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22. FebruarLatest
2023 clinical advances made by
Neues vom amerikanischen
carfilzomib inHämatologenkongress
RRMM
Therapie des Multiples Myelom
Prof. Dr. med. Hartmut Goldschmidt
GMMG-Studygroup at the University Hospital Heidelberg
Medical Clinic V
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
1
Presenting author
Disclosures
• Honoraria
– Amgen, BMS, Celgene, Chugai, GSK, Janssen,
Novartis, Sanofi
• Consulting or advisory role
– Adaptive Biotechnology, Amgen, BMS, Celgene,
Millenium Pharmaceuticals Inc., Janssen, Sanofi,
Takeda
• Research funding
– Amgen, BMS, Celgene, Chugai, Janssen, Incyte, Merck
Presenting author: Sharp and Dohme (MSD), Molecular Partners AG
Zürich, Mundipharma, Novartis, Sanofi, Takeda
Prof. Dr. med. Hartmut Goldschmidt
• Travel, accommodations, expenses
Affiliation:
– Amgen, BMS, Celgene, Chugai, GSK, Janssen,
GMMG-Studygroup at the University Hospital Heidelberg Novartis, Omnia Med Deutschland, Sanofi, Takeda
Medical Clinic V
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
2
#361, Saad Usmani et al.: KarMMa-2 KarMMa-2 Cohort 2a: Efficacy and Safety of Idecabtagene Vicleucel in Clinical High-Risk Multiple Myeloma Patients with Early Relapse after Frontline Autologous Stem Cell Transplantation Saad Usmani et al., Abstract #361, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 3
Patients with MM who relapse early after frontline therapy KarMMa-2 is a multicohort, phase 2, multicenter trial
with autologous stem cell transplant (ASCT) have high-risk (NCT03601078) designed to explore the efficacy and safety
features and markedly inferior survival vs later relapsing of ide-cel in patients with clinical high-risk MM (cohort 2)
patients1–4 Cohort 2a: Patients with early relapse within 18 months of
• Early relapse: (< 12 months post-ASCT): overall survival frontline treatment initiation including induction, ASCT,
(OS), 26 months2 and lenalidomide maintenance — this is the first
• Later relapse: OS, 91 months2 presentation of data from this cohort
Therapies with novel mechanisms of action are needed to
improve outcomes in these patients1,2 Cohort 2b: Early relapse within 18 months of initiation of
Ide-cel, a B-cell maturation antigen (BCMA)-directed frontline therapy not including ASCT
chimeric antigen receptor (CAR) T cell therapy, previously Cohort 2c: Patients with inadequate response after frontline
demonstrated frequent, deep, and durable responses in ASCT. Results presented by M. Dhodapkar,
heavily pre-treated triple-class–exposed patients5 and is Poster #3314
approved in adult patients with relapsed and refractory
multiple myeloma (RRMM) who have received ≥ 4 prior
therapies in the US6 and ≥ 3 prior therapies in the EU7
1. Paiva B, et al. Blood 2012;119(3):687-691. 2. Bygrave C, et al. Br J Haematol 2021;193(3):551-555. 3. Davies FE, et al. Blood Cancer Discov 2022;3(4):273-284. 4. Majithia N, et al. Leukemia
2016;30(11):2208-2213. 5. Munshi NC, et al. N Engl J Med 2021;384:705-716. 6. ABECMA® (idecabtagene vicleucel) [package insert]. Princeton, NJ: Bristol Myers Squibb; March 2021. 7.
ABECMA® (idecabtagene vicleucel) [summary of product characteristics]. Princeton, NJ: Bristol Myers Squibb; April 2022.
