Sonrotoclax Plus Dexamethasone Is Tolerable and Demonstrates Antimyeloma Activity in Patients
With Relapsed/Refractory Multiple Myeloma Harboring t(11;14)

P898

Binod Dhakal,1 Malin Hultcrantz,2 Susan Bal,3 Hun Chuah,4 Jonathan L. Kaufman,5 Dickran Kazandjian,6 Nitya Nathwani,7 Gordon Royle,8 Douglas W. Sborov,9 Christopher P. Venner,10 Huan Cheng,11 Adam Idoine,11 Amit Agarwal,11 Hang Quach12
Medical College of Wisconsin, Milwaukee, WI, USA; 2Memorial Sloan Kettering Cancer Centre, New York, NY, USA; 3University of Alabama at Birmingham, Birmingham, AL, USA; 4Royal Perth Hospital, Perth, WA, Australia; 5Emory University, Atlanta, GA, USA; 6University of Miami, Miami, FL, USA; 7City of Hope, Duarte, CA, USA; 8Middlemore Hospital, Auckland, New Zealand;
9Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA; 10BC Cancer Centre, Vancouver, BC, Canada; 11BeiGene USA, Inc, San Mateo, CA, USA; 12St Vincent's Health Australia, University of Melbourne, Melbourne, VIC, Australia
1••••••

first diagnosis, has high expression of B-cell lymphoma 2 (BCL2) and is a uniquedisease subset with distinct features1,2
BCL2 is an attractive therapeutic target in MM with t(11;14) because MM cells areBCL2 primed and have been particularly responsive to oral BCL2 inhibitors, suchas venetoclax, a first-generation BCL2 inhibitor2
Combining a BCL2 inhibitor with dexamethasone or a proteasome inhibitor (PI)can improve clinical outcomes compared with monotherapy2,3Although BCL2 inhibitors have shown clinical activity in patients with MM, noBCL2-targeted therapies are currently approved for MM2,4
Sonrotoclax (BGB-11417) is a more selective and a more pharmacologically potent
inhibitor of BCL2 than venetoclax, with a shorter half-life and no accumulation5
Previously presented data from the dose-escalation period of the BGB-11417-105(NCT04973605) study indicate sonrotoclax + dexamethasone was tolerable, with
no DLTs reported6
Updated safety and efficacy data are presented for patients treated with
640 mg sonrotoclax plus dexamethasone in the BGB-11417-105 study in patientswith t(11;14)-positive relapsed/refractory (R/R) MM

CharacteristicAge, median (range), years
Male sex, n (%)
ECOG PS
012R-ISS stage at initial diagnosis, n (%)
IIIIII
Unknown
Time from most recent R/R episode to first
dose, median (range), months
Cytogenic risk, n (%)
Higha
Not highUnknown
Prior therapy
No. of lines of prior systemic therapy,
median (range)
No. of prior lines of systemic therapy, n (%)
12≥3
Prior exposure
PIIMiD
Anti-CD38 antibody≥1 PI + ≥1 IMiD + ≥1 anti-CD38 antibody
Refractory status, n (%)
PIIMiD
Anti-CD38 antibody≥1 PI + ≥1 IMiD + ≥1 anti-CD38 antibody
Prior autologous transplant

METHODS• BGB-11417-105 is an ongoing, open-label, multicenter, phase 1b/2, dose-escalation•••

study of sonrotoclax as the backbone for different combination therapies,
including combination with dexamethasone or dexamethasone plus carfilzomib,
daratumumab, or pomalidomide in patients with R/R MM harboring t(11;14)(Figure 1)
Eligible patients have R/R MM with centrally confirmed t(11;14) and had received
a minimum of 3 (dose-finding cohort) or 1 (dose-expansion cohort) prior linesof therapy
Study objectives include safety, tolerability, recommended dose for expansion(RDFE, part 1), and the antitumor activity of sonrotoclax combination therapy inpatients with t(11;14)-positive R/R MM
Sonrotoclax was administered orally once daily in cohorts at escalating doses,and 40 mg dexamethasone was administered weekly;6 data at the sonrotoclax
RDFE (640 mg) are presented here

