Lenalidomide maintenance based on a genetic profile

The following sentence appears in many articles on maintenance therapy in multiple myeloma: "Lenalidomide is not effective in patients with high-risk genetic profiles." But is this statement demonstrated by clinical data? In this issue of Blood, Panopoulou et al¹ tackle this important question.

The approval of lenalidomide as maintenance therapy was obtained in 2017 by European Medicines Agency and Food and Drug Administration and, although it occurred a bit later than expected, it continues to be the only drug approved for patients with newly diagnosed multiple myeloma after autologous stem cell transplantation and given as continuous therapy. Four randomized, multicenter, phase 3 trials compared single-agent lenalidomide with placebo or no maintenance after transplant in patients with newly diagnosed multiple myeloma; and overall, lenalidomide doubled the progression-free survival rate compared with placebo.^2-5 A meta-analysis of 3 of the above-mentioned trials (CALGB 100104, IFM 2005-02, and GIMEMA RVMM-PI-209 trials) confirmed the progression-free survival benefit (52.8 months in the lenalidomide maintenance group vs 23.5 months in the placebo or observation arm) and demonstrated an overall survival benefit for lenalidomide (median not reached in lenalidomide vs 86.0 months in the placebo or observation arm).⁶ 

Beyond these efficacy results, some post hoc analyses showed the lack of efficacy of lenalidomide in patients with high-risk cytogenetic abnormalities but it is important to consider the following: (i) in the CALGB 100104 trial, the cytogenetic information was not available in most patients; (ii) in the IFM 2005-02 trial, lenalidomide was not given as maintenance therapy owing to concerns of secondary malignancies; (iii) in the RVMM-PI-209 trial, not all patients in the lenalidomide maintenance arm had received autologous stem cell transplantation.

Given this background, is there sufficient evidence that lenalidomide is not effective in patients with high-risk cytogenetic abnormalities? I do not think so and this conclusion is supported by the paper by the Myeloma UK group. In this era of precision medicine, the investigators of the Myeloma XI trial provide clarity on the efficacy of lenalidomide in patients based on extended genetic profiling beyond the classical determination of del 17p and t(4;14). For example, in patients with single cytogenetic abnormalities like del 17p, the median progression-free survival without maintenance is 26 months but for those with del 1p or t(4;14), progression-free survival without maintenance is 7.5 and 9.9 months, respectively, after transplant. In all these patients, the use of lenalidomide as maintenance therapy resulted in a median progression-free survival superior by 50 months. In patients with gain 1q, the cytogenetic abnormality most frequently found in multiple myeloma, lenalidomide as maintenance therapy resulted in a median progression-free survival of 54.4 months, with no differences between gain and amplification of 1q. The benefit in the population with no high-risk genetic profile, as expected, was confirmed. The best treatment to the best population always results in the greatest benefit, but the situation is challenging for patients with 2 or more high-risk cytogenetic abnormalities. Lenalidomide does improve the outcome in comparison with no maintenance therapy, but the median progression-free survival is shorter than in the standard risk population or those with just 1 genetic lesion.

What have we learned from this study? (i) Single agent-lenalidomide is the standard maintenance therapy after transplant in all patients, (ii) comprehensive cytogenetic screening is needed in all newly diagnosed patients with multiple myeloma, and (iii) translational and clinical research is required with new drug combinations in high-risk patients to explore if new approaches to maintenance therapy can improve the outcome for this group of patients. For example, proteasome inhibitors like carfilzomib or the antiCD38 monoclonal antibodies added to lenalidomide, or even the BCMA-targeted therapy like the bispecific monoclonal antibodies as monotherapy or in combination with lenalidomide needs to be explored. The Myeloma UK cooperative group has a new trial focused on this ultra-high-risk subgroup of patients.⁷ 

Are there limitations in this study? This is a post hoc analysis and not all patients had cytogenetic information. Does this explain not confirming the overall survival benefit or was this because of ineffective salvage therapies in the high-risk subgroup of patients? Will conventional fluorescence in situ hybridization analysis be sufficient for the evaluation of cytogenetic abnormalities? Are these results observed in patients eligible for transplant applicable to patients ineligible for transplant or patients in the relapse setting?

It is well accepted that multiple myeloma is not a single disease. One size does not fit all and the future for multiple myeloma is a risk-adapted therapy. Lenalidomide should be the standard of care after transplant in patients with standard risk or single-hit abnormality, but the optimal duration needs to be determined. Response-adapted therapy is also important and the Myeloma XI trial will explore combining response and risk status.

Conflict-of-interest disclosure: The authors declare no competing financial interests.