Saad Usmani et al., Abstract #361, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
4
• 39 patients were enrolled and underwent leukapheresis
— One patient discontinued due to physician decisiona
• Ide-cel was successfully manufactured in 38 patients
— One patient discontinued due to withdrawal of consent
— 26 (70.3%) patients received bridging therapies for MMb
— Median duration of bridging therapy was 15.0 days (range 11.0–20.0 days)
• 15 infused patients discontinued the study
• At data cut-off (March 14, 2022), median
follow-up was 21.5 months (range 2–31 months)
— 73% of patients had a follow-up > 12 months
• 22 (59.5%) patients are ongoing in the study
a One patient withdrawn due to physician decision and batch was not released. b Bridging therapy was allowed during manufacturing but stopped at least 14 days before lymphodepletion and
restricted to certain drug classes or drugs previously received.
Saad Usmani et al., Abstract #361, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
5
Primary endpoint was met,
with 45.9% achieving ≥ CR (P <
0.0001)
ORR was 83.8%
(95% CI 68.0 – 93.8)
Median time to first responsea
was
1.0 month (range 0.9 – 2.9
months)
The primary efficacy endpoint was the complete response (CR) rate (proportion of patients who achieved CR or sCR); the primary analysis was planned for at least 6 months after the last
patient received ide-cel infusion.
aResponse defined as PR or better based on IMWG Criteria by investigator assessment; measured from infusion. bPatients with PR or better (2 patients had minimal response; 4 had stable
disease and 0 had PD). cClopper-Pearson CI. dPatients with sCR or CR. Saad
Usmani et al., Abstract #361, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
6
Progression-free survivala Overall survival
Median PFS was 11.4 months (95% CI 5.6 – 19.6) Median OS was not reached; an OS event-free rate
• Median follow-up was 21.5 months (range 2 – 31 of 84.7% (SE: 6.31) was observed at 24 months
months)
aFDA censoring rule; (censoring date - ide-cel infusion date + 1) / 30.4375.
Usmani et al., Abstract #361, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
7
Summary and author´s conclusions
In this analysis of cohort 2a of the KarMMa-2 trial, T cell expansion and persistence data were
ide-cel treatment demonstrated frequent, deep consistent between cohort 2a patients and those in
responses in patients with clinical high-risk MM the KarMMa trial of heavily pre-treated patients3
who experienced early relapse within 18 months of The incidence of grade 3/4 CRS and NT were
initiating frontline therapy, including ASCT numerically lower in patients in this cohort
• Only 24.3% of patients experienced a deep response (≥CR) compared with those in later lines of treatment in
to first-line therapy, including ASCT
the KarMMa trial3
• Of note, a relatively high proportion of patients had high-
• CRS events were primarily grade 1/2, with only one grade
risk or ultra-high-risk cytogenetics
≥ 3 event
• In these very difficult-to-treat patients, the high response
• No grade ≥ 3 iiNTs or late iiNTs were reported
rates are encouraging, with an ORR of 83.8%, CRR of
45.9%, median duration of best response of 15.7 months, These results support a favorable clinical benefit-risk
PFS of 11.4 months, and extended OS (84.7% OS at 24 profile of ide-cel in a clinically high-risk patient
months; median not reached); MRD negativity was
population and its potential use in earlier lines of
sustained in 70% of evaluable patients with ≥ CR at 12
months treatment
1. Bygrave C, et al. Br J Haematol 2021;193(3):551-555. 2. Davies FE, et al. Blood Cancer Discov 2022;3(4):273-284. 3. Munshi NC, et al. N Engl J Med 2021;384:705-716.
