Enhancing MRD Testing in Hematologic Malignancies: When Negativity is a Positive Thing

Enhancing MRD Testing in Hematologic Malignancies:
When Negativity Is a Positive Thing
Noopur Raje, MD
Professor of Medicine
Harvard Medical School
Director of the Center for Multiple Myeloma
Massachusetts General Hospital

Disclosures
Advisory board/panel: Caribou Biosciences, Immuneel
Consultant: AbbVie, Amgen, Bristol Myers Squibb, Genentech,
GlaxoSmithKline, Janssen, Pfizer, Sanofi, Takeda,
Grants/research support: 2seventy Bio, Pfizer
i3 Health has mitigated all relevant financial relationships

Learning Objectives
MRD = measurable residual disease.
Distinguish the advantages and limitations of current MRD detection
methods
Evaluate consensus recommendations on indications for MRD testing in
hematologic malignancies
Explain the current and potential roles of MRD status and depth of
response as a biomarker in clinical trials
Assess the clinical utility of MRD in prognosis and treatment of selected
hematologic malignancies, including acute lymphoblastic leukemia,
chronic lymphocytic leukemia, and multiple myeloma

Why MRD?
LLS, 2021.
Depth of response matters
Treatments are very effective and therefore need more sensitive tools
to monitor disease
MRD can serve as a biomarker predictive of outcome
Tailored therapy—treatment optimization based on MRD

How Does MRD Inform Prognosis?
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; MM = multiple myeloma.
LLS, 2021; Dekker et al, 2023; NCCN, 2023a.
MRD assessment is standard clinical practice in ALL to predict
outcomes and guide therapy
MRD monitoring is used as a clinical support tool/prognostic indicator
after initial induction therapy in AML to identify impending relapse and
allow for robust post-transplant surveillance
MRD analysis in CML is well standardized and used to guide
treatment decisions with tyrosine kinase inhibitors
MRD is used in MM to measure depth of response at each stage of
treatment to inform prognosis

Acute Leukemia
LAIP = leukemia-associated immunophenotype.
van Dongen et al, 2015.
Maximum Sensitivity of Procedures for Detecting Minimal Residual Disease in Leukemia
Technique and criterion Blasts per 100,000 nucleated cells
Standard microscopy (“complete remission”) 5,000
Karyotype analysis (20 mitotic figures) 5,000
Microscopy, expert 1,000
Multiparameter flow cytometry (6)–LAIP
Multiparameter flow cytometry (8)-LAIP
10
0.1–1?
Colony growth 1
Polymerase chain reaction (PCR) 0.1
Next-generation sequencing (NGS) <0.1

“Minimal” or “Measurable” Residual Disease
Brüggemann & Kotrova, 2017.

Impact of MRD in Meta-Analysis of 16 Adult Studies
EFS = event-free survival; HR = hazard ratio; OS = overall survival; BCI = Bayesian credible intervals.
Berry et al, 2017.
Acute Leukemia

MRD Measurement Methods
Ig = immunoglobulin; TCR = T-cell receptor; BCR-ABL = breakpoint cluster region–Abelson.
Li, 2022; van Dongen et al, 1999.
Acute Leukemia
Flow cytometry
Sensitive (improving, reaching PCR in some centers)
Not standardized
Different at every institution (but efforts on the way)
Available
PCR
High sensitivity
Availability varies depends on case
Ig and TCR rearrangements can be detected in >95%
of ALL cases and can be followed
Drawbacks include failure to detect clonal evolution
(oligoclonality at diagnosis common)
Chromosomal breakpoint PCR
BCR-ABL t(9:22)
MLL-AF4 t(4:11)
E2A-PBX1 t(1;19)
TEL-AML1 t(12;21)
NGS
Feasible
At least as sensitive as PCR
Not yet widely available
Can detect clonal evolution

Advantages and Limitations of Detection
AML, ALL, and CML
Technique Method Sensitivity Advantages Limitations
Morphology
Identify and distinguish the presence
presence of leukemic cells from
nonmalignant cells in bone morrow
morrow using microscopy
5x10-2 (5%) High availability Low sensitivity
Cytogenetics
Assessment of charges in the size,
shape, structure, or number of
chromosomes in leukemia cells
1-5x10-2
High availability
Needs a bone marrow aspiration and at
and at least 20 metaphases
Allows to detect ACAs (CML)
Low sensitivity
FISH
Cytogenetic method used to detect
detect targeted abnormalities in
leukemia genes or chromosomes
1x10-2 Fast turnaround
Low sensitivity
Not used to quantify MRD
Multicolor flow
flow cytometry
cytometry
(MFC)
Identify leukemic cells with a specific
specific aberrant leukemia-
associated phenotype using a panel
panel of fluorochrome-conjugated
conjugated antibodies
ALL:
10-4 to 10-5 (0.01%-0.001%)
AML:
10-3 to 10-4 (0.1%-0.01%)
CML: N/A
Fast turnaround (<4 hours)
Relatively low cost
Provides information on antigen
expression
High availability
Variable sensitivity
Technical laboratory expertise
required
No quality assurance and less
standardized
Requires fresh cells (<48 hours)
Immunophenotypic shifts can lead
lead to false-negative results
Reduced sensitivity to detect MRD
MRD in blood samples
Not established for monitoring
during follow-up
ACA = additional chromosomal abnormalities; FISH = fluorescence in situ hybridization; N/A = not available.
Dekker et al, 2023.

