Erythropoiesis-Stimulating Agents Do Not Adversely Affect Long-Term Outcomes Nor Increase the Risk of Thromboembolic Events in Multiple Myeloma Patients Treated in the Phase III VISTA Trial.
Authors: Richardson Paul , Schlag Rudolf , Khuageva Nuriet K , Dimopoulos Meletios A. , Shpilberg Ofer , Kropff Martin H , Delforge Michel , Petrucci Maria Teresa , Rossiev Victor A , Hou Jian , Robak Tadeusz , Mateos Maria-Victoria , Anderson Kenneth C. , Cakana Andrew , Liu Kevin , Deraedt William , van de Velde Helgi , San Miguel Jesus F. 
Published: April 2020

Abstract
Introduction: Treatment of myeloma-associated anemia (both disease and treatment induced) includes erythropoiesis-stimulating agents (ESA) and/or red-blood-cell transfusions (RBCT). Limited data from patient subsets in retrospective studies have suggested that ESA may have a detrimental effect on outcomes, including reduced time-to- progression (TTP) and overall survival (OS), in patients with multiple myeloma (MM). Furthermore, ESA may increase the risk of deep-vein thrombosis (DVT) and pulmonary embolism (PE), especially in patients receiving immunomodulatory-based regimens and/or anthracyclines with glucocorticoids. Since the impact of ESA use on long-term outcomes and thromboembolic events in MM has not been extensively evaluated, we conducted a sub-analysis of the prospective multi-center, randomized, phase III VISTA trial in frontline MM (San Miguel et al. Blood 2007), to assess the potential impact of ESA use on TTP, OS and rates of DVT/PE.
Methods: Patients were randomized to receive nine 6-week cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, and days 1, 8, 22, and 29, cycles 5–9) plus melphalan (9 mg/m2) and prednisone (60 mg/m2) administered on days 1–4 of each cycle (VMP; n=340) or melphalan–prednisone (MP; n=337) alone. No protocol-specified antithrombotic prophylaxis was required. Baseline characteristics, including age, sex and disease characteristics, were similar between ESA and non-ESA groups.
Results: Median Hb level at the time of ESA initiation was 9.75 g/dl in the VMP arm and 9.30 g/dl in the MP arm; consistent with current guidelines that ESA should not be initiated until Hb is &lt;10 g/dl. The incidence of treatment-emergent anemia (defined as Hb &lt; 8.0 g/dl) was lower in the VMP arm (23%) than the MP arm (33%), and fewer patients in the VMP versus MP arm were treated with ESA (30% vs 39%, respectively; erythropoietins 20% vs 24% and darbepoietin 11% vs 18%, respectively), or RBCT (26% vs 35%, respectively), potentially reflecting greater anti-myeloma activity with VMP. Median TTP was similar between patients who received ESA and those who did not in both treatment groups (Table). While one-year OS rates were similar, 2-year OS rates appeared higher for patients receiving ESA (Table). TE complications were low in both treatment arms and were not affected by ESA use (3% vs 2% for VMP, and 3% vs 1% for MP, for patients receiving or not receiving ESA, respectively).
Conclusions: Our post-hoc analysis from a large, well-controlled multicenter phase III trial in frontline MM shows that ESA use did not adversely impact long-term outcomes with VMP or MP, and may be associated with a survival benefit. Furthermore, ESA use did not appear to increase the risk of TE complications with VMP or MP. These data suggest that ESA can be safely administered with VMP/MP for the treatment of anemia in frontline MM patients. Prospective, randomized studies are needed to further investigate the relationship between ESA and RBCT use, other agents and long-term outcomes in MM patients.
Table. TTP and OS rates by ESA and RBCT use and per treatment
VMP (n=340) MP (n=337) + ESA (n=102) − ESA (n=238) + ESA (n=131) − ESA (n=206) NE=not evaluable TTP, months (95%CI) 19.9 (18.9, NE) NE (18.3, NE) 15.0 (13.5, 21.8) 17.5 (14.7, 19.0) 1-year survival rate % (95% CI) 92.0 (86.6, 97.3) 87.8 (83.5, 92.0) 82.6 (76.0, 89.2) 81.4 (75.9, 86.9) 2-year survival rate % (95% CI) 86.7 (77.9, 95.4) 80.8 (73.1, 88.4) 77.3 (68.5, 86.1) 65.4 (55.7, 75.2) + RBCT (n=87) − RBCT (n=253) + RBCT (n=117) − RBCT (n=220) TTP, months (95%CI) NE (24.0, NE) 21.7 (18.9, NE) 14.1 (10.8, 16.6) 18.0 (15.2, 20.0) 1-year survival rate % (95% CI) 80.9 (72.4, 89.3) 91.8 (88.4, 95.3) 71.0 (62.7, 79.4) 87.7 (83.2, 92.2) 2-year survival rate % (95% CI) 67.2 (50.4, 83.9) 88.3 (83.8, 92.8) 58.3 (47.4, 69.2) 76.1 (66.9, 85.3)