Usmani et al., Abstract #361, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
8
#1918, Sagar Lonial et al.: CC-220-MM-001 Iberdomide in combination with dexamethason in relapsed/refractory multiple myeloma: results from the anti-BCMA-exposed cohort of the CC-220-MM-001 trial Sagar Lonial et al., Abstract #1918, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 9
IBER is a novel, potent, oral CELMoD™ compound EXCALIBER-RRMM study (NCT04975997) in
with greater tumoricidal and immune-stimulatory combination with DARA and DEX
effects compared with IMiD® agents1-3 Given the emergence of novel anti-BCMA therapies
• IBER increases proliferating peripheral blood and bone for RRMM, the assessment of patients with prior
marrow T cells and NK cells in patients with RRMM2 anti-BCMA exposure is an important consideration
• In preclinical models, IBER has shown marked synergy
with DEX, anti-CD38 mAbs, and PIs4-6
In the CC-220-MM-001 trial (NCT02773030), IBER +
DEX showed notable efficacy in heavily pretreated
patients, including patients who are IMiD refractory
(ORR of 31.9% and 26.2% in dose-escalation and
dose-expansion cohorts, respectively), and a Objective: to report the efficacy and safety of IBER +
manageable safety profile7 DEX in the anti-BCMA-exposed dose-expansion cohort
(Cohort I) of the
IBER is being investigated in the ongoing phase 3
CC-220-MM-001 trial
BCMA, B-cell maturation antigen; CELMoD, cereblon E3 ligase modulator; DARA, daratumumab; DEX, dexamethasone; IBER, iberdomide; IMiD, immunomodulatory drug; mAb, monoclonal
antibody; NK, natural killer; ORR, overall response rate; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma.
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
10Key eligibility criteria Treatments Endpoints aIncludingLEN or POM, a PI, an anti-CD38 mAb, and an anti-BCMA therapiy; b20mg if > 75 years of age. CAR, chimeric antigen receptor; DOR, duration of response; LEN, lenalidomide; PD progressive disease; PFS progression-free survial; POM, pomalidomide Sagar Lonial et al., Abstract #1918, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 11
Median DOR was 7.5 months (95% CI, 3.7 - 18.4) and median
PFS was 2.3 months (95% CI, 2.1 - 4.2)
aPRor better; bNone of the responding patients had received the „Other“ category of anti-BCMA therapy. C, cycle; CR, complete response; MR, minimal response; PR, partial response; reg.
Regimen; sCR, stringent CR; SD, stable disease; VGPR, very good PR
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
12 IBER + DEX was well tolerated and induced meaningful clinical activity (ORR, 34.1%) in this cohort
Responses were observed despite prior exposure to anti-BCMA therapy, regardless of modality (TCE, ADC, or
CAR T cell therapy), suggesting that IBER retains its activity in these patients
Pharmacodynamics data suggested that IBER + DEX remained immune-stimulatory
These findings support the clinical and pharmacodynamic activity of IBER in heavily pretreated patients,
including those with previous exposure to anti-BCMA therapies
Together with the IBER + DEX and IBER combinations with other standard of care agents data, these data
support the development of IBER and the ongoing randomized phase 3 EXCALIBER-RRMM trial
(NCT04975997)
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
13#3176, Marcelo Capra et al.: Ikema Subgroup Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma: Ikema Subgroup Analysis By Number of Prior Lines of Treatment Marcelo Capra et al., Abstract #3176, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 14
The primary study endpoint was
PFS, assessed by independent
response committee using the
International Myeloma Working
Group criteria
Key secondary endpoints included
ORR, ≥VGPR, MRD-, and CR rates
AEs were graded per the National
Cancer Information Center Common
Terminology Criteria for AEs version
4.03
AE, Adverse events; C, cycle; CR, complete response; d, dexamethasone; D, day; lsa, isatuximab: K, carfilzomib; MM, multiple myeloma; MRD-, minimal residual disease; ORR, overall response rate; PD,
progressive disease; PFS, progression free survival; Q2W, every 2 weeks; R-ISS, Revised International Staging System; VGPR, very good partial response.