Advantages and Limitations of Detection (cont.)
qPCR = quantitative PCR; CHIP = clonal hematopoiesis on indeterminate potential; HCT = hematopoietic cell transplant.
Dekker et al, 2023.
AML, ALL, and CML
Technique Method Sensitivity Advantages Limitations
qPCR for
fusion genes
Quantification of BCR-ABL
ABL fusion genes RNA
expression (p190 or p210
subtype)
ALL: 10-4 to 10-5 (0.01%-0.001%)
AML: 10-5 (0.001%)
CML: 10-5 (0.001%)
Standard primers used for specific
fusion genes
Fresh sample not needed
High sensitivity
Rapid turnaround
Low cost
Absence for targets in >50% of patients
patients
Limited to BCR-ABL1 in the United States
States
Risk of contamination
Not scalable for high volume
Not standardized for minor transcripts
High-
throughput
NGS
Identify, quantify, and track
track unique disease-
associated Ig mutations by
by sequencing IgH, IgK,
and IgL rearrangements as
as well as TCR
translocations, or somatic
mutations in AML
ALL: 10-6 (0.0001%)
AML: 10-4 (0.01%)
CML: N/A
Applicable to majority of patients
Can identify, quantify, and track
multiple unique clones and their
evolution
Only FDA-approved assay (for ALL)
May be used in peripheral blood
Fresh sample not needed
Can scale up for high volume
High cost
Requires diagnostic pretreatment sample
sample
Longer turnaround time than MFC (10-21
21 days)
The analysis of NGS MRD data requires a
a bioinformatic pipeline
Reliable markers not fully defined (AML)
(AML)
CHIP-associated variants not useful
before allogeneic HCT (AML)
Limited throughput if targeted approach is
approach is chosen (AML)

Impact of MRD on Outcomes and Treatment Decisions
SCT = stem cell transplant; Ph+ = Philadelphia chromosome–positive; TKI = tyrosine kinase inhibitor.
Li, 2022.
Levels of MRD before transplant are prognostic for post-transplant relapse
In some studies, allogeneic SCT improved outcomes of suboptimal MRD response to
frontline chemo, but this remains controversial
Higher levels of MRD after allogeneic SCT predict impending relapse (>60-day post-
transplant)
Patients treated with blinatumomab who achieve MRD negativity have longer survival
than those who don’t
MRD negativity after inotuzumab or blinatumomab was associated with better survival
only after FIRST salvage. In SECOND salvage, prognosis was poor regardless
For Ph+ ALL, stronger TKIs improve rates of MRD negativity (ponatinib)
Acute Leukemia

Monitoring: ALL
Dekker et al, 2023.
Incorporation of MRD in Standard Care
Standard Risk
• No high-risk lesions
• MRD neg <10-4 after induction
• Age <40 years
High Risk
• Ph+
• Ph-like
• MLL rearranged
• MRD pos >10-4
• Hypodiploid
• Age >40-50 years
Continue chemotherapy
consolidation and maintenance
MRD neg after
consolidation
Maintenance
therapy
Follow MRD every 3-4
months until the
completion of therapy
Converts to MRD+
HCT eligible
HCT ineligible
MRD neg
MRD pos
MRD neg
MRD pos
AlloHCT
Blinatumomab  AlloHCT
Continue
consolidation/maintenance
Blinatumomab  maintenance
Monitor MRD every 1-2
months for the first year
post transplant
Duration and frequency
of monitoring unknown

Monitoring: Newly Diagnosed CML
MMR = major molecular remission; DMR = deep molecular response.
Dekker et al, 2023.
First 3 months First year
After MMR
(PCR<0.1)
Side effects? Questions?
Weekly to monthly
monthly visits
Every 3 months
months
Every 6 months
months
Visits can occur more frequently
frequently
Blood counts,
check liver/kidney
liver/kidney
function
PCR for BCR-
ABL every 3
months
PCR for BCR-
ABL every 3
months
Yes
No
At Diagnosis
• Detect and
determine
BCR::ABL1
transcript type
After TKI Initiation
Molecular response
evaluation by qPCR at
3, 6, 9, and 12 months
and every 3-6 months
thereafter
Optimal response
Warning
Resistant
Continue same treatment
Continue same treatment unless
evaluation towards resistance or in
the view of MMR or DMR
Before TKI change:
Check CBC and bone marrow cytology to exclude
progression, perform cytogenetics in search of
ACA, search for BCR::ABL1 mutation
Sustained and deep
molecular response
Continue same
treatment or enter trial
Stop treatment
MRD monitoring monthly during
the first 6 months, then every 3
months, TKI resumption upon
MMR loss
TKI discontinuation
eligibility?

