Extended genetic profiling identified patients with newly diagnosed multiple myeloma (MM) who derived “exceptional” benefit from lenalidomide maintenance after autologous hematopoietic cell transplant (AHCT), according to results of the Myeloma XI trial published in Blood.1 This method differs from standard fluorescence in situ hybridization (FISH) testing and has previously been validated.2
Patients with single-hit MM – isolated del(1p), del(17p), or t(4;14) – derived the highest progression-free survival (PFS) benefit from lenalidomide maintenance; in contrast, lenalidomide maintenance in patients with double-hit MM had limited benefit.
“The results of our study can contribute more individualized information about the benefit a patient may derive from ongoing lenalidomide therapy post-AHCT, depending on the tumor genetic make-up at diagnosis,” said study author Martin F. Kaiser, MD, of the Institute of Cancer Research, London. “Whilst the results confirm the general benefit lenalidomide provides across the entire population, they highlight specific genetic characteristics that led to very rapid relapse in patients not in receipt of lenalidomide.”
Long-term lenalidomide therapy is effective against myeloma for most patients but can result in side effects like fatigue, cytopenias, or, in rare cases, increases in non-melanoma skin cancers, Dr. Kaiser noted. These effects, as well as the financial toxicity associated with long-term treatment, can prompt patients to ask about potential drug holidays or discontinuation of therapy.
To identify which patients derive the most benefit from lenalidomide maintenance, researchers looked at the outcomes of 556 people with newly diagnosed MM enrolled in Myeloma XI who were randomly assigned to lenalidomide maintenance or observation after AHCT. All patients were profiled for copy number aberrations such as t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) and their co-occurrence (no-hit, single-hit, double-hit). To do this, tumor cells were immunomagnetically purified using anti-CD38 antibodies and copy number aberrations and immunoglobulin translocations were profiled using multiplexed ligation-dependent probe amplification and quantitative reverse transcription polymerase chain reaction. The researchers noted that both methods have been validated against FISH.
More than half (51%) of patients were without risk markers, 17% had double-hit MM, and about one-third (32%) had single-hit MM.
Overall, lenalidomide maintenance was associated with a longer PFS (hazard ratio [HR]=0.50; 95% CI 0.40-0.62; p=0.002) and longer PFS2 (subsequent progression; HR=0.65; 95% CI 0.50-0.86; p=0.002) compared with observation. Overall survival (OS) was not significantly different with lenalidomide maintenance.
Patients with only one isolated high-risk marker – del(1p), del(17p), or t(4;14) – who were previously thought to potentially derive more limited benefit from lenalidomide, had about a 40-fold, 10-fold, and seven-fold, respectively, reduced risk of progression or death when treated with lenalidomide maintenance compared with observation.
For this group of patients, the median PFS was 57.3 months with lenalidomide compared with 10.9 months with observation. This benefit translated into improved PFS2 and OS for these patients.
“The outcome of these patients with lenalidomide was nearly as good as that of patients without any high-risk cytogenetic markers,” Dr. Kaiser said. “In contrast, those patients whose tumors had two or more high-risk markers at diagnosis still benefited from lenalidomide but still were likely to relapse within two years.”
The median PFS for patients with double-hit MM assigned to lenalidomide maintenance was 22.5 months compared with 10.6 months for observation; median OS was 47.3 months with lenalidomide maintenance versus 32.8 months with observation.
“It seems clear and in line with other recently reported findings that patients with two or more high-risk markers urgently require new treatment approaches,” Dr. Kaiser said. “These may well include lenalidomide, as it still improved outcomes, but likely require intensification approaches like combination maintenance therapies or entirely new drugs. This group of patients could also be prioritized for adequate clinical trial options.”
In addition, patients with isolated gain(1q) had no significant improvement in PFS with lenalidomide maintenance compared with observation. This is a smaller subgroup of patients, as gain(1q) frequently tends to co-occur with other high-risk markers, and results suggest further investigation into the clinical implications of gain(1q) in myeloma is needed.
Based on these results, Dr. Kaiser emphasized that every patient with MM should have the type of extended tumor cytogenetic profiling demonstrated in this study done at diagnosis, rather than FISH. In some patients, he said, this may require repeating a bone marrow biopsy prior to initiation of therapy.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
- Panopoulou A, Cairns DA, Holroyd A, et al. Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial. Blood. 2023;141(14):1666-1674.
- Boyle EM, Proszek PZ, Kaiser MF, et al. A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma. Genes Chromosomes Cancer. 2015;54(2):91-98.