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
151 prior line > 1 prior line The addition of Isa to Kd improved PFS regardless of number of prior LOT: In the 1 prior line subgroup, median PFS was 38.2 months for Isa-Kd vs 28.2 for Kd In the >1 prior line subgroup, median PFS was 29.2 months for Isa-Kd vs 17.0 for Kd *Cut-off date: January 14, 2022. Median follow up time: 43.86 months 1 prior line and 44.06 months for >1 prior line. Cl, confidence interval: d, dexamethasone; HR, hazard ratio: lsa, isatuximab: ITT, intent-to-treat; K, carfilzomib; LOT, lines of therapy; mPFS, median PFS; NC, not calculable; PFS, progression-free survival. Sagar Lonial et al., Abstract #1918, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 16
Best overall response
1 prior line Isa-Kd
1 prior line Kd
> 1 prior line Isa-Kd
> 1 prior line Kd
The addition of Isa to Kd improved depth of response (≥VGPR, MRD-, ≥CR, and MRD- and CR rates) both in
patients who received 1 prior line as well as those who received >1 prior line
CR, complete response: d, dexamethasone; Isa, lsatuximab; K, carfilzomib; LOT, lines of therapy; MRD-. minimal residual disease negativity; ORR,
overall response rate; VGPR, very good partial response,
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
17 The addition of Isa to Kd improved PFS and depth of response in patients with relapsed MM with a
manageable safety profile, regardless of the number of prior LOT, including those with first relapse
This post hoc subgroup analysis has limitations, including small number of patients and imbalances between
arms
Cox model adjusted for unbalanced baseline confounding factors (age, ß2-microglobulin at study entry, renal
impairment, ISS stage at study entry, 1q21 amplification, and prior exposure to PI or IMiD agents) resulted in
maintenance of the estimated effect in favor of Isa-Kd vs Kd:
• HR improved from 0.723 to 0.595 for the 1 prior line subgroup
• HR improved from 0.452 to 0.397 for the >1 prior line subgroup
These results showed an overall meaningful treatment effect consistent with the benefit observed in the
overall IKEMA study population and further support Isa-Kd as a standard-of-care treatment for patients
with relapsed MM.
Sagar Lonial et al., Abstract #1918, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
18#3237, Luciano Megala Costa et al.: Master Outcomes of MRD-Adapted Treatment Modulation in Patients with Newly Diagnosed Multiple Myeloma Receiving Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) and Autologous Transplantation: Extended Follow up of the Master Trial Luciano Megala Costa et al., Abstract #3237, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 19
Treatment Luciano Megala Costa et al., Abstract #3237, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 20
Luciano Megala Costa et al., Abstract #3237, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 21
HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p) Luciano Megala Costa et al., Abstract #3237, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 22
PFS – all patients (N = 123)
0 HRCA 91%
3-year PFS 1 HRCA 87%
2+ HRCA 51%
0 HRCA 96%
3-year OS 1 HRCA 91%
2+ HRCA 75%
HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)
Luciano Megala Costa et al., Abstract #3237, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
23• NGS-MRD response-adapted therapy is feasible in ~96% of patients in multi center
setting - 71% reaching MRD-SURE.
• Patients with standard (O HRCA) and high-risk (1 HRCA) NDMM achieving 2
consecutive MRD negative assessments have low risk of progression after cessation
of therapy.
• Patients with ultra-high risk NDMM (2+ HRCA) have high-risk of treatment failure
even if achieving MRD negativity after quadruplet therapy.
Effective novel consolidative strategies should be explored to clear MRD and
improve outcomes in patients with ultra-high-risk MM
Luciano Megala Costa et al., Abstract #3237, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
2464th ASH
Annual Meeting
Extended intensified post-ASCT consolidation with Daratumumab,
Bortezomib, Lenalidomide and Dexamethasone (Dara-VRd) for Ultra-High
Risk (UHiR) Newly Diagnosed Myeloma (NDMM) and Primary Plasma Cell
Leukemia (pPCL): the UK OPTIMUM/MUKnine Trial.