CML Milestones
IS = international scale.
NCCN, 2023.
BCR-ABL1 (IS) 3 Months 6 Months 12 Months
>10%
Possible TKI resistance
(CAUTION)
TKI resistance (STOP)
>1%-10% TKI sensitive (GO)
Possible TKI resistance
(CAUTION)
>0.1%-1% TKI sensitive (GO) TKI sensitive (TENTATIVE)
≤0.1% TKI sensitive (GO)

NHL: MRD in the GADOLIN Trial
NHL = non-Hodgkin lymphoma; IGHV = immunoglobulin heavy chain variable; IGH = immunoglobulin heavy chain; iNHL = indolent NHL; R = randomized;
ECOG = Eastern Cooperative Oncology Group; B = bendamustine; G = obinutuzumab.
Pott et al, 2020.
Method: Real-Time qPCR for IGHV and/or IGH/BCL2; Sensitivity 10-4
Inclusion criteria
• CD20-positive
• Rituximab-refractory iNHL
• Aged ≥18 years
• Documented rituximab-refractory
iNHL
• ECOG performance status of 0-2
Total enrolled: 335
G-B
B 90 mg/m2 IV (D1, D2, C1-6) and G 1,000 mg IV
(D1, D8, D15, C1; D1, C2-6), Q28 days
B
B 120 mg/m2 IV (D1, D2, C1-6), Q28 days
G
G 1,000 mg IV every 2 months
for 2 years
R
1:1
Induction Maintenance
Data cutoff
April 1, 2016

NHL: MRD in the GADOLIN Trial (cont.)
G-benda = obinutuzumab/bendamustine.
Pott et al, 2020.

NHL: MRD in the GALLIUM Study
FL = follicular lymphoma; G = obinutuzumab; D = day; C = cycle; R = rituximab; ID = identity; CR = complete response; PR = partial response;
PET = positron emission tomography; MI = mid-induction; EOI = end of induction; Q3W = every three weeks; Q4W = every 4 weeks;
Q6M = every 6 months.
Pott et al, 2016; Trotman et al, 2018.
Inclusion Criteria
• Previously untreated CD20-positive iNHL
• Age ≥18 years with FL (grade 1-3a) or
splenic/nodal/extranodal MZL
• Stage III/IV or stage II bulky disease (≥7 cm)
requiring treatment and ECOG PS 0-2
Target FL enrollment: 1,200
G-Chemo
Obinutuzumab 1,000 mg IV on Day 1, Day
8, Day 15 of Cycle 1 and Day 1 of Cycle 2-8
(Q3W) or Cycle 2-6 (Q4W) plus CHOP,
CVP, or bendamustine
R-Chemo
Rituximab 375 mg/m2 IV on Day 1 of Cycle
1-8 (Q3W) or Cycle 1-6 (Q4W) plus CHOP,
CVP, or bendamustine
G
Obinutuzumab 1,000 mg IV every 2
months for 2 years
R
Rituximab 375 mg/m2 every
2 months for 2 years
MRD Assessments
Clone ID
baseline
MI EOI
MRD during
maintenance
MRD during
follow-up (Q6M)
Induction Maintenance
R 1:1
CR
or
PR
x5

NHL: MRD in the GALLIUM Study
Pott et al, 2016; Trotman et al, 2018.
0
20
40
60
80
100
Blood/BM* Blood
Patients
(%)
N= 52 293 28 323 35 165 15 199
p=0.0041 p=0.0014
15.1
84.9
92.0
8.0
Blood/BM
R-chemo G-chemo
R-chemo
MRD+
R-chemo
MRD-
G-chemo
MRD+
G-chemo
MRD-
R-chemo G-chemo
BM
17.5
82.5
93.0
7.0
No. of patients at risk
MRD-
MRD+
80
60
40
20
0
100
12 24 36 48
0
MRD- (n=562)
MRD+ (n=69)
535
60
503
54
408
43
287
18
170
13
72
5
562
69
Probability
Months since EOI
9
0
0
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time (months)
246 237 223 214 202 197 189 163 114 71 19 11
1.0
0.8
0.6
0.4
0.2
0.0
Probability
of
PFS
No. of patients at risk
CMR + MRD-negative response (n=250)
CMR + MRD-positive response (n=16)
Non-CMR + MRD-negative response (n=24)
Non-CMR + MRD-positive response (n=8)
Censored
0
PET further refines the
prognosis

Splenic Marginal Zone Lymphoma
uMRD = undetectable MRD; R-CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; FCR = fludarabine/cyclophosphamide/rituximab.
Lyu et al, 2021.
Method: multiparameter bone marrow flow; sensitivity 10-4
uMRD Predicts Long-Term Outcome
Investigator Treatment of Choice (n=71)
Rituximab monotherapy (n=6) +MRD 33%
R-CHOP (n=55) + MRD 21.8%
FCR (n=10) + MRD 20%
→Maintenance R (2-year) (n=31)
Bone marrow
multiparameter flow every
6 months

Diffuse Large B-Cell Lymphoma (DLBCL)
Roschewski et al, 2015.
ctDNA Retrospective Analysis
198 patients with untreated DLBCL
112 with pretreatment biopsy samples
86 with serum calibration samples (no biopsy samples)
3 with insufficient biopsy
calibration samples
(<10 ng input DNA)
109 with sufficient biopsy
calibration samples
(>10 ng input DNA)
15 had no calibrating
rearrangement identified
94 had calibrating
32 had calibrating
54 had no calibrating
126 with tumor-specific clonotypes identified
108 included in analysis of outcome of interim
cell-free circulating tumor DNA
• 24 progressors
• 84 non-progressors
107 included in analysis of outcome of
surveillance cell-free circulating tumor DNA
• 17 progressors
• 90 non-progressors
Method: immunosequencing, sensitivity 10-6

DLBCL: Retrospective Analysis of ctDNA
Roschewski et al, 2015.
Method: immunosequencing, sensitivity 10-6

