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1928 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.

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Translational Research, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Yael C Cohen1,2*, Moshe E Gatt3, Efrat Luttwak, MD4*, Noa Lavi, MD5*, Chezi Ganzel6*, Evgeni Chubar, MD7*, Ory Rouvio, MD8*, Iuliana Vaxman, MD, BA9,10*, Oren Pasvolsky, MD10*, Mouna Ballan11*, Tamar Tadmor, MD12*, Anatoly Nemets, MD13*, Osnat Jarchowsky14*, Olga Shvetz, MD15*, Ofer Shpilberg, MD, MPH16*, Najib Dally, MD17*, Merav Leiba, MD18*, Assaf Weiner, PhD19*, Mor Zada, MSc20*, Shuang-Yin Wang21*, Chamutal Gur22*, Noa Lowenton-Spier4*, Liron Goor-Porges4*, Ido Amit, PhD19* and Irit Avivi, MD23*

1Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2Tel Aviv Sourasky (Ichilov) Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Department of Hematology, Hadassah Medical Center and Faculty of Medicine, Hebrew University, Jerusalem, Israel
4Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
5Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
6Shaare Zedek Medical Center, Jerusalem, Israel
7Head, Blood Bank, HaEmek Medical Center, Afula, Israel
8Soroka Medical center, Be'er She'va, Israel
9Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
10Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
11hematology, Carmel Medical Center, Haifa, Israel
12Bnai Zion Medical Center, Haifa, Israel
13Barzilai Medical Center, Ashkelon, Israel
14Hematology Department, Meir Medical Center, Kfar Saba, ISR
15Hematology, Kaplan Medical Center, affiliated with Hadassah and Hebrew University Medical School, Rehovot, Israel
16Institute of Hematology/Clinic of Histiocytic Neoplasms, Assuta Medical Centers, Tel-Aviv, Israel
17Ziv Medical Center, Institute of hematology and blood bank, Safed, Israel
18Assuta University Hospital, Faculty of Health Science, Ben-Gurion University of the Negev, Ashdod, Israel
19Weizmann Institute of Science, Rehovot, Israel
20Weizmann Institute of Science, Tel Aviv, Israel
21Wetzmann Institute of Science, Rehovot, Israel
22The Hebrew University Jerusalem, Jerusalem, ISR
23BMT Unit, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel


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.


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).


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).


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.

Disclosures: Cohen: Medison: Honoraria; GSK: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Neopharm: Honoraria. Tadmor: Janssen: Research Funding; AbbVie, Roche, Novartis, Sanofi, Takeda, Janssen, Pfizer: Consultancy, Honoraria, Speakers Bureau. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau.

*signifies non-member of ASH