Martin Kaiser, Andrew Hall, Isabelle Smith, Ruth M De Tute, Sadie
Roberts, Emma Ingleson, Kristian Bowles, Mamta Garg, Anand Lokare,
Christina Messiou, Richard Houlston, Graham Jackson, Gordon Cook,
Guy Pratt, Mark T Drayson, Roger G. Owen, Sarah R Brown, Matthew W
Jenner
The Institute for Cancer Research, London, United Kingdom; Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of
Leeds, Leeds, United Kingdom; HMDS Laboratory, St James’ Institute of Oncology, Leeds, United Kingdom; Norfolk and Norwich University
Hospitals NHS Trust, Norwich, United Kingdom; Haematology, Leicester Royal Infirmary/University Hospitals of Leicester NHS Trust, Leicester,
United Kingdom; Birmingham Heartlands Hospital, Birmingham, United Kingdom; Royal Marsden Hospital and Institute of Cancer Research,
London, United Kingdom; Department of Haematology, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; University Hospitals
Birmingham NHS Foundation Trust, Birmingham, United Kingdom; University of Leeds, Leeds, United Kingdom; Institute of Immunology and
Immunotherapy, University of Birmingham, Birmingham, United Kingdom; CTRU, University of Leeds, Leeds, United Kingdom; University
Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
25Current status Aim/Hypothesi
s
~ 20-25%
RelapseTumour genetics Gene expression
2+ HRCA GEP risk signature PB Phenotype
(Double hit) (SKY92)
~15% patients ~20% patients Primary Plasma
Cell Leukemia
Genome
Proliferatio
(PCL; ≥20%)
instability Combined profiling n
~25% patients Proliferation
Niche
independen
t
Double SKY92
hit and SKY92
Double hit
~5% ~10%
~10%
Shah V, et al., Leukemia 2018, Shah
V, et al., Leukemia 2020, Gowda L, et
al., Bone Marrow Transplantation, 54
(1089-1093), 2019
27
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
27Clinical UHiR context – digital comparator trial
Dara- V-HD Dara-
Dara-VR Dara-R
CVRd +ASCT VRd
‘Digital 18 months PFS comparison
Bayesian framework
comparator’ PFS and OS follow-up
The Prior (n=120 UHiR MM)
KCRd/ HD
R/Obs
CRd +ASCT
OPTIMUM design (appraisal framework for external comparator trials (Thorlund et al., 2020)):
- Currently no treatment standard for UHiR group – UK standard at design: VTD, single ASCT, observation
- Mirrored molecular UHiR criteria (Double hit and/or SKY92 risk signature)
- Contemporaneous external dataset: most recent UK phase 3 Myeloma XI trial for NDMM
- KCRd (carfilzomib, cyclophosphamide, lenalidomide, dexamethasone) or CRd induction
At time of design randomisation result not yet available
- Recruitment in same healthcare system
- Same NHS hospitals/geography, virtually identical trial entry criteria Brown S, et al., BMJ Open 2020 28
Jackson G., et al., PLOS Med 2021
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
28Extended Follow-up: End of Dara-VR Consolidation 2
OPTIMUM vs. Myeloma XI: PFS
Median follow-up
41.2 months
29
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
29Extended Follow-up: End of Dara-VR Consolidation
OPTIMUM vs. Myeloma XI: OS
Median follow-up
41.2 months
30
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
30Minimal residual disease
Bone marrow flow cytometry 10-5 sensitivity
MRD Status End of induction Day 100-120 post- End of Consolidation 2
ASCT
MRD- 44 (41.1%) 68 (63.6%) 50 (46.7%)
MRD+ 43 (40.2%) 15 (14.0%) 4 (3.7%)
Not evaluable 15 (14.0%) 13 (12.1%) 20 (18.7%)
Timepoint not reached 5 (4.7%) 11 (10.3%) 33 (30.8%)
Total 107 (100%) 107 (100%) 107 (100%)
84% of patients MRD- post-ASCT sustained MRD- at End Cons 2
31
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
31Adverse Event CTCAE Grade 2 Grade 3 Grade 4
Hematological
Anaemia 14 (17.5%) 3 (3.8%) 0 (0.0%)
Thrombocytopenia 16 (20.0%) 18 (22.5%) 4 (5.0%)
Neutropenia 19 (23.8%) 32 (40.0%) 3 (3.8%)
Non-Hematological
Infection
Overall 23 (28.8%) 10 (12.5%) 2 (2.5%)
Respiratory tract infection 21 (26.3%) 8 (10.0%) 2 (2.5%)
Neurological
Peripheral Neuropathy 9 (11.3%) 2 (2.5%) 0 (0.0%)
