P21 effectiveness and safety of delayed bortezomib, thalidomide and dexamethasone (vtd) regimen

Bortezomib, thalidomide, and dexamethasone (VTD) plus autologous stem cell transplantation has been the standard treatment in Europe for transplant-eligible (TE) patients (pt) with newly diagnosed multiple myeloma (NDMM) until monoclonal antibody daratumumab has been added. Approval of the triplet comes from GIMEMA-MMY-3006 clinical trials (four 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide 100 mg daily; dexamethasone 40 mg days 1 -4 and 9-12). However, some pt discontinue VTD because of severe adverse events (AE), despite its efficacy. In this real-life survey, we retrospectively evaluated the effectiveness and side effects of a delayed VTD regimen (dVTD) compared to standard VTD (sVTD) in TE NDMM patients. 74 pt were treated between 08/08/2016 and 31/07/2022 with VTD schema. sVTD was administered to 31 pt as in the trial (bortezomib on days 1-4-8-11). dVTD was administered to 43 pt with bortezomib on days 1, 8, 15 and 22 of 28-days cycles. Pt’ clinical characteristics are described in Table 1. In the sVTD group, 5 patients (16%) had one or more G3/G4 AE: among them 1 thrombocytopenia, 3 neutropenia and none G3/4 non-hematological AE. Hematological AE occurred in 50% of pt (N=15), and were anemia, thrombocytopenia and neutropenia. Six pt had G2/3 neutropenia (19.5%) resolved with granulocyte growth factors (GCSF). All cases of anemia were G1. One pt with thrombocytopenia needed transfusion. The rate of infections was 10% (N= 3) and included one case of G2 upper respiratory tract infection and two cases of G1 cystitis, resolved with antibiotic therapy. Peripheral neuropathy occurred in 10% of pt (N=3, 2 G1 cases and 1 G2) and skin changes (G1) in one case. In the dVTD group there were no G3/G4 AE. Hematological AE occurred in 9 pt (21%, G1-2). Anemia was found in 4 pt (9%, G2 only in one case, 2 cases treated with erythropoietin). Neutropenia occurred in 4 pt (9%), G2 only in one case treated with GCSF. G1 thrombocytopenia occurred in one pt (2,4%), peripheral neuropathy in 5 pt (12%), cutaneous rush in 4 pt (9%). None of pt belonging to dVTD or sVTD group had to discontinue treatment for toxicities. In sVTD group the responses after induction therapy were CR in 7 pt, VGPR in 16 pt, PR in 5 pt, PD in 3 pt with improvement after transplantation with 13 pt in CR, 10 pt in VGPR (Table 2). During follow up 12 pt progressed and underwent a second line treatment and 3 pt died for PD. In dVTD group the responses after induction therapy were CR in 6 pt, VGPR in 17 pt, PR in 17 pt, MR in 2 pt. After transplantation: 16 pt in CR, 18 pt in VGPR, 4 pt in PR, 1 pt in SD and 1 in PD. During follow up 14 pt progressed and underwent a second line treatment and 5 pt died for PD. Median PFS was 81 months in sVTD group ando not reached in dVTD (p=0.496). Median overall survival was 66 months for dVTD group and not reached for sVTD group (p=0.186). The current standard of care for NDMM pt is the combination of daratumumab with VTD. The schedule includes bortezomib on days 1-4-8-11 However, this schedule represents a discomfort for the patient mostrly for accesses to the hospital twice a week. Our findings suggest that delayed VTD is not inferior in safety and efficacy to standard VTD regimen. Using a delayed schema we achieved better patient compliance with a comparable toxicity profile, without worsening the efficacy and the survival curves. These data may support the use of the same schedule in combination with daratumumab. TABLE 1 - dVTd (43) sVTD (31) Age Median range male 41 - 70 43 - 72 Median range female 43-66 43-61 Gender Male, N (%) 22 (51%) 19 (61%) Female, N (%) 21 (49%) 12 (39%) Paraprotein (isotype) IgG-k 20 (46%) 9 (29%) IgG-L 9 (21%) 5 (16%) IgA-k 6 (14%) 2 (6.5%) IgA-L 1 (2%) 2 (6.5%) Macromolecular k 3 (7%) 7 (22.5%) Micromolecular lambda 3 (7%) 6 (19.5%) Others 2 (4%) 0 (0%) ISS stage at baseline I, N (%) 23 (53%) 5 (16%) II, N (%) 8 (19%) 15 (48.5%) III, N (%) 13 (30% 11 (35.5%) Cytogenetics risk High, N (%) 9 (21%) 6 (19.5%) Standard, N (%) 21 (49%) 20 (64.5%) Not Evaluable 13 (30%) 5 (16%) Creatinine clearance < 50 ml/min/m2 6 (14%) 9 (29%) >50 ml/min/m2 39 (86%) 22 (71%) Bone Lesions No one, N (%) 3 (7%) 8 (26%) More than 1, N (%) 40 (93%) 23 (74%) Extramedullary lesions Yes, N (%) 6 (14%) 6 (19.5%) No, N (%) 37 (86%) 25 (80.5%) Bone Marrow Involvement <60%, N (%) 28 (63%) 18 (58%) ≥60%, N (%) 8 (16%) 13 (42%) Missed, N (%) 7 (16%) 0 (0%) LDH Normal, N (%) 39 (90%) 27 (87%) Increased N (%) 4 (10%) 4 (13%)