DLBCL: Pre-Treatment Circulating Tumor DNA (ctDNA)
CAPP-Seq = cancer personalized profiling by deep sequencing.
Newman et al, 2014; Newman et al, 2016; Kurtz et al, 2018.
Method: cancer personalized profiling by deep sequencing (CAPP-Seq), sensitivity 10-4-10-5
Molecular Response (MR) by CAPP-Seq Predicts Outcome

BOVen in CLL
BOVen = zanubrutinib/obinutuzumab/venetoclax; CLL = chronic lymphocytic leukemia.
Soumerai et al, 2021.
𝚫MRD400 Predicts for BM uMRD and Sustained Post-Treatment MRD at <10-5
ΔMRD400 as a predictive marker for
post-treatment MRD kinetics (MRD
by NGS)
ΔMRD400 as a surrogate end
point for early undetectable MRD
in bone marrow
0.0
0.2
0.4
0.6
0.8
1.0
Months from End−of−Treatment
Proportion
MRD
failure−free
0 3 6 9 12 15 18
11 9 5 3 2 0 0
Failed
20 20 19 15 9 1 0
Achieved
dMRD400 failed
dMRD400 achieved
MRD response by flow cytometry
We hypothesize that patients with 𝚫MRD400 can have sustained
remission with limited treatment duration

Lessons Learned
MRD testing is feasible
It is prognostic
It can help with treatment decisions in leukemia
Ongoing work in NHL/CLL will allow us to tailor therapy in the future

Why Should We Get MRD Negativity in MM?
Depth of response matters
Biological implications
Clinical implications
Current treatments
High response rates
Need for more sensitive methods

Biological Implications
SMM = smoldering MM; NDMM = newly diagnosed MM; RRMM = relapsed/refractory MM.
Images courtesy of Noopur Raje, MD.
Representative Chromosomal/Genomic Changes Over Time in MM

Evolution of Clonal Variants in MM
Bahlis, 2012; Keats et al, 2012; Bianchi & Ghobrial, 2014; Bolli et al, 2014; Brioli et al, 2014.
Genomic changes are
present at diagnosis and
increase throughout the
disease course
Evolve over time due to
selective pressures from
treatment and factors in the
microenvironment
Probability of acquisition of
mutation may directly relate
to number of cells

Does Depth of Response Matter?
sCR = stringent CR; iCR = incomplete CR; NGF = next-generation flow; VGPR = very good PR; MGUS = monoclonal gammopathy of undetermined significance.
Images courtesy of Noopur Raje, MD.
Paiva et al, 2015.
MRD
sCR
iCR
PCRCR
NGF
NGS
Diagnosis 1012
<104
80% HD trials CR 1010
<106
MRD is the new CR

MRD: What Are the Techniques?
Sequencing of Ig-Based Method
Multiparametric Flow Cytometry
Measurement of MRD Using Ultra-Sensitive NGF
NGS Method
Sequencing of Immunoglobulin Gene
Slide courtesy of Noopur Raje, MD.

MRD Detection in the Marrow
MFC = multiparameter flow cytometry; V = variable; D = diversity; J = joining.
Kumar et al, 2016.
MFC VDJ Sequencing
Applicability Nearly 100% ≥90%
Need for baseline
sample
Not required; abnormal plasma cells can be identified in any
any sample by their distinct immunophenotypic pattern versus
versus normal plasma cells
Baseline samples required for identification of the dominant
clonotype; alternatively, a stored sample from a time point with
with detectable disease can be used to define baseline status
Sample requirements >5 million cells <1 million cells; higher numbers improve sensitivity
Sample processing
Needs assessment within 24-48 hours; requires a fresh
sample
Can be delayed; can use both fresh and stored samples
Sample quality control Immediate with global bone marrow cell analysis Not possible. Additional studies required
Sensitivity ≥1 in 10-5 ≥1 in 10-5
Information regarding
sample composition
Detailed information available on leucocyte subsets and their
their relative distribution
Information about immunoglobulin gene repertoire of B cells in the
in the studied patient samples
Turnaround and
complexity
Can be done in a few hours; automated software available
Can take several days for turnaround; required intense
bioinformatics support. Use of local laboratories could speed up
up this limitation
Standardization Standardized by the EuroFlow consortium In process
Availability
Most hospitals with four-color flow cytometry. Eight or more-
more-color flow cytometry requires experienced
centres/laboratories. Many laboratories have adopted the
EuroFlow laboratory protocols and use the EuroFlow MRD
tubes
So far limited to one company/platform

MRD Assessment: Role of Imaging
MRI = magnetic resonance imaging; FDG = fluorodeoxyglucose; CT = computed tomography.
Zamagni et al, 2020; Hillengass et al, 2012; Nosàs-Garcia et al, 2005; Hillengass et al, 2011; Lecouvet et al, 2021.
FDG-PET/CT MRI
Description
• Permits detection of lesions
demonstrating metabolic activity together
together with morphologic information
• Higher sensitivity for the detection of bone marrow
marrow infiltration by myeloma cells compared with
with skeletal X-ray and CT
• Correlates with parameters of bone marrow histology
histology and change according to stage of disease
disease and remission after therapy
Advantages • Ability to detect extramedullary disease
• Compared with PET/CT, MRI is superior for the detection
detection of diffuse bone disease and central nervous
nervous system and spinal cord imaging
Limitations
• Because not all bone lesions attributable to
attributable to MM acquire FDG, both false-
false-negative and false-positive results are
are possible in the setting of MM
• Both false-negative and false-positive results have been
been observed due to scar and necrotic tissue

