Fixed Duration Combination Therapy with Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Maintenance Leads to High Rates of Sustained MRD Negativity in Patients with High-Risk Smoldering Multiple Myeloma: Long Term Follow up of an Investigator Initiated Phase 2 Trial

Background: Patients with high-risk smoldering multiple myeloma (HR-SMM) have a 5-year risk of progression to symptomatic multiple myeloma of approximately 75% and a median time to progression of less than 2 years (Lakshman et al., Blood Cancer J 2018) (Rajkumar et al., Blood 2015). We previously reported the primary results of our phase 2 trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance (KRd-R) as prevention of symptomatic multiple myeloma in patients with HR-SMM (Kazandjian et al., JAMA Onc 2021). Herein, we present follow-up data after all patients have completed lenalidomide maintenance to evaluate the durability of responses off therapy.

Methods: Patients with HR-SMM based on the Mayo Clinic, PETHEMA, and/or Rajkumar, Mateos, and Landgren criteria were eligible for enrollment in this single-center phase 2 investigator-initiated study. Patients received eight 28-day cycles (induction) of carfilzomib, 20/36 mg/m ², with dexamethasone 20/10 (days 1,2, 8, 9, 15, 16) and lenalidomide 25 mg (days 1-21), followed by 2 years of maintenance therapy with lenalidomide 10 mg (days 1-21). The primary endpoint was the rate of minimum residual disease negative complete responses (MRD negative CR) at the end of induction as assessed by multicolor flow cytometry (MRD sensitivity 10 ^-5). Secondary objectives included progression to overt clinical multiple myeloma (end-organ damage or myeloma-defining event) or death (clinical PFS) and biochemical progression (PD) by IMWG criteria (biochemical PFS).

Results: A total of54 patients were enrolled and started treatment between May 29, 2012 and July 23, 2020. Full patient demographics and baseline disease characteristics were previously reported. (Kazandjian et al., JAMA Onc 2021) At the data cut-off of July 17, 2023, the median follow-up time was 60.2 months (range: 33.7 - 127.8). As previously reported, 38 patients (70.4%) achieved MRD negative CR by the end of induction. The median duration of MRD negative CR was 57.4 months (95% CI: 44.6 - 97.2). To date, durability of MRD negative CR has been observed up to 120.6 months and 21 patients (39%) have remained MRD negative for over 2 years (95% CI: 25.9 - 53.1%). (Figure 1) All patients attained a PR or better and the median duration of response has still not been reached. At 60 months, 75.1% of patients maintained their response (95% CI: 59.9 - 85.2%). The median clinical PFS has also not been reached. Only 5 out of 54 (9.3%; 95% CI: 3.1-20.3%) patients have progressed to clinical multiple myeloma. At 60 months, 92.7% of patients were free from clinical progression (95% CI: 78.1 - 97.9%). The probability of being free of clinical progression at 100 months was 78.9% (95% CI: 51.9 - 91.8%). While the median biochemical PFS has not been reached, patients who were MRD negative by the end of induction had significantly less risk of having biochemical progression compared to patients who still had measurable disease at completion of induction (median biochemical PFS NR vs. 41.8 (HR 0.168 (95% CI: 0.060 - 0.474) (P value < 0.0001) (Figure 2). As previously reported, KRd-R was well tolerated, with no grade 4 non-hematologic adverse events and manageable low-grade toxicities.

Discussion: Treatment of patients with HR-SMM with KRd-R has led to deep and durable remissions. At a median of 5 years of follow-up, this trial has yet to reach a median clinical PFS, indicating success in preventing serious end organ damage. However, it is still unclear if the beneficial outcomes seen in HR-SMM interventional studies are due to treatment of more susceptible disease or inherently less aggressive disease. An abstract evaluating the genomic profile of patients from this trial has been submitted to the meeting separately. Future prospective trials must capture and eventually select HR profiles based on validated genomic signatures. This study suggests that patients who achieve MRD negative remissions after induction therapy have prolonged biochemical PFS. However, further follow-up time is needed to fully understand the rates of clinical PFS and OS. To evaluate if additional treatment duration to achieve MRD negativity would be beneficial we have designed a trial using daratumumab, carfilzomib, and dexamethasone utilizing an adaptive treatment duration based on MRD status for patients with HR-SMM which is currently enrolling participants (NCT04933539).