DOI: 10.1002/hon.

2586

SUPPLEMENT ARTICLE

Multiple myeloma: Every year a new standard?

S. Vincent Rajkumar

Division of Hematology, Mayo Clinic,

Rochester, MN Abstract
The treatment of myeloma is rapidly evolving. This article reviews the current diag-
Correspondence
S. Vincent Rajkumar, Division of Hematology, nostic criteria, risk stratification, and approach to treatment of multiple myeloma.
Mayo Clinic, 200 First Street SW, Rochester, Treatment approach for both newly diagnosed and relapsed disease are discussed.
MN 55905.
Email: [email protected]
K E Y W OR D S

Funding information myeloma, prognosis, therapy

National Cancer Institute, Grant/Award Num-
bers: CA 186781, CA 168762 and CA 107476

1 | I N T RO D U CT I O N daratumumab are monoclonal antibodies targeting SLAMF7 and

CD38, respectively. Panobinostat is a deacetylase inhibitor.
Multiple myeloma (MM) accounts for about 10% of all hematologic Numerous regimens have been developed with these new drugs,
malignancies. The revised International Myeloma Working Group and each year, additional new regimens are being developed. Recent
criteria for the diagnosis of MM and related disorders are shown in data show that minimal residual disease (MRD)–negative status (as
Table 1.1 The diagnosis of MM requires the presence of one or more estimated by next‐generation molecular methods or flow cytometry)
myeloma‐defining events (MDEs) in addition to evidence of either has favorable prognostic value.3 However, additional trials are needed
10% or more clonal plasma cells on bone marrow examination or a to determine if changes in treatment need to be made on the basis of
biopsy‐proven plasmacytoma. MDE consists of established CRAB fea- MRD status. At present, MRD results are recommended mainly as a
tures (hypercalcemia, renal failure, anemia, or lytic bone lesions) and prognostic metric and not for use in making treatment decisions.
three specific biomarkers: clonal bone marrow plasma cells of 60%
or higher, serum free light chain (FLC) ratio of 100 or higher (provided
involved FLC level is ≥100 mg/L), and more than one focal lesion on
magnetic resonance imaging (MRI). Each of the new biomarkers is 2 | I N I T I A L TR E A T M EN T I N P A T I E N T S
associated with an approximately 80% risk of progression to symp- E L I G I B L E F O R TR A N S P LA N T A T I O N
tomatic end‐organ damage in two or more independent studies.
Although MM is still considered a single disease, it is in reality a Typically, patients are treated with approximately 3 to 4 cycles of
collection of several different cytogenetically distinct plasma cell induction therapy with bortezomib, lenalidomide, and dexametha-
malignancies. Trisomies and IgH translocations are considered primary sone (VRd) prior to stem cell harvest.4 If lenalidomide is not available
cytogenetic abnormalities and occur at the time of establishment of for use as initial therapy or in the presence of acute renal
monoclonal gammopathy of undetermined significance (MGUS). Other failure, other bortezomib‐containing regimens such as bortezomib‐
cytogenetic changes termed secondary cytogenetic abnormalities thalidomide‐dexamethasone (VTd) or bortezomib‐cyclophospha-
occur during disease course such as gain(1q), del(1p), del(17p), mide‐dexamethasone (VCd) can be used instead of VRd. After
del(13), RAS mutations, and secondary translocations involving MYC. harvest, patients can either undergo frontline autologous stem cell
The presence of del(17p), gain(1q), t(4;14), t(14;16), and t(14;20) are transplantation (ASCT) or resume induction therapy delaying ASCT
considered to reflect high‐risk disease. until first relapse. In general, the low‐dose dexamethasone regimen
2
Survival of MM has improved significantly in the last 15 years. (40 mg, once a week) is preferred in all regimens to minimize toxic-
There are many active drugs to treat MM in addition to alkylators ity. In a randomized trial, low‐dose dexamethasone approach was
and corticosteroids. Thalidomide, lenalidomide, and pomalidomide associated with superior survival and significantly lower toxicity.5
are termed immunomodulatory agents (IMiDs). Bortezomib, Similarly, the neurotoxicity of bortezomib can be greatly diminished
carfilzomib, and ixazomib are proteasome inhibitors. Elotuzumab and by administering bortezomib once a week instead of twice weekly

62 © 2019 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/hon Hematological Oncology. 2019;37(S1):62–65.
RAJKUMAR 63

TABLE 1 International Myeloma Working Group diagnostic criteria for MM and related plasma cell disordersa