Gastrointestinal
Diarrhoea 8 (10.0%) 1 (1.3%) 0 (0.0%)
Other
Fatigue 16 (20.0%) 0 (0.0%) 0 (0.0%)
Pain - Overall 13 (16.3%) 2 (2.5%) 0 (0.0%)
Musculoskeletal pain 11 (13.8%) 1 (1.3%) 0 (0.0%)
Cramp 4 (5.0%) 0 (0.0%) 0 (0.0%)
Flu like symptoms 7 (8.8%) 0 (0.0%) 0 (0.0%)
Rash 4 (5.0%) 0 (0.0%) 0 (0.0%)
Hepatic 5 (5.9%) 2 (2.4%) 0 (0.0%)
32
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
32Summary
• Collaborative trial designed with patients to address unmet need within healthcare system
requirements
• Extended intensified consolidation with Dara-VR(d) is an effective treatment option for UHiR MM
and PCL patients
• Continued improvement of PFS for OPTIMUM vs. Myeloma XI UHiR patients
• Early positive OS signal for OPTIMUM vs Myeloma XI UHiR patients
• Ongoing intensive consolidation required individualised dose reductions, but was tolerable for
most patients, with cytopenia and infection main AEs
• OPTIMUM design explicitly balanced intensity and toxicity vs. high unmet need
• Successful recruitment suggests high unmet need for better diagnostics and therapy
33
• Results support allocation of resources to unmet need in restricted healthcare systems
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
33#759, Katja C. Weisel et al.: Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG- Concept Trial Katja C. Weisel et al., Abstract #759, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 34
• Despite advances in therapy, patients with HRMM continue to show significantly poorer survival outcomes than
patients without HR disease1-4
• A recent study showed that ISS disease stage, LDH level, and the presence of del(17p), t(4;14), and/or
1q21+ have the greatest impact on PFS and OS3
• 1q21+ has recently been acknowledged as an independent adverse cytogenetic aberration2,3
• Co-occurrence of several HR aberrations/features leads to further deterioration of prognosis1-4
• Achievement of MRD negativity correlates with improved PFS and OS in both standard-risk and HRMM5
• Thus far, quadruplet regimens that include monoclonal anti-CD38 antibodies show unprecedented response
rates, MRD negativity rates, and PFS in patients with NDMM6-8
1q21+, gain or amplification of chromosome 1q21; CD, cluster of differentiation; HR, high-risk; HRMM, high-risk multiple myeloma; ISS, International Staging System; LDH, lactate
dehydrogenase; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival.
1. Chalopin T, et al. Br J Haematol. 2021;194:635–638; 2. Schmidt TM, et al. Blood Cancer J. 2021;11:83; 3. D'Agostino, et al. J Clin Oncol. 2022;40:3406–3418; 4. Sonneveld P, et al. Blood.
2016;127:2955–2962; 5. Cavo M, et al. Blood. 2022;139:835–844; 6. Moreau P, et al. Lancet Oncol. 2021;22:1378–1390; 7. Costa LJ, et al. J Clin Oncol. 2022;40:2901–2912; 8. Voorhees PM, et al.
Blood. 2020;136:936–945.
Katja C. Weisel et al., Abstract #759, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
35• The phase II, investigator-initiated GMMG-CONCEPT trial (NCT03104842) is investigating the MRD negativity
rate in HR NDMM patients treated with Isa-KRd, with or without subsequent ASCT, according to age and
eligibility for transplant
• The trial will report on 2 cohorts:
• First cohort: n=153 (127 TE and 26 TNE patients); recruitment August 2018–April 2020
• Second cohort: n=93 TE patients; recruitment June 2021–November 2022
• We previously reported results from an interim analysis of the first 50 enrolled patients, demonstrating an ORR
of 100% and ≥VGPR rate of 90% during induction and a median 24-month PFS of 75.5%1
• Here, we report the preplanned interim analysis of the primary endpoint (MRD negativity) after consolidation
of the first cohort (n=153)
1q21+, gain or amplification of chromosome 1q21; CD, cluster of differentiation; HR, high-risk; HRMM, high-risk multiple myeloma; ISS, International Staging System; LDH, lactate
dehydrogenase; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival.