Revised IMWG Response Criteria for MM
IMWG = International Myeloma Working Group; SUV = standard uptake value.
Kumar et al, 2016; NCCN, 2023c.
Response subcategory Response criteria
IMWG
MRD
negativity
criteria
(requires
complete
response)
Sustained MRD-negative
MRD-negative in the marrow (next-generation flow cytometry [NGFC] and/or NGS) and by
and by imaging as defined below, confirmed 1 year apart. Subsequent evaluations can be
can be used to further specify the duration of negativity
Flow MRD-negative
Absence of phenotypically aberrant clonal plasma cells by NGFC on bone marrow aspirates
aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or
(or validated equivalent method) with a minimum sensitivity of 1 in 10-5 nucleated cells or
cells or higher
Sequencing MRD-negative
Absence of clonal plasma cells by NGS on bone marrow aspirates in which presence of a
of a clone is defined as <2 identical sequencing reads obtained after DNA sequencing of
sequencing of bone marrow aspirates using the Lymphosight® platform (or validated
equivalent method) with a minimum sensitivity of 1 in 10-5 nucleated cells or higher
Imaging + MRD-negative
MRD negative as defined by NGF or NGS PLUS
Disappearance of every area of increased tracer uptake found at baseline or a preceding
preceding PET/CT or decrease to <mediastinal blood pool SUV or decrease to less than that
than that of surrounding normal tissue

Unmet Need
Allam et al, 2023.
Assessing MRD by “Liquid Biopsy”
Bone Marrow Aspirate for MRD Peripheral Blood for MRD
Advantages
• Well-established, “gold-standard”
• Commercially available
• Not invasive
• Patient preference
• More frequent measurement, allowing for dynamic
monitoring
Disadvantages
• Invasive, limited by patient tolerability
• Hemodilution
• Does not assess for extramedullary disease
• Limited by heterogenous bone marrow involvement
• Under investigation
• Not widely available
• Half-life of IgG (~23 days) and IgA (6 days) may lead to
lead to lag in MRD assessment; half-life even longer
longer with smaller concentrations
• Non-secretory disease

Mass Spectrometry Testing: Methodology
MALDI-TOF = matrix-assisted laser desorption ionization–time of flight; LC-MS = liquid chromatography–mass spectrometry;
SPEP = serum protein electrophoresis; IFX = immunofixation; MASS-FIX = matrix-assisted laser desorption ionization time of flight mass spectrometry.
Zajec et al, 2020.
Intact light chain
Clonotypic peptide
Protease digestion
Add stable isotype labeled peptide
MALDI-TOF MS
Matrix-assisted laser desorption
ionization–time-of-flight mass
spectrometry
Determine clonotypic peptide by RNA
sequencing of bone marrow aspirate or by
analysis of serum M protein
LC-MS/MS
Liquid chromatography-mass spectrometry/mass spectrometry
Examples
M-inSight (Sebia)
Easy M (Rapid Novor)
High throughput
Sensitivity <100 mg/L
Does not require knowledge of clonotypic
peptide
Polyclonal background with MALDI-TOF
limits sensitivity of this method
Requires more time than MALDI-TOF
More sensitive 0.1-0.3 mg/L
Mass spectrometry is more sensitive than SPEP/IFX (100 mg/L)
Speed of assay depends on modality: MALDI-TOF faster than LC-MS
Allows detection of therapeutic monoclonal antibodies
LC-MS more sensitive than MALDI-TOF
Reduce sulfide
bonds
M protein
Polyclonal
background Examples
MASS-FIX (Mayo Clinic); commercially available
EXENT (binding site)

Comparison of Binding Site Mass Spec to NGS
Mass spec = mass spectrometry; KRd = carfilzomib/lenalidomide/dexamethasone; miRAMM = monoclonal immunoglobulin rapid accurate mass measurements.
Derman et al, 2021.
Binding site MALDI-TOF comparable to NGS at 10−5 to 10−6
LC-MS (related to miRAMM) comparable to NGS at 10−6
or better
Compared NGS to 2 binding site mass spectrometry
methods (MALDI-TOF and LC-MS) in 36 patients with
newly diagnosed multiple myeloma who completed
KRd ×18 cycles.
Binding Site MALDI-TOF is being developed as EXENT assay

Does MRD Predict Outcome
in MM?

MRD Negativity and Outcomes in MM
Perrot et al, 2018.
MRD-Negative Patients Have Improved Outcome Irrespective of Therapy Used

MRD Assessment by NGS in IFM/DFCI 2009
RVD = lenalidomide; bortezomib/dexamethasone; CY = cyclophosphamide.
Perrot et al, 2018; Attal et al, 2017.
Transplant-Eligible Newly Diagnosed Myeloma
RVDx3
CY (3g/m2)
Mobilization
Goal: 5x106 cells/kg
RVDx5
Lenalidomide
18 months
RVDx3
CY (3g/m2)
Mobilization
Goal: 5x106 cells/kg
Melphalan 200 mg/m2 plus
ASCT
RVDx2
Lenalidomide
18 months
Randomize
Induction
Collection
Consolidation
Maintenance
MRD
MRD
Calibration
SCT at relapse

Progression-Free Survival (PFS) Overall Survival
MRD Assessment by NGS in IFM/DFCI 2009
Perrot et al, 2018.

