Bortezomib in Combination with Dexamethasone and Pegylated Liposomal Doxorubicin (DoVeD) Breaks Plateau Responses Following Initial Induction Therapy in Multiple Myeloma: Results of a Phase II Pilot Study.
Authors: Manco Megan C. , Mark Tomer , Jayabalan David S , Zafar Faiza , Pearse Roger , Crann Mary , Leonard John P. , Chen-Kiang Selina , Coleman Morton , Niesvizky Ruben 
Published: October 2019

Abstract
Abstract 2311
Poster Board II-288
Improved quality of response to induction therapy has been shown to be associated with improved long-term outcomes, including prolonged progression-free (PFS), event-free, and overall survival (OS), in newly diagnosed multiple myeloma (MM) patients (pts). Induction regimens incorporating the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have demonstrated high overall response rates (ORR), and substantial complete response (CR) and very good partial response (VGPR) rates in MM; however, while a large majority of pts respond, a proportion does not achieve ≥VGPR. Per the Norton–Simon hypothesis, the sequential, dose dense, use of agents or regimens that are not cross-resistant may improve the proportion of pts achieving CR or VGPR to induction therapy, and subsequently improve long-term outcomes. This phase II pilot study investigated the efficacy and safety of bortezomib + dexamethasone ± liposomal doxorubicin (DoVeD) in MM pts who had reached a response plateau (<25% change in M-protein level for three successive assessments) after achieving a partial response (PR) to initial induction with IMiD-containing therapy. All pts proceeded to high-dose therapy and stem cell transplantation. Pts received six 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, plus dexamethasone 40 mg on days 1–4, 8–11, and 15–18. Pts achieving <PR after two cycles or <CR after four cycles received liposomal doxorubicin 30 mg/m2 on day 4 for the remaining four or two cycles, respectively. Response to DoVeD was assessed relative to baseline prior to start of DoVeD therapy according to IMWG uniform response criteria. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 34 pts were enrolled; baseline demographics and disease characteristics are shown in the Table. Initial induction therapy comprised lenalidomide–dexamethasone in 22 pts, thalidomide–dexamethasone in 5 (followed by VAD in 1), thalidomide in 2, and thalidomide–lenalidomide–dexamethasone in 5. At data cut-off, 3 pts remained on DoVeD therapy and were not evaluated for response. The other 31 pts received a median of 6 cycles of DoVeD; liposomal doxorubicin was added in 22/31 (71%) pts, 11 after cycle 2 and 11 after cycle 4. Best responses to DoVeD were 5 (16%) stringent CR, 2 (6%) CR, 6 (19%) VGPR, and 12 (39%) PR, for a ≥VGPR rate of 42% and an ORR of 81%. Four (13%) pts achieved a minimal response, and 2 (6%) had disease progression. Median PFS was 1,210 days (95% CI: 387–1311) and 3-year PFS was 57% (95% CI: 27%–73%). Four pts died during the follow-up period. Median survival was not reached; 4-year OS was 83% (95% CI: 60%–94%). A Cox proportional hazards model controlling for age, sex, and ISS showed that only a ≥90% reduction in M-protein significantly correlated with reduction in disease progression (p=0.014). Among 33 pts who had completed one cycle of DoVeD and were thus evaluable for safety, all experienced at least one AE, including 23 (70%) who experienced at least one grade 3/4 AE. Hematologic grade 3/4 AEs during DoVeD therapy included 9/3% neutropenia and 9% grade 4 thrombocytopenia; non-hematologic AEs included fatigue, pneumonia, infection (9% each), diarrhea, constipation, irritability, hypotension (6% each), hand–foot syndrome, chest pain, and myopathy (3% each). In total, 23 (70%) pts experienced peripheral neuropathy, including 9 (27%) grade 2 and 3 (9%) grade 3 (no grade 4 PN). In conclusion, DoVeD therapy can result in further substantial reductions in tumor burden, including additional CRs and VGPRs, in MM pts whose response has reached a plateau following PR with prior IMiD-containing induction. The additional cytoreduction and increase in CR/VGPR rates achieved with this tandem approach, plus the potential associated improvement in long-term outcomes, suggest a possible paradigm shift for MM induction therapy in general.
Table Patient baseline demographics and disease characteristics Characteristic* N=34 Age, years 60.5 (27-76) Male, n (%) 19 (56) B2-microglobulin, mg/L 2.1 (1.0-10.2) Albumin, g/dL 3.5 (2.0-4.3) Durie-Salmon Stage Ia / IIa / IIIa / IIIb, n 2 / 14 / 17 / 1 ISS Stage I / II / III, n 16 / 15 / 3 Abnormalities by FISH, n (%) del 13q14 13 (38) Trisomy 11 6 (18) Hyperdiploidy 5 (15) t(4;14) 4 (12) p53 3 (9) t(11;14) 2 (6) t(14;16) 2 (6) None 16 (47) * Median (range) shown unless stated

Disclosures:
Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Crann:Milllennium: Membership on an entity's Board of Directors or advisory committees. Leonard:Milllennium: Consultancy; Johnson & Johnson: Consultancy. Coleman:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau; Immunomedics: Membership on an entity's Board of Directors or advisory committees. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.