Hyperfractionated cyclophosphamide, bortezomib and dexamethasone for initial treatment of newly diagnosed multiple myeloma with renal dysfunction Free

Renal injury due to light chain cast nephropathy is a defining feature of multiple myeloma. A prospective study previously noted no added benefit of bolus cyclophosphamide in combination with bortezomib and dexamethasone in yielding improved renal response rates when compared with bortezomib and dexamethasone alone (Bridoux et al, JCO 2020). Herein, we investigate the efficacy of low dose, hyperfractionated cyclophosphamide in addition to twice weekly bortezomib and dexamethasone with respect to renal and myeloma response in patients presenting with a new diagnosis of multiple myeloma with renal dysfunction.

In this retrospective study, patients were treated with either (1) weekly bortezomib, cyclophosphamide and dexamethasone (CyBorD), (2) hyperfractionated CyBorD regimen (iCyBorD) (cyclophosphamide 250mg/m² every 12 hours for 4 doses, bortezomib 1.3 mg/m2 days 1, 4, 8, 11, dexamethasone 20 or 40 mg day 1-4, 8-11), (3) daratumumab based treatment (dara-based) or (4) other combination treatments (other) with imids, proteasome inhibitors and steroids. All patients receiving iCyBorD proceeded to standard imid based therapies after cycle 1. Primary endpoint was renal response.

Sixty-eight patients were identified. Twelve patients each were treated with iCyBorD, CyBorD and dara-based treatments. Thirty-two patients received a variety of other treatments including combinations of lenalidomide, bortezomib, carfilzomib, dexamethasone, and liposomal doxorubicin.

Overall renal response (ORR) rates of 92% with iCyBorD (n=11) were superior to responses with dara- based and other treatments at 42% (n=5) and 44% (n=14), respectively (p= 0.0272; p=0.0049). CyBorD resulted in 75% (n=9) ORR rate (p=0.5901).

iCyBorD resulted in a faster time to initial renal response at a median of 11 vs 64 days with dara-based treatments (p=0.0411). Time to initial renal response was similar when compared with other treatments and CyBorD at a median of 37 and 38 days, respectively. Time to best renal response was comparable at a median of 26, 64, 37, and 44 days with iCyBorD, Dara-based, other treatments and CyBorD, respectively (p=0.1628). After 1 cycle, eGFR improvement with iCyBorD was 162% as compared with 19% with dara-based (p= 0.0047), 19% with other treatments (p=0.0007) and 46% with CyBorD (p=0.1036).

Time to initial myeloma response was in those treated with iCyBorD was 9 days vs dara-based (19 days) (p=0.3522), other treatments (25 days) (p=0.0943), and CyBorD (27 days) (p=0.0008). Time to best myeloma response was comparable amongst all groups at a median of 66, 45, 83, and 85 days with iCyBorD, dara-based, other treatments, and CyBorD, respectively (p=0.2090).

Time to reduction in free light chains (FLC) by half from start of treatment was superior in patients treated with iCyBorD at a median of 9 days as compared with other treatments at 28 days (p-value: 0.0051) and CyBorD at 27 days (p= 0.0376). Time to half reduction in FLC with dara-based treatments was 14 days (p= 0.3433). Time to treatment initiation from date of diagnosis was noted to be 2, 33, 28 and 6 days for iCyBorD, dara-based, other treatments and CyBorD, respectively. Time to initiation of treatment with iCyBorD vs dara-based or other treatments was significantly shorter (p= 0.0002 and 0.0013, respectively).

Amongst those treated with iCyBorD, grade 3 events occurred in 5 (42%) patients with neutropenia, and 1 (8%) each with thrombocytopenia and a gastric ulcer. iCyBorD administration was not associated with any neutropenic infections. With dara-based regimens, 2 (17%) patients developed grade 3 neutropenia and 1 (8%) lung infection. In those receiving other combination regimens, 3 (9%) grade 3 neutropenia, 1 (3%) grade 3 thrombocytopenia events were noted. Among CyBorD patients: 1(8%) patient each developed grade 3 neuropathy, and pancreatitis.

In the setting of renal dysfunction attributed to cast nephropathy, a strategy of initial treatment with iCyBorD and subsequent transition to standard of care combination treatment with -imids and anti-CD38 monoclonal antibodies may facilitate superior overall renal response rates through rapid disease control. This regimen may present an efficacious alternative in the setting of possible treatment delays or inability to administer combination treatment with -imids and anti-CD38 monoclonal antibodies.