VRD x6 cycles followed ASCT, VRD x2 consolidation and maintenance with lenalidomide or ixa-len, and some
patients fixed duration of therapy and some patients continuous therapy
MRD Assessment by NGF in GEM2012MENOS65
VRD = bortezomib/lenalidomide/dexamethasone; ASCT = autologous stem cell transplant; ixa-len = ixazomib-lenalidomide.
Paiva et al, 2020.

Combining PET and Flow-Negative: PFS
Moreau et al, 2017.

MAIA: Transplant-Ineligible Newly-Diagnosed
Myeloma
ORR = objective response rate; D-Rd = daratumumab/lenalidomide/dexamethasone.
Facon et al, 2018.
Efficacy: ORR and MRD (NGS; 10-5 sensitivity threshold)
Study Design
Significantly higher ORR, ≥CR rate, ≥VGPR rate, and MRD-negative rate with D-
Rd
24%
7%
0
5
10
15
20
25
30
D-Rd
(n = 368)
Rd
(n = 369)
MRD-negative
rate,
%
P <0.0001
3.4X
No. at risk
Rd MRD negative
D-Rd MRD negative
Rd MRD positive
D-Rd MRD positive
27
89
342
279
%
surviving
without
progression
0
20
40
60
80
100
0 3 6 9 121518 42
Months
27
27
89
305
258
27
88
280
247
27
88
253
232
27
86
227
223
27
86
209
214
27
86
192
204
0
0
0
0
21
70
128
133
2124 30
12
55
82
91
1
12
17
23
25
84
175
187
Rd MRD-negative
Rd MRD-positive
D-Rd MRD-negative
D-Rd MRD-positive
3336
0
5
3
6
5
33
45
53
0
1
2
0
39

GRIFFIN (D-VRd vs VRd) Study in TE-NDMM
TE-NDMM = transplant-eligible NDMM; CrCI = creatinine clearance; IV = intravenous; SC = subcutaneous; PO = orally;
GCSF = granulocyte colony-stimulating factor; QW8= every 8 weeks.
Kaufman et al, 2020; Voorhees et al, 2020.
Phase 2 study of D-VRd vs VRd in transplant-eligible NDMM, 35 sites in US with enrollment
from 12/2016 to 4/2018
Induction:
Cycles 1-4
Consolidation:
Cycles 5-6
Primary end points:
• sCR rate (by end of consolidation)
• 1-sided alpha of 0.1
• 80% power to detect 15% improvement
• (50% vs 35%), N=200
Secondary end points:
• Rates of MRD negativity (NGS 10-5), CR, ORR,
≥VGPR
Maintenance:
Cycles 7-32
21-day cycles 28-day cycles
Stem cell mobilization with GCSF ± plerixafor
Key eligibility criteria
• Transplant-eligible
NDMM
• 18-70 years of age
• ECOG PS score 0-2
• CrCl ≥30 ml/min
D-VRd
D: 16 mg/kg IV Days 1, 8, 15
V: 1.3 mg/m2 SC Days 1, 4, 8, 11
R: 25 mg PO Days 1-14
d: 20 mg PO Days 1, 2, 8, 9, 15, 16
VRd
V: 1.3 mg/m2 SC Days 1, 4, 8, 11
d: 20 mg PO Days 1, 2, 8, 9, 15, 16
T
R
A
N
S
P
L
A
N
T
D-VRd
D: 16 mg/kg IV Day 1
V: 1.3 mg/m2 SC Days 1, 4, 8, 11
d: 20 mg PO Days 1, 2, 8, 9, 15, 16
VRd
V: 1.3 mg/m2 SC Days 1, 4, 8, 11
d: 20 mg PO Days 1, 2, 8, 9, 15, 16
D-R
D: 16 mg/kg IV Day 1
Q4W or Q8W
Cycles 7-9;
15 mg PO Days 1-21
Cycle 10+
R
R:25 mg PO Days 1–21
Cycles 7-9;
15 mg PO Days 1-21
Cycle 10+
R
A
N
D
O
M
I
Z
A
T
I
O
N
TE-NDMM
21-day cycles

GRIFFIN: MRD by NGS
Sborov et al, 2022.
D-VRd vs VRd in Transplant-Eligible NDMM

GRIFFIN: Longitudinal Outcomes
Sborov et al, 2022.
D-VRd vs VRd in Transplant-Eligible NDMM

Number at risk
8 8 8 6 1 0
114 114 111 78 19 0
55 55 54 37 7 0
R-ISS-3
R-ISS-2
R-ISS-1
0
20
40
60
80
100
0 12 24 36 48 60
Time from study entrance (months)
P=0.38
R-ISS-I, median PFS: not reached
R-ISS-II, median PFS: not reached
R-ISS-III, median PFS: not reached
Progression-free
survival
(%)
R-ISS-3
R-ISS-2
R-ISS-1
Number at risk
0
20
40
60
80
100
18 13 8 3 0 0
150 119 99 58 18 0
59 51 45 26 4 0
0 12 24 36 48 60
R-ISS-I, median PFS: not reached
R-ISS-II, median PFS: 38 months
R-ISS-III, median PFS: 14 months
HR 1.63, 95% CI 1.15 – 2.30; P=0.006
Progression-free
survival
(%)
MRD-negative MRD-positive
Risk is dynamic: patients with adverse prognosis may shift into a favorable one upon
achieving deep responses to treatment
MRD Negativity and Outcomes in MM (cont.)
R-ISS = revised International Scoring System.
Paiva et al, manuscript in review, 2023.
Similar Outcome With MRD Negativity Irrespective Of Standard/High-Risk
MM

