Comparison of Anti-CD38 Based Quadruplets As Induction Therapy for Newly Diagnosed Multiple Myeloma
Authors: Kastritis Efstathios , Fotiou Despina , Theodorakakou Foteini , Solia Irene , Spiliopoulou Vasiliki , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Kanellias Nikolaos , Roussou Maria , Migkou Magdalini , Eleutherakis-Papaiakovou Evangelos , Terpos Evangelos , Gavriatopoulou Maria , Dimopoulos Meletios 
Published: December 2024

Background: Quadruplets that contain anti-CD38 monoclonal antibodies have become the new standard of care in newly diagnosed multiple myeloma (NDMM). Daratumumab (or Isatuximab) with VRd or KRd have shown substantial responses rates in transplant eligible and ineligible patients and very high rates of undetectable MRD after induction and consolidation. However, the use of lenalidomide may be associated with some toxicities (such as rash, thrombotic complications, acute renal toxicity) necessitating discontinuation or may be considered as a less feasible option due to severe renal dysfunction requiring dose adjustments. For such selected cases, combinations of anti-CD38 with VCd (bortezomib, cyclophosphamide and dexamethasone) remain an option.
Aim: In the current analysis we aimed to compare the outcomes of patients that were treated with induction therapy with anti-CD38 plus VRd to patients treated with anti-CD38 plus VCd, to identify potential difference in outcomes.
Methods: The analysis included 156 consecutive NDMM patients treated in the Department of Clinical Therapeutics, Athens, Greece, of which 97 received Dara-VRd and 59 had Dara-VCd.
Results: The median age of the whole cohort was 60 years (range 32-89), 45% were females, 56% had IgG, 22% IgA and 20% light chain only MM, 36% had ISS-1, 30% ISS-2 and 33% ISS-3 disease, 23% had high risk (HR) cytogenetics, per R-ISS stage distribution was 23%, 58% and 19% for R-ISS-1, -2 and -3 and per R2-ISS the distribution was 17%, 31% 42% and 11% for R2-ISS-I, -II, -III and -IV respectively. Patients that were treated with Dara-VCd were older but the difference was not statistically significant (median 63 vs 60 years and 33% vs 26% were older than 65, p=0.361), however, Dara-VCd treated were more anemic (i.e hemoglobin was &lt;10 gr/dl in 54% vs 32%, p=0.006), had more often severe renal dysfunction with eGFR &lt;30 ml/min/1.73 m2 (51% vs 14%, p&lt;0.001), elevated LDH (35% vs 10%, p&lt;0.001), ISS-3 stage (63% vs 15.5%, p&lt;0.001) and R-ISS-3 stage (37.5% vs 6%, p&lt;0.001) disease. High risk (HR) cytogenetics were present in 22% and 25% respectively and distribution in R2-ISS was not significantly different (10%, 29% , 46% & 15% for Dara-VCd vs 22%, 32% 38% and 8% for Dara-VRd for stages I to IV respectively). At the end of induction, the best responses for Dara-VCd vs Dara-VRd was sCR/CR in 11.5% vs 18%, VGPR in 56% vs 62% and PR in 33% vs 16%, for a combined ≥VGPR rate of 66.5% vs 80% for Dara-VCd vs Dara-VRd (p=0.071). After adjusting for differences in baseline characteristics (eGFR, ISS-3, elevated LDH, anemia), Dara-VRd was associated with a higher probability of achieving CR/VGPR , but this was not statistically significant (OR: 2.1, 95% CI 0.78-5.6, p=0.143). Notably, the severity of baseline anemia was the most important variable associated with achievement of CR/VGPR after induction (OR: 0.32, 95%CI 0.13-0.8, p=0.015). HDM with ASCT as consolidation was used in 37% and 53% of the patients that received Dara-VCd and Dara-VRd induction respectively (p=0.127). The median follow-up of the whole cohort is 24 months; disease progression or death has occurred in 23 (15%) patients and 12 (8%) have died, all death were due to disease progression. Median PFS has not been reached for any of the two groups, but 3-year PFS is 70% for Dara-VCd and 84% for Dara-VRd treated patients, respectively (p=0.11). Adjusting for baseline differences, use of HDM-ASCT and use of maintenance, Dara-VRd was associated with longer PFS (HR: 0.467, 95% CI 0.14-0.86, p=0.01), along with use of maintenance and of HDM-ASCT. Median OS has not been reached for any of the two groups and the 3-year OS is 82% for Dara-VCd and 89% for Dara-VRd. Adjusting for baseline differences, use of HDM-ASCT and use of maintenance, Dara-VRd was associated with longer OS but this was not statistically different (p=0.098).
Conclusions: In conclusion, Dara-VRd is associated with higher rates of deeper responses (i.e CR & VGPR) after induction. Although the current analysis is underpowered and the follow up still relatively short, Dara-VRD seems to be associated with better short- and long-term outcomes. Nonetheless, anti-CD38 with VCD could be an option for special populations, such as those with severe renal dysfunction, or severe lenalidomide intolerance.