Disorder Disease Definition

Non‐IgM monoclonal gammopathy of All 3 criteria must be met:

undetermined significance (MGUS) • Serum monoclonal protein (non‐IgM type) < 3 g/dL
• Clonal bone marrow plasma cells < 10%b
• Absence of end‐organ damage such as hypercalcemia, renal insufficiency, anemia, and bone
lesions (CRAB) that can be attributed to the plasma cell proliferative disorder
Smoldering MM Both criteria must be met:
• Serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥ 500 mg per 24 h
and/or clonal bone marrow plasma cells 10%‐60%
• Absence of myeloma‐defining events or amyloidosis
MM Both criteria must be met:
• Clonal bone marrow plasma cells ≥ 10% or biopsy‐proven bony or extramedullary plasmacytoma
• Any one or more of the following myeloma‐defining events:
○ Evidence of end‐organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically
▪ Hypercalcemia: serum calcium > 0.25 mmol/L (>1 mg/dL) higher than the upper limit of
normal or >2.75 mmol/L (>11 mg/dL)
▪ Renal insufficiency: creatinine clearance < 40 mL/min or serum creatinine > 177 μmol/
L (>2 mg/dL)
▪ Anemia: hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin
value < 10 g/dL
▪ Bone lesions: one or more osteolytic lesions on skeletal radiography, computerized
tomography (CT), or positron emission tomography–CT (PET‐CT)
○ Clonal bone marrow plasma cell percentage ≥ 60%
○ Involved:uninvolved serum free light chain (FLC) ratio ≥ 100 (involved FLC level must be ≥
100 mg/L)
○ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size)
IgM MGUS All 3 criteria must be met:
• Serum IgM monoclonal protein < 3 g/dL
• Bone marrow lymphoplasmacytic infiltration < 10%
• No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder
Light‐chain MGUS All criteria must be met:
• Abnormal FLC ratio (<0.26 or >1.65)
• Increased level of the appropriate involved light chain (increased kappa FLC in patients with
ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26)
• No immunoglobulin heavy chain expression on immunofixation
• Absence of end‐organ damage that can be attributed to the plasma cell proliferative disorder
• Clonal bone marrow plasma cells < 10%
• Urinary monoclonal protein < 500 mg/24 h
Solitary plasmacytoma All 4 criteria must be met:
• Biopsy‐proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
• Normal bone marrow with no evidence of clonal plasma cells
• Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
• Absence of end‐organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions
(CRAB) that can be attributed to a lympho‐plasma cell proliferative disorder
Solitary plasmacytoma with minimal marrow All 4 criteria must be met:
involvementc • Biopsy‐proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
• Clonal bone marrow plasma cells <10%
• Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
• Absence of end‐organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions
(CRAB) that can be attributed to a lympho‐plasma cell proliferative disorder

Abbreviation: MM, multiple myeloma.

a
Reproduced from Rajkumar et al.1
b
A bone marrow can be deferred in patients with low‐risk MGUS (IgG type, M protein < 15 g/L, normal FLC ratio) in whom there are no clinical features
concerning for myeloma.
c
Solitary plasmacytoma with 10% or more clonal plasma cells is considered as MM.
64 RAJKUMAR

