A number of publications from 2014 that impact our understanding and treatment of multiple myeloma (MM) stand out. First, insights into the mechanism of action of thalidomide and its analogues came fast and frequently. It was previously shown that thalidomide binds cereblon. This drug-protein interaction is critical for both the teratogenicity that gave thalidomide its notoriety and also the surprising ability of thalidomide and its newer derivatives lenalidomide and pomalidomide to treat MM. Using complementary approaches, two groups described another critical link by demonstrating that the transcription factors Ikaros1 (IZKF1) and Aiolis (IZKF3) are selectively bound by cereblon. Interestingly, after binding, these immunomodulatory drugs activate cereblon, resulting in rapid degradation of Ikaros and Aiolis.1,2 This is important because Ikaros and Aiolis are regulators of B- and T-cell lymphoid development3,4 and are critical for normal plasma cell development in mice. This discovery highlights that all of the immune modulators use the same basic mechanism of action, albeit with increasing potency. These findings also raise the possibility of using biomarkers to predict drug response and exploring new ways to target these pathways.
With more direct therapeutic relevance, the results of the Phase III ASPIRE clinical trial were published. This trial tested the hypothesis that three drugs would be better than two in relapsed MM. The trial compared carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) and met its primary end point by demonstrating that KRd significantly extended progression-free survival (PFS) by 8.7 months (26.3 months with KRd vs. 17.6 months with Rd). The overall response rate was 87.1 percent with KRd and 66.7 percent with Rd. In the KRd and Rd groups, 31.8 percent versus 9.3 percent of patients achieved a complete response, respectively (p<0.0001). Perhaps most importantly, KRd consistently improved Global Health Status/Quality of Life compared with Rd over 18 cycles of treatment. The study also was reassuring with respect to toxicity, as treatment discontinuation due to an adverse event occurred in 15.3 percent (KRd) and 17.7 percent (Rd) of patients. In each group, 7.7 percent versus 8.5 percent of patients died while still on study treatment. The significance of this study is that it confirms that a more aggressive approach with three drugs is tolerable and dramatically improves outcome for relapsed MM patients. Use of this or similar combinations should now be the standard of care in relapsed disease.
Finally, a randomized trial reconfirmed the role of transplantation in MM patients younger than 65 years. This trial also highlighted that using combinations of drugs for longer as maintenance results in the longest PFS period for patients. All patients received four cycles of Rd then were randomized to melphalan, prednisone, and lenalidomide (MPR), or to high-dose melphalan and autologous hematopoietic stem cell transplantation (HSCT). A second randomization consisted of continuous lenalidomide or no maintenance. Both PFS and overall survival were significantly longer with high-dose melphalan plus HSCT compared with MPR (median PFS, 43 vs. 22.4 months [p<0.001]; four-year overall survival, 81.6% vs. 65.3%; p=0.02). Median PFS was significantly longer with lenalidomide maintenance compared with no maintenance (41.9 months vs. 21.6 months; p<0.001). Patients treated the least aggressively (e.g. with Rd followed by MPR but no maintenance) had a 21.8-month PFS, while those treated most aggressively (transplantation plus maintenance) had a 54.7-month PFS. This study thus further emphasizes the value of depth of response and continuous therapy in improving outcomes in MM patients.
In summary, using combination therapy for longer and striving for a deeper response improves outcomes. Better understanding of the mechanism of action of the most potent drugs in MM will result in further advances, while the introduction of monoclonal antibodies targeting CD38 (daratumumab, SAR650984) or SLAMF7 (elotuzumab) to chemotherapy regimens should provide further advances in 2015 and beyond.