POLLUX and CASTOR: RRMM
PD = progressing disease.
Avet-Loiseau et al, 2016; Palumbo et al, 2016; Dimopoulos et al, 2016.
DRd (n=286)
D 16 mg/kg IV
Weekly: Cycles 1-2
Every 2 weeks: Cycles 3-6
Every 4 weeks until progression
R 25 mg PO (the same as Rd alone)
d 40 mg
Rd (n=283)
R 25 mg PO
Days 1-21 of each cycle until progression
d 40 mg weekly until PD
R
A
N
D
O
M
I
Z
A
T
I
O
N
POLLUX
DVd (n=251)
D 16 mg/kg IV
Weekly: Cycles 1-3
Every 3 weeks: Cycles 4-8
Every 4 weeks: Cycles 9+
V 1.3 mg/m2 SC (the same as Vd alone)
d 20 mg
Vd (n=247)
V 1.3 mg/m2 SC on Days 1, 4, 8, and 11
for 8 cycles
d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12
for 8 cycles
CASTOR
Evaluation of MRD
 At time of suspected CR
 3 and 6 months after suspected CR
Evaluation of MRD
 At time of suspected CR
 At 6 and 12 months after the first dose
R
A
N
D
O
M
I
Z
A
T
I
O
N

POLLUX and CASTOR
Avet-Loiseau et al, 2016.
Lower risk of progression in MRD-negative patients
More patients achieve MRD negativity when adding daratumumab
PFS benefit in MRD-positive patients who received daratumumab-containing
regimens versus standard-of-care
PFS in Patients with RRMM According to MRD Status at 10–5
POLLUX CASTOR

MRD: Benefit by Line of Therapy in MM
Munshi et al, 2020.

MRD: Independent Prognostic Factor for PFS
Munshi et al, 2020.
Multiple Myeloma

MRD: Independent Prognostic Value for OS
Munshi et al, 2020.
Multiple Myeloma

Can We Use MRD to Tailor Therapy?
No data to support stopping therapy for those who are MRD-negative
or giving additional treatments to those who are MRD-positive
Prospective trials specifically designed to ask:
How long do we continue treatment?
Do we change treatment?
Do we add agents?
Do we stop treatment?
Multiple Myeloma

MASTER: Daratumumab/Carfilzomib/Len/Dex
Costa et al, 2021; Costa et al, 2023.
Newly Diagnosed Multiple Myeloma
Dara-KRd
• Dara 16 mg/m2 Days 1, 8, 15, 22 (Days 1, 15: C 3-6; Day 1: C >6)
• Carfilzomib (20) 56 mg/m2 Days 1, 8, 15
• Lenalidomide 25 mg Days 1-21
• Dex 40 mg PO Days 1, 8, 15, 22
Autologous transplantation and MRD response-adapted consolidation and treatment
cessation:
Dara-KRd ×4
allogeneic
HCT
Dara-KRd ×4 Dara-KRd ×4
Lenalidomide
maintenance
MRD-SURE–Treatment-free observation and MRD surveillance
MRD MRD MRD MRD
2nd MRD-negative (<10-5) 2nd MRD-negative (<10-5) 2nd MRD-negative (<10-5)
Induction Consolidation Consolidation

MASTER: Dara/Carfilzomib/Len/Dex Final Analysis
Costa et al, 2021.
NDMM Best MRD Response by Phase of Therapy
High-risk cytogenetic abnormalities (HRCA)
gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)
Primary end point
NGS MRD <10-5
Secondary end point
NGS MRD <10-6
All patients 0 HRCA
Post
induction
(n=118)
Post
AHCT
(n=118)
MRD-
directed
consolidation
(n=118)
80%
65%
38%
MRD (–) MRD (+)
MRD (–) MRD (+)
Post
induction
(n=50)
Post
AHCT
(n=50)
MRD-
directed
consolidation
(n=50)
78%
60%
40%
Post
induction
(n=44)
Post
AHCT
(n=44)
MRD-
directed
consolidation
(n=44)
82%
73%
41%
1 HRCA
Post
induction
(n=24)
Post
AHCT
(n=24)
MRD-
directed
consolidation
(n=24)
79%
63%
29%
2+ HRCA
Post
induction
(n=118)
Post
AHCT
(n=118)
MRD-
directed
consolidation
(n=118)
66%
48%
24%
Post
induction
(n=50)
Post
AHCT
(n=50)
MRD-
directed
consolidation
(n=50)
64%
44%
30%
Post
induction
(n=44)
Post
AHCT
(n=44)
MRD-
directed
consolidation
(n=44)
73%
59%
25%
Post
induction
(n=24)
Post
AHCT
(n=24)
MRD-
directed
consolidation
(n=24)
58%
38%
8%