Figure 1. Study Design in Patients Harboring t(11;14) R/R MM
Part 1aPart 2b

Determination of RDFE for sonrotoclax + dexamethasone
Dose level 4:
640 mg
Dose level 3:
320 mg
Dose level 2:
160 mg
Dose level 1:
80 mg(Starting dose)

n=3

Sonrotoclax 640 mg +Dexamethasone 40 mg (N=32)
69 (48-80)
15 (46.9)

n=3
Sonrotoclax
RDFE

Cohort 2:
sonrotoclax (RDFE)+ dexamethasone (n=35)

n=3•Table 3. Most Common TEAEsa

5 (15.6)
17 (53.1)
4 (12.5)
6 (18.8)

Patients, n (%)

Sonrotoclax 640 mg +Dexamethasone 40 mg (N=32)

1.9 (0.4-93.8)
9 (28.1)
22 (68.8)
1 (3.1)3 (1-12)6 (18.8)
5 (15.6)
21 (65.6)
32 (100)32 (100)
23 (71.9)
23 (71.9)
18 (56.3)
23 (71.9)
18 (56.3)
15 (46.9)
20 (62.5)•Patients, n (%)
Any TEAEa
Grade ≥3Serious
Leading to death
TEAE leading to dose modification
Dose interruption
Sonrotoclax
Dexamethasone
Dose reduction
Sonrotoclax
Dexamethasone
Treatment discontinuation
Sonrotoclaxb
Dexamethasonec

RESULTS• As of March 25, 2024, a total of 32 patients were treated at the RDFE of 640 mg

Adverse events were graded per CTCAE v5.0. b n=1 each; hematuria, metastatic pancreatic cancer. c n=1 each; hematuria, metastatic pancreaticcancer, agitation.
a– No DLTs were observed during dose-escalation and low rates ofhematologic toxicities and infections continued to be observed duringdose-expansion• Sonrotoclax + dexamethasone combination treatment provided deep anddurable responses in this R/R population– Most patients achieved a positive response, with an ORR of 75%

Fatigue

9 (28.1)

2 (6.3)

Insomnia

9 (28.1)

1 (3.1)

Diarrhea

7 (21.9)0• The study is ongoing and other combination treatments with sonrotoclax are

Constipation

5 (15.6)

0Nausea

5 (15.6)0Abdominal distension

3 (9.4)0

Arthralgia

3 (9.4)0Decreased appetite

3 (9.4)0Dizziness

3 (9.4)0Dyspnea

3 (9.4)0

Gastroesophageal reflux disease

3 (9.4)0Headache

3 (9.4)0

Acute kidney injuryb

2 (6.3)2 (6.3)Retinal detachment

2 (6.3)2 (6.3)

TEAEs of any grade in ≥3 patients or grade ≥3 in ≥2 patients. b Neither acute kidney injury was considered related to sonrotoclax by the investigator (1 incontext of fatigue that was considered related to disease and 1 in context of urinary tract infection).
aTable 4. Hematologic and Infection TEAEs
Patients, n (%)
Any hematologic TEAE
Platelet count decreased

2 (6.3)

Neutrophil count decreased

1 (3.1)

Thrombocytopenia

1 (3.1)COVID-19

2 (6.3)Upper respiratory tract infection

2 (6.3)

Influenza

1 (3.1)

Lower respiratory tract infection

1 (3.1)

Pneumonia parainfluenza viral

1 (3.1)•ORRb
75%1004.2sCR

16.7

CR29.2

VGPR4025.0

PR2012.5

MR12.5SD80600Sonrotoclax 640 mg + dexamethasone 40 mg(n=24)
Responses were assessed by the investigator per the IMWG 2016 response criteria.7 b ORR was defined as best overall response of PR or better.
MR, minor response; sCR, stringent complete response; VGPR, very good partial response.

