Deciphering the genetics of refractory myeloma

Principal investigator: Dr Martin Kaiser

Institution: Institute of Cancer Research, London

Award amount: £1,000,000

Duration: 5 years

Project status: Active

Funding: The DFN Foundation

The inaugural Jacquelin Forbes-Nixon Fellowship is held by Dr Martin Kaiser at the Institute of Cancer Research. Dr Kaiser’s fellowship supports the drive for patients to receive the best treatment for their myeloma, as informed by the genetics of their myeloma.

Dr Kaiser is the Chief Investigator of the OPTIMUM / MUK nine trial. In this trial, newly diagnosed myeloma patients were screened for genetic markers of ultra high-risk myeloma. Patients with ultra high-risk genetic changes were invited to enter the treatment arm of the trial where they received an intensive treatment combination prior to a stem cell transplant, consolidation and maintenance treatment. This is one of the first trials which tested an intensive treatment combination (Dara-CVRd) in UK patients with ultra high-risk myeloma as identified by advanced genetic tests that are not routinely available.

Patient samples collected throughout the trial are used to monitor the response to treatment. Further molecular analysis of the myeloma cells in these samples will add to our understanding of the changes occurring in myeloma cells and how these relate to the response to treatment or progression of the disease. This ground-breaking work will inform how we treat high-risk patients.

Dr Kaiser is active member of the UK NCRI group, the UK Myeloma Forum and is vice chair of the UK Myeloma Research Alliance (UKMRA).  Through his network, Dr Kaiser successfully collaborates with leading international research groups and key opinion leaders with an emphasis on treatment standards and progressing knowledge of the genetics of myeloma.

How this research project will help myeloma patients

Dr Kaiser’s work forges the link between what we are learning about myeloma in the laboratory and the treatments patients receive, the goal being that each patient can receive the best treatment for them, based on the genetics of their myeloma.

Supported by Dr Kaiser’s research, treatment guidelines now include the need to identify patients with high-risk genetics. Results from the OPTIMUM / MUK nine trial demonstrate that patients with ultra high-risk myeloma may benefit from early intensive treatment.

August 2023: the latest results

The latest results from the trial reveal that intensive treatment significantly enhances outcomes for patients with ultra high-risk myeloma, a group typically less responsive to standard treatments. 

In this portion of the trial, 107 newly- diagnosed ultra high-risk myeloma patients received a strong five-drug treatment, Dara-CVRd, followed by high-dose therapy and stem cell transplantation. 

The results are encouraging, and over 95% of patients responded to the treatment. 100-120 days after transplantation, most achieved a significant reduction in paraprotein levels.  

At an 18-month follow-up, 84 of 103 patients (81.7%) still showed no signs of active myeloma, indicating long-lasting responses. 

However, it’s essential to note that some individuals did not respond well, underlining the need for more research in this challenging area. 

Watch: Dr Kaiser explains these results, how the trial was designed with tolerability and quality of life in mind, and how this research will help patients.

Key Outputs

Kaiser et al., (2023) Daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone as induction and extended consolidation improves outcome in ultra-high-risk multiple myeloma. Read more: https://pubmed.ncbi.nlm.nih.gov/37315268/

Kaiser et al., (2022) Extended intensified post-ASCT consolidation with daratumumab, bortezomib, lenalidomide and dexamethasone (Dara-VRd) for ultra-high risk (UHiR) newly diagnosed myeloma (NDMM) and primary plasma cell leukemia (pPCL): The UK Optimum/Muknine trial.
Read more: https://doi.org/10.1182/blood-2022-159540

Rata et al., (2022) Implementation of whole-body MRI (MY-RADS) within the OPTIMUM/MUKnine multi-centre clinical trial for patients with myeloma. Read more: https://insightsimaging.springeropen.com/articles/10.1186/s13244-022-01253-0

Davies, et al., (2022) Perspectives on the risk-stratified treatment of multiple myeloma. Read more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894570/

Kaiser et al., (2021) Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK OPTIMUM / MUK nine trial. Presentation at the Annual Meeting of the American Society of Clinical Oncology, June 2021.
Read more: https://meetinglibrary.asco.org/record/195431/abstract

Brown et al., (2021) MUK nine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia.
Read more: https://bmjopen.bmj.com/content/11/3/e046225.long

Publications from Martin Kaiser’s research which support the revision of the International Staging System to include high-risk cytogenetics, were cited in: Sive et al., (2021) Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline.
Read more: https://onlinelibrary.wiley.com/doi/10.1111/bjh.17410

Croft et al., (2021) Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.
Read more: https://pubmed.ncbi.nlm.nih.gov/33262523/

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