1. Chalopin T, et al. Br J Haematol. 2021;194:635–638; 2. Schmidt TM, et al. Blood Cancer J. 2021;11:83; 3. D'Agostino, et al. J Clin Oncol. 2022;40:3406–3418; 4. Sonneveld P, et al. Blood.
2016;127:2955–2962; 5. Cavo M, et al. Blood. 2022;139:835–844; 6. Moreau P, et al. Lancet Oncol. 2021;22:1378–1390; 7. Costa LJ, et al. J Clin Oncol. 2022;40:2901–2912; 8. Voorhees PM, et al.
Blood. 2020;136:936–945.
Katja C. Weisel et al., Abstract #759, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
36*Inclusionof another n=93 in cohort 2 from 2021-2022; † Following a protocol amendment, patients in the second cohort with ≥3 copies of 1q21 were eligible. ASCT, autologous stem-cell transplant; d, dexamethasone; HDT, high-dose therapy; HRMM, high-risk multiple myeloma; Isa, isatuximab; ISS, International Staging System; K, carfilzomib; ND, newly-diagnosed; ND, newly diagnosed multiple myeloma; R, lenalidomide; TE, transplant-eligible; TNE, transplant-ineligible. Katja C. Weisel et al., Abstract #759, ASH 2022. Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 37
100%
TE patients (Arm A) TNE patients (Arm B)
80% MRD status, n (%)
(n=93*) (n=24†)
p = 0.0004
Negative 63 (67.7) 13 (54.2)
60%
Patients (%)
p=0.012 Positive 3 (3.2) 0 (0)
67.7% Not done / missing 2 (2.2) 0 (0)
40% 54.2%
95%-CI Timepoint not reached 25 (27.0) 11 (45.8)
95%-CI
20% [0.589; 1]
[0.358; 1] 6 TE and 2 TNE patients were not assessable
0%
TE patients (Arm A) TNE Patients (Arm B)
MRD-negative (10-5)
Of 72 TE patients reaching end of consolidation, 66 had an evaluable MRD-result and of
those, 63 were MRD-negative
*MRD-IA population according to SAP; †MRD population according to SAP. IA, interim-analysis; MRD, minimal residual disease; SAP, statistical analysis plan; TE, transplant-eligible; TNE,
transplant ineligible.
Katja C. Weisel et al., Abstract #759, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
38 Among newly diagnosed high-risk myeloma High and deep response rates were achieved in
patients, treatment with Isa-KRd +/- HDM during both TE (ORR: 94.9%, ≥VGPR: 90.9%) and TNE
induction and consolidation induced deep (ORR: 88.5%, ≥VGPR: 88.5%) patients, with
responses responses deepening over time
The trial met the primary endpoint of MRD Isa-KRd is well tolerated, and the overall safety
negativity post-consolidation and reached statistical profile is consistent with previous reports of the
significance with 67.7% MRD-negative TE patients individual drugs demonstrating low rates of
and 54.2% MRD-negative TNE patients peripheral neuropathy
74% of patients included into the trial reached the The trial is fully enrolled and ongoing with
primary endpoint (TE population) additional analyses on survival and HR subgroup
63/66 evaluable TE patients were MRD-negative at analyses to follow
the end of consolidation
Our data support the use of optimized quadruplet therapy in first-line treatment,
especially in patients with high-risk disease
HR, high risk; MRD, minimal residual disease; TE, transplant-eligible; TNE, transplant ineligible; VGPR, very good partial response.
Katja C. Weisel et al., Abstract #759, ASH 2022.
Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt
39Danke! Heidelberg, Germany Neues vom amerikanischen Hämatologenkongress| 22. Februar 2023 | Prof. Hartmut Goldschmidt 40
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