Relapsed/refractory patients

Phase I/II study of vorinostat-based quadruplet to treat RRMM patients

A significant improvement in the survival rates of patients with Multiple Myeloma (MM) has been observed in this era of novel agents. Nevertheless, in the long-term, a substantial number of patients become refractory to currently available therapies. In particular, new options are 

Vorinostat is an oral class I/II histone deacetylase inhibitor (HDACi), known to inhibit cancer cell growth and induce cell death, and is FDA approved for the treatment of a number of cancers. However, due to its synergy with bortezomib, and positive outcomes in MM patients with renal impairment it warrants further investigation in MM. To this end, Johannes M. Waldschmidt, from the Department of Haematology, Oncology and Stem Cell Transplantation, University of Freiburg, Germany, and colleagues, conducted a phase I/II trial to assess the maximum tolerated dose (MTD) of vorinostat (V) in a quadruplet regimen, combined with  bortezomib (B), doxorubicin (D), and dexamethasone (D) (VBDD) in relapsed and refractory (RR) MM patients. The results were published in Haematologica in April 2018.

Study design
  • Phase I:
    • Oral vorinostat at 100mg (DL0), 200mg (DL1), 300mg (DL2) on day (d) 1–4, 8–11 and 15–18 according to a standard 3+3 design in a 28d cycle
    • Subcutaneous (SC) bortezomib at 1.3mg/m² on d1, 8, and 15
    • Intravenous (IV) doxorubicin at 9mg/m² on d1 and 8
    • Oral dexamethasone at 40mg for cycle 1 and at 20mg weekly for cycles 2–6
  • Enrollment to the next dose level was allowed if ≤1/3 pts, or ≤2/6 pts experienced a dose-limiting toxicity (DLT) at a given dose level
  • Phase II: additional patients (pts) were treated once they reached the maximum dose of vorinostat
  • Pts continued VBDD for a total of 6 cycles
Patient characteristics:
  • N = 33 pts; relapsed = 23 pts and RR = 10 pts
  • Median age (years) = 62 (47–77)
  • Type of MM: IgG = 17 pts; IgA = 11 pts; Light chain only = 5 pts; light chain k vs ƛ = 20 vs 13 pts
  • International staging system (ISS): I = 4 pts; II = 28 pts
  • Cytogenetics (CG): High-risk* = 6 pts; unfavorable =17 pts, favorable CG = 16 pts
  • Prior therapy: autologous stem cell transplant (ASCT) = 30 pts; bortezomib = 29 pts; IMiDs = 14 pts

(High-risk = t(4;14), del 17p; Unfavorable =  del(17p13), t(4;14), t(14;16); t(14;20), c-myc overexpression/translocation   and chromosome 1 aberrations; favorable = t(11;14), hyperdiploidy, isolated del13q14, normal karyotype)

Key Findings:
  • ≥ 1 VBDD cycle for all pts; six VBDD cycles = 67% of pts
  • Median follow-up = 30.8 months
  • Maintenance with: VD = 8 pts; VTD = 4 pts
  • Median progression free survival (PFS) = 9.6 months
  • Median overall survival (OS) = 33.8 months
  • Best response for all pts:
    • CR = 1 pt; very good partial response (VGPR) = 7 pts and partial response (PR) = 14 pts
    • Stable disease (SD) = 9 pts; progressive disease (PD) = 2 pts
  • Response in bortezomib-refractory pts (n = 7): PR = 2 pts; minimal response (MR) = 1 pt; SD = 2 pts and PD = 1 pt
  • Vorinostat-based therapy revealed a dose-response relationship: ORR (DL0 vs DL1 vs DL2) = 33% vs 66% vs 70%
  • ORR in CG-subgroups (HR vs unfavorable vs favorable) = 50% vs 47% vs 88%
  • Two-thirds of pts had lower paraprotein level and decreased serum-free light chain levels at the end of treatment
  • Decrease in relative HDAC activity observed in samples from 11/16 pts
  • Decrease in bone marrow plasma cells (BMPCs) and BM-HDAC6-IHC-expression level during therapy (the latter showed better renal function, CG and lower BMPCs in comparison to non-responders)
  • No of deaths = 17 pts (non-VBDD related)
  • Most common grade 3 adverse events (AE): anemia (24%), thrombocytopenia (12%), infections (18%), sepsis (9%)
  • Grade 4 AEs: anemia (3%), thrombocytopenia (12%) and leukopenia (3%)

This study is the first to define a vorinostat-based quadruplet (VBDD) for the treatment of MM, indicating tolerability and efficacy in RRMM patients. Both quality of life and response improved in RRMM patients when treated with VBDD. The cost-effectiveness of VBDD in comparison with daratumumab-conatining regimens may make this an attractive option for late stage disease.

References
  1. Waldschmidt JM. et al. Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma). Haematologica. April 2018. DOI: 10.3324/haematol.2018.189969
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