Abstract

Smoldering multiple myeloma (MM) is an asymptomatic clonal plasma cell condition considered as a premalignant entity that may evolve over time to symptomatic MM. Based on a “poorly defined” risk of progression, some well-intended investigators proposed prospective interventional trials for these individuals. We believe this may be a harmful intervention and favor a close “wait and watch” approach and rather enroll these patients in dedicated observational biological studies aiming to better identify patients who will evolve to MM, based on their plasma cells' biology, including genomics, epigenetics, and the immune microenvironment.

1.
Kyle
RA
,
Elveback
LR
.
Management and prognosis of multiple myeloma
.
Mayo Clin Proc
.
1976
;
51
(
12
):
751
-
760
.
2.
Kyle
RA
,
Remstein
ED
,
Therneau
TM
, et al
.
Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma
.
N Engl J Med
.
2007
;
356
(
25
):
2582
-
2590
.
3.
Thorsteinsdóttir
S
,
Gíslason
GK
,
Aspelund
T
, et al
.
Prevalence of smoldering multiple myeloma based on nationwide screening
.
Nat Med
.
2023
;
29
(
2
):
467
-
472
.
4.
Pérez-Persona
E
,
Vidriales
MB
,
Mateo
G
, et al
.
New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells
.
Blood
.
2007
;
110
(
7
):
2586
-
2592
.
5.
Lakshman
A
,
Rajkumar
SV
,
Buadi
FK
, et al
.
Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria
.
Blood Cancer J
.
2018
;
8
(
6
):
59
-
66
.
6.
Hill
E
,
Dew
A
,
Morrison
C
, et al
.
Assessment of discordance among smoldering multiple myeloma risk models
.
JAMA Oncol
.
2021
;
7
(
1
):
132
-
134
.
7.
Mateos
M-V
,
Kumar
S
,
Dimopoulos
MA
, et al
.
International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)
.
Blood Cancer J
.
2020
;
10
(
10
):
102
-
110
.
8.
Cowan
A
,
Ferrari
F
,
Freeman
SS
, et al
.
Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study
.
Lancet Haematol
.
2023
;
10
(
3
):
e203
-
e212
.
9.
Dang
M
,
Wang
R
,
Lee
HC
, et al
.
Single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease
.
Cancer Cell
.
2023
;
41
(
6
):
1032
-
1047.e4
.
10.
Zavidij
O
,
Haradhvala
NJ
,
Mouhieddine
TH
, et al
.
Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma
.
Nat Cancer
.
2020
;
1
(
5
):
493
-
506
.
11.
Sklavenitis-Pistofidis
R
,
Aranha
MP
,
Redd
RA
, et al
.
Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma
.
Cancer Cell
.
2022
;
40
(
11
):
1358
-
1373.e8
.
12.
Bailur
JK
,
McCachren
SS
,
Doxie
DB
, et al
.
Early alterations in stem-like/resident T cells, innate and myeloid cells in the bone marrow in preneoplastic gammopathy
.
JCI Insight
.
2019
;
5
(
11
):
e127807
.
13.
Spisek
R
,
Kukreja
A
,
Chen
LC
, et al
.
Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy
.
J Exp Med
.
2007
;
204
(
4
):
831
-
840
.
14.
Mateos
MV
,
Hernández
MT
,
Giraldo
P
, et al
.
Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma
.
N Engl J Med
.
2013
;
369
(
5
):
438
-
447
.
15.
Rajkumar
SV
,
Dimopoulos
MA
,
Palumbo
A
, et al
.
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
.
Lancet Oncol
.
2014
;
15
(
12
):
e538
-
548
.
16.
Lonial
S
,
Jacobus
S
,
Fonseca
R
, et al
.
Randomized trial of lenalidomide versus observation in smoldering multiple myeloma
.
J Clin Oncol
.
2020
;
38
(
11
):
1126
-
1137
.
17.
Mina
R
,
Musto
P
,
Rota-Scalabrini
D
, et al
.
Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial
.
Lancet Oncol
.
2023
;
24
(
1
):
64
-
76
.
18.
Burgos
L
,
Tamariz-Amador
L-E
,
Puig
N
, et al
.
Definition and clinical significance of the monoclonal gammopathy of undetermined significance–like phenotype in patients with monoclonal gammopathies
.
J Clin Oncol
.
2023
;
41
(
16
):
3019
-
3031
.
19.
Kazandjian
D
,
Diamond
B
,
Papadimitriou
M
, et al
.
Genomic profiling to contextualize the results of intervention for high-risk smoldering myeloma
.
medRxiv
.
Preprint posted online 31 August 2023
.
20.
Oben
B
,
Froyen
G
,
Maclachlan
KH
, et al
.
Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
.
Nat Commun
.
2021
;
12
(
1
):
1861
-
1869
.
21.
Bustoros
M
,
Anand
S
,
Sklavenitis-Pistofidis
R
, et al
.
Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
.
Nat Commun
.
2022
;
13
(
1
):
3449
-
3455
.
22.
Bustoros
M
,
Sklavenitis-Pistofidis
R
,
Park
J
, et al
.
Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression
.
J Clin Oncol
.
2020
;
38
(
21
):
2380
-
2389
.
You do not currently have access to this content.
Sign in via your Institution