aFigure 3. Treatment Duration, First Response, and Improved Responsea

Sinusitis

1 (3.1)

Tooth infection

1 (3.1)

Urinary tract infection

1 (3.1)

Vascular device infection

1 (3.1)

Viral infection

1 (3.1)First sCR
First CRFirst VGPRFirst PRFirst MRFirst SDFirst PDOngoing treatment
Death012345678910 1112 13 14Months since first dose

151617181920Responses were assessed by the investigator per IMWG 2016 response criteria.7 Only changes to improved response or PD are shown per IMWG.
MR, minor response; sCR, stringent complete response; VGPR, very good partial response.
aREFERENCES
1.
2.
3.
4.

Bal S, et al. Am J Cancer Res. 2022;12:2950-2965.
Inam S, et al. Expert Rev Hematol. 2021;14:323-327.
Kaufman JL, et al. Am J Hematol. 2020;96:418-427.
International Myeloma Foundation.
https://www.myeloma.org/multiple-myeloma-drugs

5. Hu N, et al. AACR 2020. Abstract 3077.
6. Quach H, et al. ASH 2023. Abstract 1011.
7. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346.

DISCLOSURES

Preferred terms in system organ class infections and infestations.

• Among 24 efficacy-evaluable patients, the ORR was 75% (n=18; 95% CI, 53-90),•Figure 2. Best Overall Response by Investigatora

4 (12.5)

7 (21.9)

abeing investigatedSonrotoclax 640 mg + Dexamethasone
40 mg (N=32)

Any infectiona

Sonrotoclax 640 mg +Dexamethasone 40 mg (N=32)
28 (87.5)
10 (31.3)
6 (18.8)
1 (3.1)7 (21.9)
6 (18.8)
5 (15.6)
10 (31.3)010 (31.3)
3 (9.4)2 (6.3)3 (9.4)in a heavily pretreated population(95% CI, 53-90) and VGPR or better rate of 50% (95% CI, 29-71), with
4% of patients achieving sCR and 17% achieving CR

Table 2. Overall Safety Summary

Dose escalation guided by mTPI-2 and safety monitoring committee recommendation. b Cohort 2 started after doublet RDFE was determined.
mTPI-2, modified toxicity probability interval; RDFE, recommended dose for expansion.

• These results indicate that sonrotoclax plus dexamethasone is well toleratedGrade ≥3High-risk group consisted of patients with genetic subtype t(4;14), 1p deletion, del(17p13), and 1q21 amplification.
ECOG PS, Eastern Cooperative Oncology Group performance status; IMiD, immunomodulatory drugs; PI, proteosome inhibitor;
R-ISS, Revised International Staging System.

therapy (1 TEAE of metastatic pancreatic cancer [new diagnosis] and1 non-TEAE of liver failure due to hepatocellular carcinoma 5 months after
discontinuing study drug due to PD)
Serious TEAEs occurred in 6 patients (19%) and grade ≥3 TEAEs occurred in
10 patients (31%)

CONCLUSIONSAny Gradeaasonrotoclax + dexamethasone (part 1, n=10; part 2, n=22) with a median follow-upof 4.6 months (range, 0.1-19 months)– There are 22 patients (69%) with ongoing study treatment and 10 patients(31%) have discontinued treatment due to disease progression (n=6), AE (n=2;hematuria, pancreatic cancer), patient withdrawal (n=1; due to pill burden after
1 dose), and physician decision (n=1; worsening not meeting PD criteria)
The median number of prior lines of therapy was 3 (range, 1-12) and 66% ofpatients had ≥3 prior lines (Table 1)– All patients had prior PI and immunomodulary drug (IMiD) exposure and mosthad prior anti-CD38 therapy (72%)– Many patients were refractory to PI (56%), IMiDs, (72%), anti-CD38 therapy(56%), and ≥1 PI + IMiD + anti-CD38 (47%)•diarrhea (22%), and constipation and nausea (each 16%) (Table 3)
Hematologic TEAEs occurred in 4 patients (13%) (thrombocytopenia [grade 3],platelet count decreased [grades 1 and 3], and neutrophil count decreased[grade 3]) (Table 4)
No patients experienced a DLT (assessed during the first 21 days of part 1)