30
0 6 12 18 24
0
0.
2
0.
4
0.
6
0.
8
1.
0
2+ HRCA
(ultra-high risk)
P<0.001
1 HRCA
0 HRCA
50 49 46 36 27 10
44 4 36 30 23 9
24 22 19 12 7 2
0 HRCA
1 HRCA
2+
HRCA
At risk (n): Months
Probability
of
PFS
Months
0 6 12 18 24 30
0
0.2
0.4
0.6
0.8
1.0
1 HRCA
0 HRCA
2+ HRCA
(Ultra-high
risk)
P=0.003
50 49 46 36 29 11
44 44 36 30 23 9
24 23 19 13 9 3
0 HRCA
1 HRCA
2+
HRCA
At risk (n):
Probability
of
OS
Progression-free survival
1 HRCA: 97%
0 HRCA: 91%
2+ HRCA:
58%
2-yr PFS
Overall survival
1 HRCA:
100%
0 HRCA: 96%
2+ HRCA:
76%
2-yr OS
MASTER: Final Analysis By Cytogenetic Risk Group
Costa et al, 2021.
NDMM
HRCA gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)

SKylaRk Trial: Transplant-Eligible NDMM
TE = transplant-eligible
O’Donnell et al, 2023.
Isatuximab, Once-Weekly Carfilzomib/Len/Dex
Maintenance (stratified based on cytogenetics and MRD status)
• Lenalidomide 10 mg PO Days 1-21
High-risk and/or MRD-positive:
• Carfilzomib 56 mg/m2 IV Days 1, 15
• Isatuximab 10 mg IV Day 1
Screening
Enrollment
Induction (Cycles 1-4)
• Carfilzomib 56 mg/m2 IV Days 1, 8, 15
• Dexamethasone 20 mg PO Days 1, 2, 8, 9, 15, 16
• Isatuximab 10 mg IV Q1W for 8 weeks then Q2W for 16 weeks, thereafter Q4W
Autologous SCT Transplant-deferred
Consolidation (Cycles 5-6)
Induction (Cycles 5-8)
Stem cell collection (SCT)

SKylaRk Trial: Transplant-Eligible NDMM (cont.)
O’Donnell et al, 2023.
Response to Therapy Survival

Ongoing MM Trials Using MRD
maint = maintenance.
Ramasamy et al, 2023; Clinicaltrials.gov, 2023b; Shah et al, 2021; Clinicaltrials.gov, 2023c.
Identifier MRD Treatment Study Population
Primary
Outcome
Sponsor
MRD
Modality
A. MRD testing to guide treatment after initial therapy
RADAR
+
Randomization to arms including R
maint, RVd consolidation + R maint,
R-isa maint, or isa-RVd
consolidation + R isa maint
Standard-risk
patients after auto
SCT
PFS
University of
Leeds
NGF
(10−5)
− Isa maint
NCT04140162
+ Consolidation with dara-RVd Following induction
with dara-R
MRD
University of
Michigan
NGS
− Maint dara-R
NCT03901963
AURIGA
+ Dara-R
After auto SCT MRD Janssen NGS
(10−5)
− R
NCT03224507
MASTER
+ Additional dara-KRd After dara-KRd and
auto SCT
MRD
University of
Alabama
NGS
(10−5)
− Observation (if MRD-negative ×2)

Ongoing Trials Using MRD
SWOG = Southwest Oncology Group; auto-SCT = autologous-SCT.
Clinicaltrials.gov, 2023a; Clinicaltrials.gov, 2023d; Clinicaltrials.gov, 2023e; Clinicaltrials.gov, 2023c; Clinicaltrials.gov, 2023g.
Identifier MRD Treatment Study Population
Primary
Outcome
Sponsor MRD Modality
B. MRD testing to guide treatment during maintenance
NCT04221178
+ Not applicable
Patients on 3 years of
continuous maint
MRD-
negative at 1
year
Memorial Sloan
Kettering
NGF (10−5)
− Discontinue maint
NCT04108624
MRD2STOP
+ Continue maint (off protocol)
Patients on maint
therapy and CR
MRD
University of
Chicago
NGS (10−6 and
exploring 10−7)
and PET CT
− Discontinue maint
NCT04071457
DRAMMATIC
SWOG S1803
+
Continue previously assigned
maint therapy
After 2 years of
maintenance
(previously
randomized to dara-R
vs R following auto-
SCT)
OS SWOG NGS
−
Randomization to continue vs
stopping previously assigned
maint therapy
NCT03710603
PERSEUS
+ Continue dara-R
After 24 months of
maint therapy with
dara-R
PFS
European
Myeloma
Network
NGS (10−5)
−
If MRD negative sustained for
12 months: discontinue dara;
continue R
NCT03697655
PREDATOR
+ Dara Patients after 1-2 prior
lines of therapy who
are MRD-negative
Event-free
survival
Polish Myeloma
Consortium
NGF (10−5)
− Observation

When Should You Order MRD Testing?
As part of clinical trial when included as required testing
All patients with high-risk myeloma after they attain a CR
Concept of sustained MRD negativity repeat testing to tailor therapy
Patient requests MRD testing
Multiple Myeloma

Future Directions
cfDNA = circulating free DNA.
Role of advanced imaging techniques
PET-MRI
Alternate disease specific radio-isotopes
Blood-based MRD assessment
cfDNA
Circulating cells
Sensitive assessment for monoclonal protein
Mass spectrometry-based assays

Key Takeaways
HR = high-risk.
MRD testing allows for better comparison of efficacy of new treatment
combinations given high response rates
Potential for regulatory end point in addition to PFS and OS
MRD conversion occurs over time
Ongoing studies to tailor therapy
Reasonable to test HR patients, with the goal of getting maximum
response with therapy
Sustained MRD negativity should be the goal—POTENTIAL CURE

Our Patients
nraje@mgh.harvard.edu
@NoopurRajeMD
Acknowledgments

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