Paper Details

ABSTRACT

Introduction

High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to symptomatic multiple myeloma (MM). Several therapeutic trials have shown benefit of early intervention in HR-SMM, and the majority used progression to active MM as the primary end point based on the 2014 IMWG revised diagnostic criteria for MM. Biochemical progression (BPD) is an established end point in MM clinical trials as a predictor of end organ damage but the significance of BPD in HR-SMM is unknown. It is critical to understand the role of BPD in HR-SMM, as patients enrolled in studies do not want to wait until end organ damage prior to change in management strategy.

Methods

We pooled individual-level data from 372 patients enrolled across 9 HR-SMM trials. BPD is defined per the IMWG uniform response criteria as progressive disease based on a ≥25% increase from nadir in any of the following: serum M-protein, with an absolute increase of ≥0.5 g/dL; the difference between involved and uninvolved serum free light chains (dFLC), with an absolute increase of ≥100 mg/L; or bone marrow plasma-cell percentage, with an absolute increase of ≥10 percentage points.

The primary analysis cohort comprised 208 patients from 6 Dana-Farber Cancer Institute (DFCI) phase II clinical trials evaluating combination therapies with elotuzumab-lenalidomide and dexamethasone (Rd), nivolumab-Rd, ixazomib-Rd, daratumumab-bortezomib-Rd, Rd, and teclistamab. External validation data were obtained from 164 patients enrolled across three clinical trials: QuiRedex (Rd), GEM-CESAR (carfilzomib, lenalidomide and dexamethasone (KRD) with autologous stem cell transplantation), and Bethesda/NIH study of KRD.

Post-BPD progression-free survival (PFS) was defined as the interval from BPD to progression to MM based on 2014 IMWG revised diagnostic criteria or death from any cause. Patients without an event were censored at the earlier of last follow-up or enrollment in a subsequent clinical trial. PFS was estimated using the Kaplan–Meier method. Prespecified high-risk SMM subgroups were defined by any of the following: (1) Mayo/IMWG 20/2/20 model, (2) IMWG risk score (score >12), (3) PANGEA model, or (4) the Consensus Genomic Staging (CGS). We also evaluated the timing of BPD relative to therapy and its association with development of MM.

Results

Median age was 61 years (range 30-86); 53% were male, and 4% had light-chain only disease. HR-SMM was identified in 56% by the Mayo/IMWG 20/2/20 model, 16% by IMWG risk score, 22% by CGS, and 17% by PANGEA. Median follow-up was 3.2 years (IQR: 2.0–5.2) for the DFCI cohort and 4.9 years (IQR: 2.6–7.8) for all trials.

Among the DFCI cohort, 91 patients (44%) developed BPD at a median of 4.24 years from start of trial therapy. Median time from Cycle 1 Day 1 to progression to MM or death was 10.12 years. After achieving BPD, median time to MM or death was 5.18 years.

We then compared HR-SMM, as defined by the above current criteria, to the non-HR-SMM patients who were enrolled on these trials based on previously established high-risk criteria. Following BPD, median PFS was 2.26 versus 5.18 years for Mayo/IMWG 20/2/20 high-risk versus non-high-risk (n=43 vs 48, p=0.077); 1.03 years versus 8.85 years for IMWG risk score high-risk versus non-high-risk (n=18 vs 71, p=0.005); 1.91 years versus 8.85 years for PANGEA high-risk versus non-high-risk (n=15 vs 76, p=0.017); 1.95 versus 8.85 years for CGS high-risk versus standard-risk (n=25 vs 64, p<0.001). The timing of BPD relative to treatment was also associated with post-BPD outcomes. Median PFS was 1.91 years when BPD developed during treatment (n=19), 3.27 years when it developed within 6 months from the last treatment dose (n=19), and 5.18 years when it developed >6 months after the last dose (n=53) (p=0.003).

Findings remained consistent when pooling in the QuiRedex, GEM-CESAR, and Bethesda/NIH trials (167 patients with BPD, 62 events; median PFS 3.84 years), with a median PFS of 3.2 years for Mayo/IMWG 20/2/20 high, 1.91 years for IMWG risk score high, 2.26 years for CGS high, and 2.26 years for BPD on treatment.

Conclusions

In previously treated SMM patients, BPD in a high-risk population by Mayo/IMWG 20/2/20, IMWG risk score, PANGEA or CGS identifies patients at risk of developing MM within 2 years. This was also the case among patients who exhibited BPD while still on therapy. This supports the use of BPD as a primary or co-primary endpoint in future HR-SMM trials.