Improving the outcomes of multiple myeloma patients with high-risk abnormalities (HRA) continues to pose a therapeutic challenge, but the future of multiple myeloma treatment is bright, with so many active drugs and immunotherapies on the horizon, a recent Amgen-sponsored educational meeting in Perth heard.
Doctor M Hasib Sidiqi from the Fiona Stanley Hospital, Murdoch, WA has recently returned from a two-year fellowship at the Mayo Clinic under the mentorship of Doctor Morie Gertz, Doctor Angela Dispenzieri and Doctor Shaji Kumar. He provided a first-hand account of the Mayo Clinic Rochester’s management approach to Multiple Myeloma, including the Clinic’s approach to improving outcomes in patients with high-risk abnormalities (HRA).
Improved outcomes in high-risk patients still an unmet need
While developments in the treatment of multiple myeloma continue to improve outcomes for many patients, those with high-risk abnormalities (HRAs) such as patients with Del(17p) mutations continue to do poorly,1 explained Dr Sidiqi. There is also growing recognition of the poor prognosis of those with double and triple hit myeloma, he said, where each successive high-risk abnormality has a negative impact on overall survival.2
Dr Sidiqi described the Mayo Clinic’s strategies to improve outcomes in these patients with the use of intensive induction regimens, including carfilzomib-based combinations, followed by autologous stem cell transplant (ASCT) – including tandem stem cell transplant in some cases – and intensification of maintenance therapy with either carfilzomib- or bortezomib-based therapy. He acknowledged the limited phase 3 data in the high-risk setting.
Dr Sidiqi explained that the Mayo Clinic’s management protocol for transplant-eligible patients has been updated two to three times in the last couple of years, reflecting the rapid advances in treatment approaches.
Intensified maintenance therapy may limit the prognostic impact of HRA
Dr Sidiqi presented data from a retrospective review of patients at the Mayo Clinic over seven years who had received induction with bortezomib-lenalidomide-dexamethasone (VRd) followed by ASCT (n = 243).3 Patients had received only one line of therapy prior to transplant and were transplanted within 12 months of diagnosis. HRAs were present in 34% of patients.
The risk-stratified data showed that HRA was a strong predictor of worse progression-free survival (PFS) and overall survival (OS) in patients who did not receive maintenance therapy. However, patients receiving maintenance therapy appeared to have similar PFS and OS, irrespective of cytogenetics.3 Dr Sidiqi explained that high-risk patients tended to receive intensified maintenance therapy beyond single-agent lenalidomide (bortezomib, carfilzomib or doublet and triplet regimens based on physician preference) at the clinic. While acknowledging the small numbers of patients in each therapy group, Dr Sidiqi suggested that the data does seem to support intensive maintenance therapy after ASCT to overcome the poor prognostic impact of high-risk cytogenetic abnormalities.
Upfront transplant remains the standard of care in newly-diagnosed multiple myeloma
With highly-active antimyeloma agents now available, Dr Sidiqi said it’s inevitable that the question of the ongoing need for upfront transplant will arise. He referred to data showing a PFS benefit for RVd plus upfront transplant compared to salvage transplantation, but no clear OS benefit.4 However, he pointed out that around 20% of patients who did not undergo upfront transplantation were found to be disease refractory at relapse and no longer eligible for transplant. ‘This means you might miss the boat for around one in five patients in providing an effective line of therapy,’ he said.
The Mayo Clinic offers transplantation to patients up to the age of 75 years. Dr Sidiqi presented data of similar outcomes in patients over 70 years compared with younger patients who had undergone ASCT,5 but the older patient cohort showed a higher rate of hospitalisation and more difficult stem cell mobilisation. ‘However, this data supports the use of transplant in fit elderly patients with myeloma,’ he said.
Tandem transplant is gaining more support in some institutions, noted Dr Sidiqi. Although the STaMINA study6 showed no benefit with tandem transplant, he explained that a large proportion of patients randomised to tandem transplantation in the study did not go on to receive the second transplant. He referred to European data7 and a recent integrated analysis8 that have shown the benefit of tandem transplant in high-risk patients. “In terms of tandem transplantation, the data is mixed, but the European data and the integrated analysis are encouraging, and it may be worth considering this option in high-risk patients,” he said.
Binder M, et al. Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma. Blood Cancer 2017; 7, e600; doi:10.1038/bcj.2017.83. https://www.ncbi.nlm.nih.gov/pubmed/28862698
Sidiqi MH, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma. Blood Cancer 2018;8(11):106. DOI: 10.1038/s41408-018-0147-7. https://www.ncbi.nlm.nih.gov/pubmed/30409963
Cavo M, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Networks (EMN02/HO95 MM trial). DOI:10.1200/JCO.2016.34.15_suppl.800 2017. https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.8000
Cavo M, et al. Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies. Blood 2018;132(suppl 1):Abstract 124.