Breaking bad…proteins

The papers by Muchtar et al and Palladini et al in this issue of Blood each reflect the progress and challenges associated with light chain (AL) treatment, which requires a delicate balance between the rapid, effective eradication of clonal plasma cells and the increased toxicity profile observed when cytotoxic therapy (usually well-tolerated in myeloma patients) is applied to individuals with AL.^1,2 

Systemic AL amyloidosis is a progressive and deadly disease: a disorder of protein conformation in which fibrils of immunoglobulin ALs produced by clonal bone marrow plasma cells accumulate as amyloid deposits in different organs to cause damage and dysfunction. The use of rapidly acting and efficacious drugs early in the disease course is particularly important in AL because organ damage can progress until achievement of better than very good partial responses (VGPRs). In patients with hematologic VGPRs or complete responses, levels of the toxic AL have presumably been reduced to a degree sufficient to allow egression from amyloid deposits and/or to minimize direct tissue injury; these patients consistently experience more organ responses and longer survival.³ 

Although newer approaches designed to directly dissolve amyloid deposits are under development, the current strategies are characterized by 2 phases: (1) administration of antimyeloma treatment to kill the monoclonal plasma cell source of these fibrillar infiltrates, followed by (2) observation and clinical support of patients to see if regression of the amyloid deposits, manifested by improvement in organ dysfunction, occurs over time. Unfortunately, when new treatments, including high-dose melphalan and stem cell transplantation (ASCT), were introduced, it quickly became apparent that approaches with minimal morbidity and mortality in myeloma carried a much higher risk of serious and potentially fatal toxicities such as fluid overload, multiorgan failure, and sudden death in patients with AL.^4,5  Subsequent efforts have focused on the need to improve the therapeutic index of AL treatments in potentially fragile patients, for their broader use in “breaking bad” AL proteins.

The findings by Muchtar et al are reassuring that progress is being made in the therapy of AL, which is a relatively uncommon disease. Most studies of new treatments (such as ASCT, bortezomib, immunomodulatory derivatives [IMiDs], and combination regimens) were adopted into clinical practice following relatively small retrospective or phase 1-2 studies.^4-8  In their paper, the authors tapped the Mayo Clinic database to analyze the outcome of approximately 1500 AL patients seen over a 15-year period in their center.¹  They have documented a significant decrease in deaths within 6 months of diagnosis in more recent years, as well as trends for better response rates, longer overall survival, and earlier diagnosis. In addition to informative observations, this analysis highlights the utility of a large patient database in assessing the real-world impact of new therapeutic interventions, particularly in infrequent diseases such as AL. Conversely, given the potential influence such studies may have on practitioner decisions, efforts ensuring the completeness and accuracy of these databases should be a high priority in the future.

This issue also includes the results of a phase 2 study on AL by Palladini et al using the combination of dexamethasone and pomalidomide, a potent IMiD approved and widely used as second- or third-line treatment of myeloma after failure of lenalidomide. IMiD regimens containing thalidomide and later lenalidomide have been assessed in AL and, particularly in the case of lenalidomide, benefit a variable proportion of patients.^4,8  However, complete responses are relatively uncommon, and lenalidomide use may be complicated by fluid retention, fatigue, myelosuppression, and an increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP); side effects again are more problematic in AL than in myeloma.³  In myeloma, pomalidomide has been positioned only for patients who have failed lenalidomide. In AL, trials of pomalidomide have been conducted in the relapsed setting as well, but have included some patients who are IMiD-naïve. The earlier introduction of pomalidomide has appeal because it may exert more profound plasma cell killing, is easy to give in patients with renal dysfunction, and, anecdotally, may be better tolerated than lenalidomide. The current study evaluated the continuous administration of pomalidomide and weekly dexamethasone in 28 patients previously treated with an alkylating agent and a proteasome inhibitor. Although the median number of prior regimens was not reported, fewer than half had been previously exposed to IMiDs (lenalidomide in 25%). Hematologic responses were seen in 68%, occurred rapidly, and included a better than VGPR in almost one-third of patients. As expected, median survival was significantly longer in responding patients and in those without evidence of marked cardiac dysfunction measured by elevations in the serum biomarkers NT-proBNP and troponin. Grade 3 or 4 toxicity was observed in 54%, which was similar in nature to that observed in other IMiD trials in AL and included fluid retention, infection, atrial fibrillation, and venous thromboembolism.²  Nevertheless, analogous to the recent trend noted previously by Muchtar et al, no deaths occurred within the initial 100 days of pomalidomide therapy. However, these side effects and the rates of pomalidomide dose reduction (32%) and discontinuation (29%) resulting from adverse events emphasize the challenges in optimizing the treatment of AL and support future trials to explore dose and schedule modifications to improve tolerance.²  Such efforts might include dose reduction of pomalidomide, as suggested by the authors, dose reduction of dexamethasone, or administration of pomalidomide on days 1 through 21 of a 28-day schedule (as approved for myeloma) rather than continuously; pomalidomide combinations as initial therapy for AL would also be of interest.

Exciting laboratory research also portends well for identifying better prognostic factors and treatment strategies in AL. Fluorescence in situ hybridization cytogenetics, preferential organ tissue trophism according to AL variable region gene selection, relevance of marrow minimal residual disease, and chemical characteristics of specific ALs that predict their predisposition for self-aggregation are subjects of active investigation, and the results may be leveraged in the future to improve management strategies.^9-11  We look forward to the next analysis of the Mayo Clinic or other large AL database to demonstrate that further improvements in outcomes for AL patients have been achieved in the real-world setting.