https://orcid.org/0000-0002-4086-6453
In this issue of Blood Advances, Ragon et al1 provide evidence that second primary malignancies (SPM) that develop in patients with multiple myeloma (MM) after autologous hematopoietic stem cell transplant (auto-HCT) have a deleterious impact on survival outcomes. Authors analyzed a data set from the Center for International Blood and Marrow Transplant Research that consisted of ∼4000 patients who received auto-HCT for MM followed by posttransplant maintenance and found that the occurrence of SPM was associated with inferior progression-free survival (PFS) and overall survival (OS; hazard ratios [HRs], 2.62 and 3.85, respectively) using multivariate analysis. For the subgroup of patients who developed second hematological malignancies (SHMs), the deleterious impact on PFS and OS was even more pronounced (HRs, 5.01 and 8.13, respectively).
Overall, the incidence of SPM in this study was relatively low compared to previous reports,2 at 4% (n = 175), including 112 solid tumors (64%) and 63 SHMs (36%), perhaps partially because of underreporting, inherent to a retrospective real-world registry-based study. In a meta-analysis of the 3 major posttransplant lenalidomide maintenance therapy trials, the cumulative incidence of SPM in the maintenance arm was 13.4%, including 6.1% hematological malignancies and 7.3% solid tumors.2 Recently, an analysis of more than 4300 participants of the United Kingdom National Cancer Research Institute (UK NCRI) Myeloma XI trial presented at the 64th annual meeting of the American Society of Hematology (ASH) in 2022 showed an SPM incidence of 12.2% at 7 years among transplant-eligible patients who received lenalidomide maintenance therapy.3 Importantly, nonmelanoma skin malignancies, included in some reports of SPM,3,4 were not included in the study by Ragon et al, thereby substantiating the impact of the included SPM on survival outcomes.
One of the novelties of this registry-based study is that all patients received posttransplant maintenance therapy, mostly lenalidomide-based (72%). The choice of this cohort reflects the widespread use of lenalidomide maintenance therapy in clinical practice, owing to its proven capability to improve survival outcomes.2 Posttransplant maintenance therapy acts as a double-edged sword, improving PFS and OS while increasing the risk of SPM. Ultimately, the net effect of lenalidomide maintenance therapy is improved survival outcomes. Indeed, despite the detrimental impact of SPM, the reports by Ragon et al and others5 still indicate that the progression of MM remains the primary cause of death, even among patients who develop an SPM. Therefore, the report by Ragon et al should not deter treating physicians from providing optimal treatment to prevent relapse of MM after auto-HCT.
That being said, are there ways to mitigate the risk of SPM while maintaining the benefits of posttransplant maintenance therapy? In another analysis from the UK NCRI Myeloma XI trial presented at the 64th annual ASH meeting in 2022, the PFS benefit associated with the lenalidomide maintenance therapy was decreased after 4 years of maintenance.6 In the study by Ragon et al, details regarding the duration of maintenance and its correlation to SPM were not provided, and this warrants further research. Limiting the duration of maintenance based on the patient's response and risk profile could balance risks and benefits, thereby reducing its potential negative impact. Furthermore, an improved understanding of the biological mechanisms that lead to the development of SPM7 could provide the basis of personalized genome-based approaches that will allow tailored MM treatment and further minimize the risk of SPM.
Despite the abundant literature on the increased risk of SPM in MM, there is little guidance for the treating physician faced with a patient with MM who now presents with a second malignancy after auto-HCT, also when considering an International Myeloma Working Group consensus on SPM in MM.8 How should the patient be managed? If the patient is receiving posttransplant maintenance therapy, should it be stopped? How do MM and its treatment affect the treatment of SPM? These are usually case-to-case decisions, depending on variables such as the type of second malignancy; the type of treatment the patient requires for the SPM; and the toxicity profile of ongoing maintenance, if administered. To effectively manage patients with dual malignancies, gathering more detailed data on these clinical scenarios is crucial, particularly for the most common solid tumors, such as melanoma, genitourinary tract malignancies, and myeloid hematological malignancies, as highlighted in the study by Ragon et al.
The study revealed encouraging 1-year OS rates (67%) for patients with SHM who received allogeneic (allo-HCT), as evidenced by a small subset of 9 patients.1 These findings suggest that allo-HCT may be a viable therapeutic option, leading to extended remission periods for both hematological malignancies. However, retaining the eligibility for allo-HCT in previously heavily-treated patients can be challenging. Thus, it is crucial to prioritize prompt diagnosis and timely intervention. Furthermore, the observation that the upper range of the interval from auto-HCT to SPM was 8 years highlights the need for prolonged surveillance and greater support for long-term survivor surveillance programs.
The realm of antimyeloma therapies is in a state of continual transformation. Several ongoing trials are exploring the potential of posttransplant maintenance therapy intensification with lenalidomide-based combinations.9,10 To accurately discern the trends in SPM dynamics in patients with MM, it is essential to gather long-term data from prospective trials and updated registry studies.
In conclusion, the study conducted by Ragon et al emphasizes the crucial clinical implications of SPM in patients with MM undergoing auto-HCT and posttransplant maintenance therapy. Because of the improving survival rates of patients with MM, SPM diagnoses are expected to increase. However, survival outcomes for patients with SPM remain unsatisfactory, underscoring the need to enhance our understanding of these malignancies' biology, prevention, early detection, and management. It is imperative that SPM are recognized as a pressing concern in modern MM management.
Conflict-of-interest disclosure: Q.B. reports research funding from Acrotech Pharma, GSK, and Stemline Therapeutics. O.P. declares no competing financial interests.