and by administering the drug subcutaneously instead of the intrave- because in newly diagnosed MM, VRd, VCd, and VTd are active regi-
nous route. mens in relapsed disease.
New options for initial therapy in younger patients include Three daratumumab‐based combinations have shown efficacy:
carfilzomib‐lenalidomide‐dexamethasone (KRd); daratumumab, DRd; daratumumab, bortezomib, and dexamethasone (DVd); and
lenalidomide, and dexamethasone (DRd); and daratumumab plus daratumumab, pomalidomide, and dexamethasone (DPd).8 Other
VRd. But additional data on impact of these regimens compared with options include KRd; ixazomib, lenalidomide, dexamethasone (IRd);
that of VRd are needed. A randomized trial in the United States elotuzumab, lenalidomide, and dexamethasone (ERd); and various
(referred to as the Endurance trial) is currently ongoing comparing pomalidomide‐based regimens such as DPd and carfilzomib,
VRd versus KRd as initial therapy. pomalidomide, and dexamethasone (KPd). For aggressive relapses,
anthracycline‐containing regimens may be useful.
Other drugs to consider for relapse include panobinostat, a pan‐
3 | INITIAL TREATMENT IN PATIENTS NOT deacetylase inhibitor, and bendamustine‐containing regimens such as
ELIGIBLE FOR TRANSPLANTATION
bendamustine, lenalidomide, and dexamethasone; or bendamustine,
bortezomib, and dexamethasone. Venetoclax appears to have single‐
In patients with newly diagnosed MM who are not candidates for
agent activity in patients with t(11;14) subtype of MM.
ASCT because of age or other comorbidities, initial therapy with VRd
Two of the most exciting investigational options are chimeric anti-
is administered for approximately 8 to 12 cycles, followed by mainte-
gen receptor T cells (CAR‐T) targeting B‐cell maturation antigen
nance therapy with lenalidomide. Alternatives to VRd include VCd and
(BCMA) such as bb2121,9 and GSK2857916 (a humanized anti‐BCMA
VTd as discussed earlier.
antibody that is conjugated to monomethyl auristatin‐F, a microtubule
disrupting agent).10 Other agents with single‐agent activity that are
4 | STEM CELL TRANSPLANTATION promising include isatuximab, selinexor, and LGH‐447 (a pan PIM
kinase inhibitor).
A recent trial by the Intergroupe Francophone du Myelome compared
early versus delayed ASCT in patients treated with VRd followed by ACKNOWLEDGEMENTS
lenalidomide maintenance.6 Patients were randomized to receive This study was supported in part by grants CA 107476, CA 168762,
either VRd (3 cycles) followed by ASCT and then VRd consolidation and CA 186781 from the National Cancer Institute, Rockville, MD,
(2 cycles) versus VRd × 8 cycles with ASCT reserved for relapse. Both USA.
arms received lenalidomide maintenance for 1 year. A significant
improvement in progression‐free survival (PFS) was seen as expected CONFLIC T OF INT E RE ST
with early ASCT, but this has so far not been translated into a differ-
S.V.R. declares no conflict of interest.
ence in overall survival (OS). Allogeneic transplantation is still investi-
gational but can be considered for young patients with high‐risk
AUTHOR CONT R IBUT ION
disease in first relapse.
S.V.R. conceived the paper, researched the literature, and wrote the
manuscript.
5 | MAIN T E NAN C E T HE R A PY
RE FE RE NC ES
Maintenance with lenalidomide is the standard of care for most
1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Mye-
patients after initial therapy. In a meta‐analysis of randomized tri- loma Working Group updated criteria for the diagnosis of MM.
als, a significant improvement in PFS and OS was seen with Lancet Oncol. 2014;15(12):e538‐e548.
lenalidomide maintenance compared with placebo or no therapy.7
2. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in
For high‐risk patients, bortezomib‐based maintenance should be survival in MM: changes in early mortality and outcomes in older
considered. patients. Leukemia. 2014;28(5):1122‐1128.

3. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working

Group consensus criteria for response and minimal residual disease
6 | R E LA P S E D M M assessment in MM. Lancet Oncol. 2016;17(8):e328‐e346.

Almost all patients with MM eventually relapse. The choice of a treat- 4. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib, lenalidomide and
dexamethasone vs. lenalidomide and dexamethasone induction
ment regimen at relapse is complicated and is affected by many fac-
followed by lenalidomide and dexamethasone maintenance in patients
tors including the timing of the relapse, response to prior therapy, with newly diagnosed myeloma without intent for immediate autolo-
aggressiveness of the relapse, and performance status (TRAP). gous stem cell transplant: results of the randomised phase III SWOG
Patients who are eligible for transplantation should be considered trial S0777. Lancet. 2017;389(10068):519‐527.

for the procedure if they have never had one before or if they have 5. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high‐
had an excellent remission duration with the first transplantation, dose dexamethasone versus lenalidomide plus low‐dose
RAJKUMAR 65

dexamethasone as initial therapy for newly diagnosed MM: an open‐ a multicenter study of bb2121 anti‐BCMA CAR T cell therapy. Blood.
label randomised controlled trial. Lancet Oncol. 2010;11(1):29‐37. 2017;130:740.
6. Attal M, Lauwers‐Cances V, Hulin C, et al. Lenalidomide, bortezomib, 10. Trudel S, Lendvai N, Popat R, et al. Deep and durable responses in
and dexamethasone with transplantation for myeloma. N Engl J Med. patients (Pts) with relapsed/refractory MM (MM) treated with mono-
2017;376(14):1311‐1320. therapy GSK2857916, an antibody drug conjugate against B‐cell
7. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) mainte- maturation antigen (BCMA): preliminary results from part 2 of study
nance (MNTC) after high‐dose melphalan and autologous stem cell BMA117159. Blood. 2017;130:741.
transplant (ASCT) in MM (MM): a meta‐analysis (MA) of overall survival
(OS). J Clin Oncol. 2016;34 (suppl):A8001. (abstract)
How to cite this article: Rajkumar SV. Multiple myeloma:
8. Rajkumar SV, Kyle RA. Progress in myeloma—a monoclonal break-
through. N Engl J Med. 2016;375(14):1390‐1392. Every year a new standard? Hematological Oncology.

9. Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily 2019;37(S1):62–65. https://doi.org/10.1002/hon.2586
pretreated patients with relapsed/refractory MM: updated results from