Low Intensity Daratumumab to Treat Rersistent/Recurrent Minimal Residual Disease in Multiple Myeloma

The disease course of most patients with multiple myeloma (MM) is still characterized by a repeating pattern of periods of remission and relapse as their cycle. Relapse is attributed primarily to minimal residual disease (MRD). At any stage in the disease evolution, achievement of MRD negativity will predict for a better outcome. Despite its incorporation into the IMWG response criteria, what has not been clearly defined, however, is what to do when MRD positivity beyond a threshold level is detected, particularly when MRD levels are positive but overt relapse is not yet recognized.

Daratumumab (DARA) targeting CD38 as an immunity therapy holds great promise. We referred to the pharmacokinetic data of smoldering myeloma from CENTAURUS study, and used the frequency of 16mg/kg DARA once every 4 weeks for early intervention in MM patients with persistent/recurrent MRD. We hypothesized that this therapy could be used to target and eliminate MRD to ultimately prolong progression-free survival in MM.

A total of 23 patients were included in this study between January 2022 and December 2022. All participants were DARA-naïve and had achieved partial remission (PR) and above effects after first-line therapy including bortezomib and lenalidomide. DARA treatment after enrollment was given until clinical overt disease progression (PD) or unacceptable toxicity. We used next-generation flow assay (10^-5) for subsequent regular BM aspirate MRD assessment.

Among the 13 persistent MRD patients, all have achieved varying degrees of remission (CR/sCR: 8 cases (61.5%), VGPR: 4 cases (30.8%), and PR: 1 case (7.7%)). According to the IMWG criteria, 5 cases (50%) were accompanied by an increase in M protein, but had not yet reached the level of progression/biochemical relapse among the 10 MRD recurrent patients. For the perspective of response rate, 78.3% (18/23) patients achieved MRD negativity. In the persistent and recurrent MRD groups, the MRD conversion rates was 84.6% (11/13) and 70% (7/10), respectively (P>0.05). According to cytogenetic grouping, the conversion rate was 90.9% (10/11) and 66.7% (8/12) in the standard-risk and high-risk group, respectively(P>0.05). There was 1 case of standard-risk, 2 cases of double-hit and 2 cases of triple-hit among the 5 remaining positive patients. In the DARA monotherapy group and the DARA combining previous treatment agents group, the MRD conversion rate was 70% (7/10) and 84.6% (11/13), respectively (P>0.05). There was no statistically significant difference in the MRD conversion rate, regardless of intervention methods, MRD status or risk stratification.

For the duration of negative MRD, until July 15, 2023, with a median follow-up of 12.3m [7.3-18.1m], the median duration of negative MRD in 18 reactive patients with negative MRD did not reach, superior to previous reports without additional intervention. In the persistent and recurrent MRD group, the percentage of MRD negativity lasting>12m is 81.8%(9/11) and 100%(7/7), respectively(P>0.05). Among the 2 patients who had once turned negative, progression occurred at the 9th and 12th month after DARA intervene, respectively. The percentage of MRD negativity lasting>12m is 100%（10/10）and 75%(6/8) in the standard-risk and high-risk group respectively(P>0.05). During the follow-up period, all the 4 patients who ultimately experienced PD were double hit high-risk MM, and there were no cases of PD in the standard-risk group.

According to the NCI-CTCAE version 5.0, the rate of adverse events was low, similar to CASSIOPEIA trial. There were 2 cases of infusion reactions grade 1 during the first infusion. DARA dose delay occurred in 2 patients (1 due to severe COVID-19 pneumonia, and 1 due to hepatitis B virus activation). The most common adverse reaction was decreased immunoglobulin levels in 82.6% (19/23) cases. The median IgG level was monitored at 4.7 (3.6-10.2) g/L with 13% (3/23) IgG≤4g/L. The forthcoming results from MRD driven therapy trials are highly anticipated.