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Reviews on Recent Clinical Trials, 2022, 17, 9-10

PERSPECTIVE
ISSN: 1574-8871
eISSN: 1876-1038

Minimal Residual Disease in Multiple Myeloma: an Important Tool in

Clinical Trials
BENTHAM
SCIENCE

1,* 1
Alessandro Gozzetti and Monica Bocchia
1
Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Policlinico “Santa Maria alle Scotte”,
Siena, Italy

ARTICLE HISTORY
Received: September 23, 2021
Revised: October 07, 2021
Accepted: October 07, 2021
DOI:
10.2174/1574887116666211123092915
Abstract: Minimal residual disease (MRD) detection represents a great advancement in multiple
myeloma. New drugs are now available that increase depth of response. The International Myelo-
ma Working Group recommends using next-generation flow cytometry (NGF) or next-generation
sequencing (NGS) to search for MRD in clinical trials. Best sensitivity thresholds have to be con-
firmed, as well as timing to detect it. MRD has proven as the best prognosticator in many trials and
promises to enter also in clinical practice to guide future therapy.

Keywords: Multiple myeloma, minimal residual disease, next-generation flow, cure, complete remission, therapy.

1. MULTIPLE MYELOMA: NOVEL DRUGS AND ients in CR ultimately relapse after a different range of
Reviews on Recent Clinical Trials

