Controversies in the initial therapy of patients with multiple myeloma

The greatest excess mortality in multiple myeloma (MM) is in older patients, Prof Graham Jackson, Freeman Hospital, Newcastle Upon Tyne Hospitals, Newcastle, UK, told the Haematology Association of Ireland 2024 Annual Meeting. Prof Jackson gave an insightful talk about controversial issues in the initial therapy of MM, with a focus on risk factors for poorer treatment outcomes. Age has a significant impact on progression-free survival (PFS), mortality, and the overall outlook for this patient group, he said, adding that clinicians “need to be very careful about what drives these poorer outcomes”.

Prof Jackson highlighted that cytogenetic risk is the “biggest driver of poor outcomes in younger people”, while performance status has the biggest impact on overall survival in older patients, with frailty scores having a direct correlation with negative outcomes. “Cytogenetics become relatively less important” in older patients, he said.

Describing “other things to think about when assessing risk”, Prof Jackson said that beta-2 microglobulin “remains consistently important”, alongside lactate dehydrogenase, albumin, and cytogenetics. “It [elevated beta-2 microglobulin] is still one of the highest driving factors of poorer outcomes,” he said.

Prof Jackson then talked about cytogenetic risk factors in MM, such as double-hit and triple-hit disease. He noted that “the more copies of chromosome 1q patients have, the poorer the outcomes”, and presented the empirical data underpinning current understanding of cytogenetics, including findings from Myeloma 11. Delegates also heard that bone marrow-independent myeloma poses significantly high risk, and that PET (positron emission tomography) can also be considered a biomarker of disease, with those who are PET-negative at diagnosis achieving better outcomes.

“We know that myeloma which begins to live outside the bone marrow and is no longer dependent on the bone marrow microenvironment heralds a poorer prognostic disease,” he added, giving plasma cell leukaemia as an example.

Prof Jackson acknowledged that “we are behind in diagnostics” for MM, while discussing the assessment of minimal residual disease (MRD).

“Patients hate bone marrows, it’s one of the drawbacks in terms of assessing MRD in bone marrow assessment and we need to move on.”

He then discussed the potential of mass spectrometry for detecting clonal light chains in the peripheral blood, saying it “can give us information about MRD, possibly without the need to go to bone marrow”. He admitted “there’s a long way to go on this journey, but I would predict that mass spectrometry will take over the assessment of MRD in future”.

Prof Jackson then summarised that MRD-negative and PET-positive patients had worse outcomes, while optimal outcomes are associated with MRD- and PET-negative disease.

Prof Jackson acknowledged the different available regimens in the north and south of Ireland and advocated that “all patients should receive DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone] upfront”. He presented the data showing that “the addition of daratumumab to our frontline transplant eligible patients is very important”, and the evidence guiding maintenance therapy.

“Adding daratumumab to maintenance compared with observation does make a difference to median PFS,” he said.

He also said that DVRd is more cost-effective than DVTd (daratumumab, bortezomib, thalidomide, dexamethasone), adding that “the unholy combination” of bortezomib and thalidomide is also more neurotoxic than bortezomib and lenalidomide.

Prof Jackson also explored the evidence and “move in the US” away from frontline transplantation. “The sort of outcomes we’re seeing with DVRd mean that transplant is adding less and less in terms of PFS,” he said, and went on to describe several current approaches in maintenance therapies.

The final part of Prof Jackson’s talk examined “the grey zones” of assessing transplant eligible patients, emphasising age, comorbidities, and patient choice as vital considerations. He demonstrated poorer outcomes associated with those over 65 and discussed alternative options for transplant ineligible patients, such as quadruple therapy. Concluding, Prof Jackson said that “assessing risk is becoming more and more complicated as treatment regimes improve”, and emphasised that excess deaths are still highest in oldest patient groups. “And the great goal is that immunotherapy is coming to our newly diagnosed patients.”