Upfront 28-Day Metronomic Therapy for High-Risk Multiple Myeloma (HRMM)
Authors: Thanendrarajan Sharmilan , Alapat Daisy V. , Zangari Maurizio , Schinke Carolina , Heuck Christoph , van Rhee Frits , Rosenthal Adam , Epstein Joshua , Yaccoby Shmuel , Davies Faith E , Morgan Gareth J , Barlogie Bart 
Published: October 2019

Abstract
Introduction: Despite major advances in MM therapy with the inclusion of novel agent combinations for induction prior to and after autotransplant-supported high-dose melphalan, the 15% of patients with GEP-defined HRMM continue to fare poorly with PFS and OS not exceeding 2 and 3 years, respectively. This poor outcome has not been improved with less dose-intense and more dose-dense Total Therapy 5. Having previously reported on 16-day metronomic therapy with low-dose doxorubicin (DOX) and cisplatin (DDP) plus VTD (Papanikolaou, Haematologica), we explored further extension of such metronomic treatment to 28 days (metro-28) also in newly diagnosed HRMM patients.
Patients and Methods: All patients signed a written informed consent and data analysis was approved by our IRB. In the outpatient setting, a single cycle of metro-28 comprised DOX and DDP each at 1.0mg/m2/d for 28d by continuous infusion (CI), along with VTD (bortezomib 1.0mg/m2 on days 1-4, 7-10, 13-16, 19-22, 25-28; DEX 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 50-100mg/d x 28d; some patients also received vincristine [VCR] at a flat daily dose of 0.07mg/d x 28d by CI.
Results: Fourteen patients were initiated on metro-28. Their characteristics included age >=65y in 12; albumin <3.5g/dL in 8; B2M >5.5mg/L in 7; cytogenetic abnormalities [CA] were present in 10; GEP70 HRMM in 9/13; PR subgroup in 8/13 (Table 1). The median follow up is 11mo. As portrayed in Figure 1A, no patient has died; the 6mo PFS estimate was 85% (Figure 1B); responses included CR in 3/14, VGPR in 7/14 and PR in 10/14 (Figure 1C); and the PR duration estimate at 6mo is 80% (Figure 1D). Of interest, GEP70 scores morphed to low risk in 3/13. Vascular density (CD34) decreased markedly in most patients evaluated. Toxicities were minor; myelosuppression was virtually absent; alopecia was not encountered. Subsequent salvage therapies included repeat metro-28, combination chemotherapy (PACMED) and autotransplants.
Conclusion: We conclude that metro-28 is a promising and safe strategy for elderly patients with HRMM, and we hypothesize an anti-angiogenic mechanism of action in addition to direct anti-MM effects.
Table 1. Patient characteristics Factor n/N (%) Age >= 65 yr 12/14 (86%) Albumin < 3.5 g/dL 8/14 (57%) B2M >= 3.5 mg/L 9/12 (75%) B2M > 5.5 mg/L 7/12 (58%) Hb < 10 g/dL 10/14 (71%) Cytogenetic Abnormalities 10/14 (71%) CA within 1 Year of Therapy 10/14 (71%) CA within 90 Days of Therapy 9/14 (64%) GEP 70-Gene High Risk 9/13 (69%) GEP PR Subgroup 8/13 (62%) GEP Proliferation Index >= 10 7/13 (54%) GEP Centrosome Index >= 3 7/13 (54%) n/N (%): n- Number with factor, N- Number with valid data for factor
Figure 1. Figure 1.

Disclosures
Thanendrarajan: University of Arkansas for Medical Sciences: Employment. Alapat:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Onyx: Research Funding; Millennium: Research Funding; Novartis: Research Funding. Schinke:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Foundation Medicine: Honoraria; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Rosenthal:Cancer Research and Biostatistics: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Davies:Janssen: Consultancy; Onyx: Consultancy; University of Arkansas for Medical Sciences: Employment; Millenium: Consultancy; Celgene: Consultancy. Morgan:MMRF: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment.