Daratumumab Carfilzomib Lenalidomide Dexamethasone Provides Effective Salvage for Functionally and Cytogenetically High-Risk Myeloma Patients, Except Those Expressing Module-1 Transcriptional Signature: Extended Follow-up from Kydar Multicenter Clinical/Translational Trial.

Background

Myeloma patients (Pts) with resistance to a bortezomib-based induction therapy, either primary refractory or those relapsing early after completing induction, define a population of functional high-risk myeloma, shown to be associated with dismal prognosis. We designed a phase 2 clinical-translational trial to evaluate the safety and efficacy of a quadruple salvage regimen of carfilzomib (CFZ)/ lenalidomide (LEN)/dexamethasone (DEX) / daratumumab (DARA) (KRD-D) in myeloma Pts with functional high-risk (KyDaR, NCT04065789), and to identify molecular pathways of refractoriness based on transcriptional signatures associated with clinical resistance. Here we report final clinical data following 18-months (mo) study treatment and extended survival follow-up.

Methods

Forty-one newly diagnosed myeloma Pts treated with a bortezomib-containing induction regimen, who either: i) failed to achieve a minimal response after 2 cycles or a partial response (PR) after 4 cycles (cohort A), ii) had early relapse within 18 months from starting of therapy (cohort B) were enrolled to receive second line KRD-D treatment in eighteen 28-day (d) cycles (C) or until disease progression/unacceptable toxicity. CFZ: 56 mg/m² IV days 1,8,15 (C 1-9), d 1,15 (C 10-18). LEN: 25 mg (Frail: 15mg) d1-21; Dex 40mg (Frail: 20mg) weekly; DARA: IV 16mg/Kg weekly (C 1-2), q14d (C 3-6), q28d. After 18 cycles, Pts continued to receive DARA/LEN. We applied longitudinally our calibrated protocol for single cell RNA sequencing (scRNA-seq) of myeloma plasma cells (Ledergor et al, Nat Med 2018) to identify transcriptional signatures associate with response or resistance, defined as PR or better (IMWG criteria) after 3 cycles. Primary endpoints were safety and tolerability. Secondary endpoints included overall response rate (ORR); progression free survival (PFS), and overall survival (OS).

Results

Forty-one Pts enrolled across 14 medical centers in Israel between June 2018-August 2019, patients had highly aggressive MM characteristics: 67% had intermediate/high risk and 30.5% had double hit FISH abnormalities, 39% had extramedullary disease, and 38% were frail. High expression of module-1 scRNAseq transcriptional signature associated with therapy resistance as previously described (Cohen YC et al, Nat Med 2021) was detected in 36%. At end-of study data cut-off (12NOV2021) the median follow-up was 30.7 mo (95% CI 26-35.3), and the median number of CFZ cycles administered was 10 (range 1-18). Nineteen Pts completed 18-months of KRD-D therapy. Reasons for early therapy discontinuation (n=22) included: disease progression (12), adverse event (AE, 6), consent withdrawal (3) and physician decision (1). All Pts had at least 1 treatment emergent AE (TEAEs), most were grade 1-2; There were 35 patients with TEAE grade ≥3, 4 (9.8%) patients discontinued study therapy due to AEs. Grade ≥3 TEAEs occurring in ≥10% of Pts included neutropenia (34%), thrombocytopenia (24%), sepsis (22%), pneumonia (19%) and musculoskeletal pain (12%); 4 patients died due to TEAEs (1 myocardial infarction, 3 sepsis). Durable and deep responses were achieved. ORR was 90% (37/41): near CR-stringent CR 22% / very good partial response 42% / PR 27%. Median duration of response was 25.6 mo (95% CI 11.5-39.7). Median PFS and OS were 15.4 and 28.2 months, respectively; 18-month PFS and OS were 49% and 57%, respectively. In univariable analysis, cohort (A vs B), age (≤70 vs >70) and high-risk cytogenetics (yes vs no) yielded similar OS. Over-expression of module-1 was highly predictive of poor PFS (3.8 mo vs not reached [NR], p=0.000006 and OS (13.8 mo vs NR, p=0.0003) [Fig1A]. A factorial analysis of module-1 X double-hit FISH showed the dominance of the former in prediction of OS [Fig 1B]. Frail Pts (IMWG criteria) had a median OS of 25 mo [95% CI 8.0-41.4] vs NR in intermediate/Fit Pts (p=0.07).

Conclusions

A cohort of functionally high-risk MM Pts, based on their resistance to an upfront bortezomib-based induction, were effectively salvaged by second line KRD-D quadruple regimen, achieving an ORR of 90% and durable responses. High expression of module-1 transcriptional signature, as discovered by scRNA-seq analysis was present in 36% of these Pts, and identified an ultra-high-risk population in which KRD-D provided inferior survival. Such patients may be considered for early experimental interventions such as novel immune-therapeutics.