NOVEL THERAPEUTIC STRATEGIES
Multiple myeloma (MM) represents the second hemato-
logical cancer after non-Hodgkin’s lymphomas [1]. While
the disease is still defined as incurable, in the past 20 years,
MM patients have experienced great advances in progres-
sion-free survival (PFS) and overall survival (OS) [2-5]. OS
has increased from a median of 3-4 years to a median of 8-9
years [5]. The introduction of novel drugs changed the per-
spective of the disease completely. These drugs are: i) the
immunomodulatory (IMID’s) thalidomide, lenalidomide,
and pomalidomide; ii) the proteasome inhibitors (PI’s) Borte-
zomib, Carfilzomib, Ixazomib; iii) the monoclonal anti-
bodies (MoA) Daratumumab, Elotuzumab, Isatuximab, Be-
lantamab. These drugs can be used alone or combined or in
triplets and quadruplets and leading to overwhelming re-
sponses that can reach 90% of the treated patients [4]. Also,
particular aggressive conditions, such as extramedullary dis-
ease, can benefit from these associations [6-8]. Strategies,
such as consolidation therapy and maintenance after autolo-
gous stem cell transplantation (ASCT) further improved PFS
and OS [8,9].
2. THE CONCEPT OF MINIMAL RESIDUAL DIS-
EASE
Drugs are so efficacious that MM patients can show the
disappearance of the disease very quickly. Until just a few
years ago, complete remission (CR) was defined by the dis-
appearance of the monoclonal component in serum and
urine and by <5% of monoclonal plasma cells in the bone
marrow. This is not enough nowadays since most of the pat-
*Address correspondence to this author at the Hematology, University of
Siena, Azienda Ospedaliera Universitaria Senese, Policlinico “Santa Maria
alle Scotte”, Siena, Italy; Fax: +39-0577586185; E-mail: gozzetti@unisi.it
1876-1038/22 $65.00+.00
years. MRD has introduced a few years ago as Next-Genera-
tion Flow (NGF) and Next-Generation Sequencing (NGS)
[10,11]. These techniques can allow identifying monoclonal
-5 -6
myeloma plasma cells 10 or 10 . New clinical trials that
want to test new drug efficacy have to consider applying
MRD techniques to measure depth of response quickly. Mea-
suring only PFS and OS can require longer follow-up in clin-
ical trials, while single MRD negativity detection can allow
immediate results. Recent response criteria defined by the In-
ternational Myeloma Working Group (IMWG) introduced
MRD as a tool to judge the depth of response [12]. Both
NGF or NGS are allowed to measure MRD due to local avai-
-5
lability, and 10 was indicated as the target cut-off. A sus-
tained MRD negativity at one year can be the first evidence
for long-term remission [13]. Many trials are now evaluating
MRD as an endpoint. A recent meta-analysis was done in
8098 patients enrolled in 44 studies [13] regarding MRD ef-
fect on PFS and 4297 patients from 23 studies regarding OS.
MRD negativity measured by NGF or NGS was associated
with increased PFS and OS, with statistical significance. In
this meta-analysis, MRD was always predictive for survivals
-4 -5 -6
at different sensitivity levels of 10 , 10 , 10 , although the
-6
best threshold was set at 10 when differences for MRD neg-
ativity were more marked and if MRD negativity was detect-
ed at 12 months from initial treatment. MRD keeps its signif-
icance irrespective of age. This was confirmed in the large
MAIA trial that compared Daratumumab-lenalidomide-dex-
amethasone (Dara-Rd) vs lenalidomide-dexamethasone (Rd)
in transplant-ineligible MM patients>65 years of age [14].
Median PFS has not been reached for the Dara-Rd arm at
more than 50 months of follow up, and MRD negativity was
detected in 31% of these patients vs 10% in the RD group.
Three-years PFS was 76% vs 37% for both groups of pa-
tients, respectively.
© 2022 Bentham Science Publishers
10 Reviews on Recent Clinical Trials, 2022, Vol. 17, No. 1
3. MRD CONS
MRD pitfalls are present. First, bone marrow haemo-dilu-
tion can be a problem when using both NGF or NGS, and
samples need to be adequate to have a reliable result.
Another problem arises from the possibility of a patchy dis-
ease in the bone marrow and the possibility of false-negative
results [11]. Liquid biopsy (i.e. MRD done on peripheral
blood) in the future will help in disease monitoring. So far,
neither NGF nor NGS proved to be adequate for peripheral
blood MRD, and analysis of the bone marrow is still the
gold standard. Finally, MRD in the bone marrow always
needs to be accompanied by radiological techniques such as
PET-CT that proved to be very useful in special cases of ex-
tramedullary disease [15-17].
CONCLUSION
MM patients still relapse after a variable period of remis-
sion. Besides the need for novel, more efficacious drugs, al-
so better prognosticators are needed. MRD measured by
NGF or NGS entered into the MM diagnostic armamentari-
um and are routinely performed in clinical trials. MRD
holds promises to enter also the clinical practice to have
more personalized treatments.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics,
2021. CA Cancer J Clin 2021; 71(1): 7-33.
http://dx.doi.org/10.3322/caac.21654 PMID: 33433946
[2] Gozzetti A, Candi V, Papini G, Bocchia M. Therapeutic advance-
ments in multiple myeloma. Front Oncol 2014; 4: 241.
http://dx.doi.org/10.3389/fonc.2014.00241 PMID: 25237651
[3] Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and
novel mechanisms of action in multiple myeloma in 2013: a report
from the International Myeloma Working Group (IMWG).
Leukemia 2014; 28(3): 525-42.
http://dx.doi.org/10.1038/leu.2013.350 PMID: 24253022
[4] Mohty M, Terpos E, Mateos MV, et al. Multiple myeloma treat-
ment in real-world clinical practice: results of a prospective, multi-
Gozzetti and Bocchia
national, noninterventional study. Clin Lymphoma Myeloma Leuk
2018; 18(10): e401-19.
http://dx.doi.org/10.1016/j.clml.2018.06.018 PMID: 30030033
[5] Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival
in multiple myeloma and the impact of novel therapies. Blood
2008; 111(5): 2516-20.
http://dx.doi.org/10.1182/blood-2007-10-116129 PMID:
17975015
[6] Castillo JJ, Jurczyszyn A, Brozova L, et al. IgM myeloma: A mul-
ticenter retrospective study of 134 patients. Am J Hematol 2017;
92(8): 746-51.
http://dx.doi.org/10.1002/ajh.24753 PMID: 28383205
[7] Gozzetti A, Cerase A. Novel agents in CNS myeloma treatment.
Cent Nerv Syst Agents Med Chem 2014; 14(1): 23-7.
http://dx.doi.org/10.2174/1871524914999140818111514 PMID:
25134940
[8] Kocoglu MH, Badros AZ. Newly diagnosed multiple myeloma:
current treatment strategies, emerging therapeutic approaches and
beyond. Expert Rev Hematol 2020; 13(6): 669-86.
http://dx.doi.org/10.1080/17474086.2020.1756258 PMID:
32290719
[9] Gozzetti A, Bacchiarri F, Sammartano V, et al. Long-term safety
of rapid daratumumab infusions in multiple myeloma patients.
Front Oncol 2020; 10: 570187.
http://dx.doi.org/10.3389/fonc.2020.570187 PMID: 33415072
[10] Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next generation
flow for highly sensitive and standardized detection of minimal
residual disease in multiple myeloma. Leukemia 2017; 31(10):
2094-103.
http://dx.doi.org/10.1038/leu.2017.29 PMID: 28104919
[11] Gozzetti A, Raspadori D, Bacchiarri F, et al. Minimal residual dis-
ease in multiple myeloma: state of the art and applications in clini-
cal practice. J Pers Med 2020; 10(3): 120.
http://dx.doi.org/10.3390/jpm10030120 PMID: 32927719
[12] Kumar S, Paiva B, Anderson KC, et al. International Myeloma
Working Group consensus criteria for response and minimal resid-
ual disease assessment in multiple myeloma. Lancet Oncol 2016;
17(8): e328-46.
http://dx.doi.org/10.1016/S1470-2045(16)30206-6 PMID:
27511158
[13] Munshi NC, Avet-Loiseau H, Anderson KC, et al. A large meta-a-
nalysis establishes the role of MRD negativity in long-term survi-
val outcomes in patients with multiple myeloma. Blood Adv
2020; 4(23): 5988-99.
http://dx.doi.org/10.1182/bloodadvances.2020002827 PMID:
33284948
[14] Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalido-
mide and dexamethasone for untreated myeloma. N Engl J Med
2019; 380(22): 2104-15.
http://dx.doi.org/10.1056/NEJMoa1817249 PMID: 31141632
[15] Kaddoura M, Dingli D, Buadi FK, et al. Prognostic impact of post-
transplant FDG PET/CT scan in multiple myeloma. Blood Adv
2021; 5(13): 2753-9.
http://dx.doi.org/10.1182/bloodadvances.2020004131 PMID:
34242392
[16] Lecouvet FE, Vekemans MC, Van Den Berghe T, et al. Imaging
of treatment response and minimal residual disease in multiple
myeloma: state of the art WB-MRI and PET/CT. Skeletal Radiol
2021.
http://dx.doi.org/10.1007/s00256-021-03841-5 PMID: 34363522
[17] Bertamini L, D’Agostino M, Gay F. MRD assessment in multiple
myeloma: progress and challenges. Curr Hematol Malig Rep
2021; 16(2): 162-71.
http://dx.doi.org/10.1007/s11899-021-00633-5 PMID: 33950462