Abstract

Initial management of high-risk myeloma remains a treatment challenge. Risk is defined by a combination of clinical and biological features, with fluorescence in situ hybridization detection of specific cytogenetic abnormalities driving categorization. High-risk abnormalities include t(4;14), t(14;16), t(14;20), del(17p), and +1q. Clinical features such as plasma cell leukemia, presence of 5% to 20% circulating plasma cells, and extramedullary disease all are factors in high-risk presentations. The driving principle of treatment of the high-risk patient is the use of a regimen with the greatest likelihood of a deep and prolonged remission, as defined by minimal residual disease negativity. I will describe prior and current treatment approaches, including induction, the role of autologous transplantation, and posttransplantation consolidation and maintenance therapy selection using the best available data to provide a rationale for these decisions. This case-based roundtable walks through treatment of a patient with newly diagnosed high-risk myeloma.

References

References
1.
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
-
e548
.
2.
Palumbo
A
,
Avet-Loiseau
H
,
Oliva
S
, et al
.
Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group
.
J Clin Oncol
.
2015
;
33
(
26
):
2863
-
2869
.
3.
Sonneveld
P
,
Avet-Loiseau
H
,
Lonial
S
, et al
.
Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group
.
Blood
.
2016
;
127
(
24
):
2955
-
2962
.
4.
Chng
WJ
,
Chung
TH
,
Kumar
S
, et al
.
Gene signature combinations improve prognostic stratification of multiple myeloma patients
.
Leukemia
.
2016
;
30
(
5
):
1071
-
1078
.
5.
Usmani
SZ
,
Crowley
J
,
Hoering
A
, et al
.
Improvement in long-term outcomes with successive Total Therapy trials for multiple myeloma: are patients now being cured?
Leukemia
.
2013
;
27
(
1
):
226
-
232
.
6.
Fernández de Larrea
C
,
Kyle
RA
,
Durie
BG
, et al
;
International Myeloma Working Group
.
Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group
.
Leukemia
.
2013
;
27
(
4
):
780
-
791
.
7.
Granell
M
,
Calvo
X
,
Garcia-Guiñón
A
, et al
;
GEMMAC (Grup per l’estudi del mieloma i l’amiloïdosi de Catalunya)
.
Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition
.
Haematologica
.
2017
;
102
(
6
):
1099
-
1104
.
8.
Jackson
GH
,
Davies
FE
,
Pawlyn
C
, et al
;
UK NCRI Haemato-oncology Clinical Studies Group
.
Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol
.
2019
;
20
(
1
):
57
-
73
.
9.
Walker
BA
,
Mavrommatis
K
,
Wardell
CP
, et al
.
A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
.
Leukemia
.
2019
;
33
(
1
):
159
-
170
.
10.
Thakurta
A
,
Ortiz
M
,
Blecua
P
, et al
.
High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma
.
Blood
.
2019
;
133
(
11
):
1217
-
1221
.
11.
Richardson
PG
,
Weller
E
,
Lonial
S
, et al
.
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma
.
Blood
.
2010
;
116
(
5
):
679
-
686
.
12.
Durie
BG
,
Hoering
A
,
Abidi
MH
, et al
.
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial
.
Lancet
.
2017
;
389
(
10068
):
519
-
527
.
13.
Attal
M
,
Lauwers-Cances
V
,
Hulin
C
, et al
;
IFM 2009 Study
.
Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma
.
N Engl J Med
.
2017
;
376
(
14
):
1311
-
1320
.
14.
Perrot
A
,
Lauwers-Cances
V
,
Corre
J
, et al
.
Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma
.
Blood
.
2018
;
132
(
23
):
2456
-
2464
.
15.
Joseph
N
,
Gupta
VA
,
Hofmeister
CC
, et al
.
Efficacy of induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in 1000 newly diagnosed multiple myeloma (MM) patients [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
3294
.
16.
Jakubowiak
AJ
,
Dytfeld
D
,
Griffith
KA
, et al
.
A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma
.
Blood
.
2012
;
120
(
9
):
1801
-
1809
.
17.
Korde
N
,
Roschewski
M
,
Zingone
A
, et al
.
Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma
.
JAMA Oncol
.
2015
;
1
(
6
):
746
-
754
.
18.
Gay
F
,
Cerrato
C
,
Scalabrini
DR
, et al
.
Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized FORTE Trial in newly diagnosed multiple myeloma (NDMM) [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
121
.
19.
Gay
F
,
Cerrato
C
,
Petrucci
MT
, et al
.
Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial [abstract]
.
J Clin Oncol
.
2019
;
37
(
15 suppl
):
8002
.
20.
Yoshimi
A
,
Balasis
ME
,
Vedder
A
, et al
.
Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML
.
Blood
.
2017
;
130
(
4
):
397
-
407
.
21.
Cavo
M
,
Gay
FM
,
Patriarca
F
, et al
.
Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 Study [abstract]
.
Blood
.
2017
;
130
(
suppl 1
):
401
.
22.
Stadtmauer
EA
,
Pasquini
MC
,
Blackwell
B
, et al
.
Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 Trial
.
J Clin Oncol
.
2019
;
37
(
7
):
589
-
597
.
23.
McCarthy
PL
,
Holstein
SA
,
Petrucci
MT
, et al
.
Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis
.
J Clin Oncol
.
2017
;
35
(
29
):
3279
-
3289
.
24.
Gay
F
,
Jackson
G
,
Rosiñol
L
, et al
.
Maintenance treatment and survival in patients with myeloma: a systematic review and network meta-analysis
.
JAMA Oncol
.
2018
;
4
(
10
):
1389
-
1397
.
25.
Jackson
GH
,
Davies
FE
,
Pawlyn
C
, et al
.;
UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol
.
2019
;
20
(
1
):
57
-
73
.
26.
Goldschmidt
H
,
Lokhorst
HM
,
Mai
EK
, et al
.
Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial
.
Leukemia
.
2018
;
32
(
2
):
383
-
390
.
27.
Nooka
AK
,
Kaufman
JL
,
Muppidi
S
, et al
.
Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients
.
Leukemia
.
2014
;
28
(
3
):
690
-
693
.
28.
Nooka
AK
,
Kaufman
JL
,
Hofmeister
CC
, et al
.
Daratumumab in multiple myeloma
.
Cancer
.
2019
;
125
(
14
):
2364
-
2382
.
29.
Moreau
P
,
Attal
M
,
Hulin
C
, et al
.
Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study
.
Lancet
.
2019
;
394
(
10192
):
29
-
38
.
30.
Voorhees
PM
,
Rodriguez
C
,
Reeves
B
, et al
.
Efficacy and updated safety analysis of a safety run-in cohort from griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara‐Vrd) vs. Vrd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT) [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
151
.
31.
Salwender
H
,
Bertsch
U
,
Weisel
K
, et al
.
Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma
.
BMC Cancer
.
2019
;
19
(
1
):
504
.
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