IMWG high -risk markers, but also
identified additional patients , which were different between the signatures . However, when
de-convoluting overlapping prognostic associa tions, either through multivariable modelling
or by sub-group analysis of patients with the presence of isolated risk markers, the additional
prognostic value of GEP exceeded that of the other markers.
Whilst the present study has its limitations, such as the highly heterogeneous treatment
patients received in CoMMpass, t hese findings are in keeping with an increasing number of
independent reports confirming the added prognostic value of RNA transcriptional profiling
to the 2025 IMS-IMWG risk definition 8-10. It is also in keeping with the diagnostic and
prognostic value transcriptional profiling has added for other B-cell malignancies, e.g. in B-
acute lymphoblastic leukaemia, where integrated diagnostic pathways with DNA and RNA
profiling are increasingly used 11.
But as evidence continues to build , how realistically could GEP testing be integrated into
routine myeloma diagnostic pathways - provided it took a mere 14 years from publication of
the initial myeloma genome to the 2025 IMS -IMWG HR guideline? As described above,
diagnostic practice has advanced across oncology , including access to GEP for multiple
tumour entities. Of note, health economic evaluation of the MMProfiler/SKY92 assay by UK
NICE has recently started 12 and similar evaluations are ongoing elsewher e. If successful,
these could provide equitable access to advanced diagnostics for myeloma patients in
respective healthcare systems. Importantly, the addition of advanced risk stratification with
minimal residual disease tools and others ( Figure 1) can provide a fully integrated pathway
approach to patient care.
Open questions remain regarding how much recalibration of existing risk factors and addition
of new factors will be required with novel T -cell engaging (TCE)/ redirecting therapies,
especially considering bispecific antibodies moving into earlier lines of therapy. For instance,
first sub-group analyses of the MajesTEC -3 trial have shown long-lasting remissions in
traditional ultra-high-risk subgroups (2+HRCA) that are unprecedented 13. Nonetheless, this
promptly raises new questions such as the optimal duration of TCE therapy, where again an
assessment of key prognostic factors is likely to provide valuable information and guidance.
The present work adds to a body of evidence suggesting that transcriptional profiling should
be considered in clinical routine.
References
1. Chung TH, Chang JG, Tan TK, Chng WJ. Risk factors and their contributions
to prognosis in multiple myeloma. Haematologica. xxx
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lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the
Myeloma XI trial. Blood. 2023;141(14):1666-1674.
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abnormalities and high-risk disease in newly diagnosed and relapsed/refractory multiple
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10. McAvera RM, Cymer I, Quinn J, et al. SKY92 identifies high-risk newly
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12. NICE: MMprofiler for estimating risk in newly diagnosed multiple myeloma.
National Institute for Health and Care Excellence. 2026;GID-HTG10153.
13. Plenary Abstracts Session & Oral Presentations. Hemasphere.
2026;10:e70419.
Figure Legend 1: Outline of an integrated diagnostic workflow in multiple
myeloma. Combining DNA genomics and RNA transcriptomics for currently accredited
diagnostics and potential future diagnostic applications. MRD, minimal residual disease;
CTPC, circulating tumour plasma cells. *Requires definition of diagnostically accredited
calling criteria.