14 (43.8)
16 (50.0)
2 (6.3)• An overall summary of TEAEs is shown in Table 2– Two patients died on study; neither death was considered related to study

n=10Dose level −1:40 mg•• The most common any-grade TEAEs were fatigue and insomnia (each 28%),

Table 1. Baseline Demographics and Disease Characteristics

Patients, %INTRODUCTION• Multiple myeloma (MM) with t(11:14), found in approximately 15%-20% of patients at

VGPR or better rate was 50% (n=12; 95% CI, 29-71), and CR or stringent CR (sCR)
rate was 21% (CR, n=4; sCR, n=1; 95% CI, 7-42) (Figure 2)
Of 5 patients with CR/sCR, 2 achieved minimal residual disease negativity basedon a threshold of 10-5 using a flow cytometry assay
The median time to response was 0.7 months and median duration of response(DOR) was 8 months (95% CI, 4 to not estimable; Figure 3)– Ten patients improved upon their first response, the longest DOR was18 months, and 2 patients had more than 1 year on treatment

BD: Consultancy, Honoraria, and Speakers Bureaus: Janssen, Karyopharm, GSK, Arcellx, Sanofi, Genentech, Pfizer. MH: Consultancy: Bristol Myers Squibb,
Johnson & Johnson; Research Funding: GSK, AbbVie, BeiGene, Daiichi Sankyo. SB: Consultancy/Honoraria: AbbVie, Adaptive Biotechnologies, Bristol
Myers Squibb, Janssen, and MJH Lifesciences; Research Funding: Bristol Myers Squibb, BeiGene, Fate Therapeutics, AbbVie, Amyloid Foundation.
HC: Consultancy: AbbVie; Research Funding: Thermo Fisher Scientific; Travel, accommodations, expenses: AbbVie. JLK: Consultancy: Bristol Myers Squibb,Ceigene, AbbVie, Incyte, Sanofi, Sebia; Research Funding: Ceigene, Janssen, Sutro Biopharma, Amgen, AbbVie/Genentech, Bristol Myers Squibb, Novartis,GSK, Heidelberg Pharma, Takeda; Travel, accommodations, expenses: Sanofi, Bristol Myers Squibb. DK: Current Employment: Karyopharm Therapeutics,
MJH Life Sciences, Arcellx; Consultancy and Honoraria: AlphaSights, Aperture Medical Technology, LLC, Aptitude Health, Arcellx, Bridger Consulting
Group, Bristol Myers Squibb, Curio Science, Sanofi; Ended employment in the past 24 months: MMRF, Plexus Communications. DWS: Consultancy and/or Research Funding: GSK, Janssen, Sanofi, AbbVie, BMS, Pfizer, Bioline, Arcellx, Gilead, Amgen, Cantex, RocheX. CPV: Honoraria: Janssen, Sanofi, Pfizer,Amgen, Forus. HC, AA, AI: Employment: BeiGene and holds stock with BeiGene. HQ: Consultancy, Honoraria, and/or Research Funding: GSK, BMS,Amgen, Antengene, Sanofi, Karyopharm, AbbVie, Roche. NN, GR: No disclosures.

ACKNOWLEDGMENTS

The authors thank the investigators, site support staff, and especially the patients for participating in this study. The authors would also like to thank
Xin Wang (BeiGene) for assistance in development of this presentation and Rocco Crescenzo (BeiGene) for contributions to the study and developmentof the abstract. This study was sponsored by BeiGene Ltd. Medical writing support was provided by Angela R. Eder, PhD, of Nucleus Global, an Iniziocompany, and supported by BeiGene.

Presented at the EHA2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain