Characterization of NDMM patients treated with daratumumab, lenalidomide, bortezomib and dexamethasone who fail to achieve a VGPR or have early progression Free

In patients with newly diagnosed multiple myeloma (NDMM) four drug induction therapy is associated with improved outcomes with high rates of undetectable MRD, improved PFS and predicted overall survival of over 90% at four years. Risk factors for early mortality include a failure to achieve a deep response with induction therapy, cytogenetic risk status and early progression. Recent data from the MIDAS trial, which used quadruplet induction regimen, showed that patients with t(11;14) are less likely to achieve MRD negativity than other standard risk patients. We evaluated patients who failed to achieve a VGPR with induction therapy and/or those who progressed early to identify factor associated with decreased overall survival (OS).

We combined two independent data sets for this evaluation. We used the Emory Myeloma Database and the Database of the Department of Clinical Therapeutics in Athens, Greece, totaling 462 patients. Both datasets were collected under IRB approved protocols. All patients were treated with induction therapy with a combination of daratumumab, lenalidomide, bortezomib and dexamethasone (DRVD). Patients could be treated with or without transplant and maintenance per patient and investigator discretion. We independently identified patients who failed to achieve a VGPR with induction and/or had progression. Analysis was performed using SPSS v29.0 Chicago, IL. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. The median PFS and OS follow-up for the cohort was 44.5 and 33.6 months.

We identified 112 (24.2%) patients who met the outlined criteria. The estimated OS for these patients was 65% at four years, confirming the increased risk of early mortality for this patient population. The factors that were associated with a ‘failure to achieve a VGPR’ were the presence of t(11;14) (yes vs no 35.9% vs 64.1%, p<0.021) and del13q (yes vs no 26.7 % vs 73.3%, p<0.015). In this group the baseline hemoglobin, calcium, creatinine, LDH, β2microglobulin, age, sex, risk stage or the presence of del17p, t(4;14) or t(14;16) were not associated with a failure to achieve a VPGR. The estimated median PFS was 31.2 months. The presence of del17p (yes vs no 18.96 vs 35.19 m, p=0.03), ISS (III vs I: 19.41 vs 41.1 m, p<0.014) and transplant (no vs yes: 6.89 vs 38.99 m, p<0.001), maintenance therapy (no vs yes:11 vs 37.79 m, p=0.004) were associated with decreased PFS. The presence of del17p (yes vs no 41.33 m vs NR m, p<0.001, transplant (no or yes: 34.5 m vs NR, p<0.001)), and ‘failure to achieve a VGPR’ post transplant (yes: 42.2 m vs. NR, p=0.065) were all associated with a decreased OS. The presence of t(11;14) or del13q, while associated with failure to achieve a VGPR, were not associated with a decreased PFS or OS in this cohort.

In patients with NDMM, a subset of patients treated with DRVD fail to achieve a VGPR and/or have early progression which are associated with a decrease in OS. We have identified the presence of t(11;14) and del13q as two factors associated with failure to achieve a VGPR. Within this group of functionally high risk patients, the failure to have a deep response did not have a further impact on PFS or OS. Whereas the presence of del17p, higher ISS stage and failure to achieve a VGPR post-transplant are all associated with an additional decrease in survival. This data supports differential treatment approaches based on specific clinical and cytogenetic characteristics in patients who fail to achieve a VGPR with quadruplet induction therapy.