“A fortuitous combination of circumstances”

In this issue of Blood, Larocca et al report encouraging data on the 3-drug combination of cyclophosphamide, pomalidomide, and prednisone among relapsed myeloma patients, for a “fortuitous combination,” as Charles Dickens wrote in Our Mutual Friend.¹ 

Cyclophosphamide is one of the oldest active agents in oncology and has been experiencing a recent renaissance in the myeloma community. Its mechanism of action as an alkylating agent is decidedly “old school.”²  Pomalidomide is the newest agent approved for the treatment of relapsed and refractory myeloma and has activity when combined with dexamethasone even among patients proven to be resistant to lenalidomide.³  The availability of pomalidomide for patients with refractory myeloma has been a major step forward, yet there is clearly room to further enhance response rates and response duration. This is where the fortuitous combination comes into play. The benefit of combination therapy has been demonstrated in the induction therapy setting, in which the use of 3 agents induces a deeper response than is seen with 2 agents, and this is associated with superior posttransplant outcomes.⁴  Among patients with early relapse, there is a single trial testing 3 agents (bortezomib/thalidomide/dexamethasone) vs 2 agents (thalidomide/dexamethasone).⁵  In this study, the use of a 3-drug regimen improved overall response rate, depth of response, and progression-free survival with a trend toward improved overall survival.⁶  To further build on this concept of 3 vs 2 drugs in the early-relapse setting, ongoing phase 3 studies will provide further evidence to address this question with other new agents such carfilzomib (carfilzomib/lenalidomide/dexamethasone vs lenalidomide/dexamethasone), panobinostat (panobinostat/bortezomib/dexamethasone vs bortezomib/dexamethasone), elotuzumab (elotuzumab/lenalidomide/dexamethasone vs lenalidomide/dexamethasone), and pomalidomide (pomalidomide/bortezomib/dexamethasone vs bortezomib/dexamethasone). From a tumor biology perspective, the use of combination therapy also offers the potential benefit of suppressing and eliminating more subclones, which may delay the development of refractory relapse.

Given data with newly diagnosed and early-relapse patients supporting combination therapy, the pressing question now is, does the effect of combination therapy hold true even in the refractory relapse setting? There are data supporting the clinical benefit associated with minor responses in the relapsed and refractory disease, using bortezomib,⁷  pomalidomide,⁸  and carfilzomib,⁹  and it is also known that patients with refractory disease may be more debilitated and unable to tolerate aggressive combination treatments. In contrast, patients with refractory disease may stand to benefit the greatest from combination therapy. Thus, should we abandon the use of single-agent therapy in favor of combinations in all settings? The data from Larocca et al¹  clearly demonstrate the benefits of triple drug combinations, combining the old with the new, and it appears that this regimen both is more active than pomalidomide/dexamethasone in lenalidomide-refractory patients and is well-tolerated. However, the patients, although lenalidomide-resistant, were less heavily pretreated overall (1-3 prior lines vs >5 for the Richardson study⁸ ). This difference in inherent drug exposure limits the ability to extrapolate the pomalidomide/cyclophosphamide/prednisone data from Larocca to the generalized refractory myeloma patient population.

The unanswered question remaining for the clinician is, who is this regimen best suited for? It appears that the pomalidomide/cyclophosphamide/prednisone combination is effective and can be safely administered with very encouraging results. However, it remains unclear whether the benefits of combination therapy realized in early lines of therapy can be routinely applied to a sicker, less robust, refractory population after numerous lines of prior treatment. Until these types of trials are performed in the refractory relapse population, decisions regarding combination therapy, although they may be biologically appealing, need to be based on the physical and hematological reserve of the refractory patient in question. Thus, although the combination may be fortuitous, circumstances of an individual patient will dictate the ultimate utility and success of this approach.