Breaking the Plateau Response in Myeloma: Preliminary Results of a Phase II Pilot Study of Sequential Bortezomib in Combination with Dexamethasone and Pegylated Liposomal Doxorubicin (DoVeD) in Patients No Longer Responsive to Standard Induction Regimens.
Authors: Di Carlo Brian A. , Stern Jessica L. , Schuster Michael , Shore Tsiporah , Harpel John , Pearse Roger , Zafar Faiza , Dymek Joanne , Ryan Jessy , Jayabalan David , Chen-Kiang Selina , Ely Scott , Leonard John P. , Coleman Morton , Niesvizky Ruben 
Published: October 2019

Abstract
Thalidomide/lenalidamide with dexamethasone and vincristine/doxorubicin/ dexamethasone (VAD) are induction regimens for the treatment of MM. While most patients (pts) respond, the majority do not achieve a complete response (CR). In randomized trials, several groups have shown that meaningful responses (i.e. CR, near CR, and very good PR) correlate with longer survival. Our group has thus looked for methods to increase the percentage of pts achieving CRs by incorporating sequential, non cross-resistant agents. Bortezomib in combination with dexamethasone is superior to dexamethasone alone for relapsed/refractory multiple myeloma. The liposomal formulation of doxorubicin (Doxil) has significant anti-myeloma activity and less risk of toxicity compared with standard anthracyclines. This study was designed to treat patients whose response had reached a plateau (<25% change in paraprotein x 3 sequential determinations) in partial remission with initial induction regimens (lenalidomide/dexamethasone, thalidomide, thalidomide/dexamethasone, and VAD) to determine whether the introduction of bortezomib/dexamethasone +/− pegylated liposomal doxorubicin for six cycles (DoVeD study) can further cytoreduce and improve quality of the response. Pts’ initial treatments consisted of either BiRD (Biaxin, Revlimid, dexamethasone), thalidomide/dexamethasone or VAD received in the community setting. All pts enrolled on the study were intended to proceed into autologous stem cell transplantation. Pts were treated for six 21-day cycles receiving bortezomib at 1.3 g/m2 on days 1, 4, 8, and 11, with three, four day pulses of high dose dexamethasone. If a PR or better was not achieved after cycle 2, pts received liposomal doxorubicin on day four of every cycle. Pts who did not achieve a CR by the end of cycle four, received day four liposomal doxorubicin for cycles five and six. Eleven pts have been accrued to the study, eight of which have completed all six cycles and are evaluable. There have been 5 CRs and 3 PRs as determined by standard criteria. One pt who achieved a CR had the (4,14) translocation. Five out of the eight pts had the chromosome 13 deletion. Four of these five pts achieved a CR, three of whom have achieved a cytogenetic CR (standard cytogenetics and FISH). All pts were able to move on to autologous stem cell transplantation. Expected toxicities were seen with the high dose corticosteroids (fatigue, muscle weakness, insomnia, myalgias, hyperglycemia all grade 1–2). One pt required a dose reduction of the dexamethasone. Cytopenias were limited to grade 1 and 2 as was peripheral neuropathy. No further dose reductions were necessary. In conclusion, the DoVeD regimen is able to break the plateau typical of pts receiving standard induction therapy, inducing further cytoreduction. Our data suggest that pts with chromosome 13 deletion, in particular, may benefit from bortezomib as part of their up-front induction therapy. Though further study of this approach is warranted, the evidence suggests a possible paradigm shift for induction therapy in general. Non cross-resistant agents given in tandem can increase the percentage of patients achieving CR.