Treatment of Smoldering Multiple Myeloma

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1		Tyler Lussier	+ 2152 word(s)	2152	2022-02-09 04:39:40	\|
2	format correct	Nora Tang	-2 word(s)	2150	2022-02-28 01:59:15	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells11010130

Smoldering multiple myeloma was first identified in 1980. It is a heterogeneous asymptomatic precursor to multiple myeloma, a cancer of plasma cells, and the intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma.

smoldering multiple myeloma multiple myeloma treatment

1. Introduction

Smoldering multiple myeloma (SMM) or asymptomatic multiple myeloma (AMM) is a heterogeneous asymptomatic precursor to multiple myeloma (MM)^[1]. It is the intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and MM, where there is a subset of patients with indolent disease and a subset with a progressive disease^[1]^[2]^[3]. SMM has an overall higher risk of progression to MM compared to MGUS^[2], at 10% per year versus 1% per year.

The term SMM was first proposed in 1980 by Kyle and Greipp after reviewing all of the MM patients at the Mayo Clinic before 1 January 1974^[4]. This led to the discovery of six patients who met the diagnosis criteria for MM at the time of ≥10% abnormal bone marrow plasma cells (BMPCs) and a serum M-protein concentration >3 g/dL^[4], but they did not present with the characteristic CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features of MM^[1]^[4]. Therefore, these patients were said to have SMM as an analogy to smoldering acute leukemia^[4], an asymptomatic precursor to acute leukemia.

In 2003, the International Myeloma Working Group (IMWG) proposed new criteria for the diagnosis of MM as well as its related precursors of MGUS and SMM^[5]. SMM was defined here as M-protein ≥ 3 g/dL and/or clonal BMPCs ≥ 10% with no related end-organ damage^[5], which are the CRAB features, or recurrent bacterial infections related to the malignancy. The diagnostic criteria for SMM as well as MM and MGUS were updated by the IMWG in 2014^[1]. Diagnosis of SMM now requires the absence of myeloma-defining events^[1], specifically the CRAB features and nonrecurrent bacterial infections, as well as serum M-protein (IgG or IgA) ≥ 3 g/dL or urinary M-protein ≥ 500 mg/24 h and/or 10–60% clonal BMPCs. In this new model, SMM patients with an 80% risk of progression at 2 years are now considered to have active MM and should be offered treatment^[1]. An 80% risk of progression is found in patients with one or more of the following biomarkers: clonal BMPC ≥ 60%, involved: uninvolved (i:u) serum free light chain ratio (FLCr) ≥ 100, and/or >1 focal lesion on magnetic resonance imaging (MRI). This change was made due to improved treatment options having been developed that are less toxic, as well as the strong signs of improvement with early treatment of asymptomatic high-risk patients^[1]^[6]. This also better aligns this malignancy with others because signs of severe end organ damage such as lytic bone lesions and renal failure are no longer required prior to the commencement of treatment^[1]. Properly distinguishing patients who have indolent disease versus those who will progress quickly using risk stratification models is a very important issue as it determines who will be offered treatment and when^[1]^[6]. Clinical trials involving high-risk SMM patients have also been conducted, which are presented here.

2. Treatment of Smoldering Multiple Myeloma

The standard of care for SMM patients is currently observation and not treatment^[1]. However, several clinical trials have been conducted to investigate different treatments for patients with SMM with the goal to extend the TTP or even prevent progression to symptomatic MM.

One phase 2 clinical trial conducted by Lust et al. targeted interleukin 1 (IL-1) with inhibitors^[7]. First, an in vitro study was done to determine the effectiveness of the inhibitor in IL-6 expressing MM cells^[7]. IL-6 has been shown to be essential for the development of myeloma and interleukin 1 (IL-1) β is a major stimulator of its production^[8]^[9]. The disease could be controlled by IL-1Ra alone in patients with less than 20% BMPCs^[7], while patients with over 20% BMPCs required IL-1Ra in combination with low-dose dexamethasone. At the conclusion of this trial, IL-1Ra reduced the IL-6 levels and lowered the number of BMPCs^[7], while dexamethasone reduced the IL-1β levels in SMM patients. This led to a chronic disease state in patients with an improved PFS^[7].

Mateos et al. (2013) performed a phase 3 trial with high-risk SMM patients^[6]. Patients were assigned either treatment with lenalidomide and dexamethasone followed by lenalidomide maintenance or observation^[6]. Lenalidomide is an immunomodulatory drug and dexamethasone is a glucocorticoid^[6]. The median TTP and 3-year survival rate improved significantly in patients receiving the treatment^[6], with 77% PFS in the treatment group versus 30% in the control group. OS increased from 80% in the control group to 94% in the treatment group with 90% of the treated patients reaching partial response (PS) or greater during lenalidomide maintenance^[6]. The conclusion of this trial was that the treatment with lenalidomide and dexamethasone followed by a lenalidomide maintenance could be used to treat high-risk SMM patients and extend the TTP, PFS, and OS^[6].

Mateos et al. (2016) conducted a long-term follow up of the Mateos ’s 2013 study ^[6]^[10]. The results confirmed the extended TTP in patients treated with both drugs in comparison with the observation group^[10]. Furthermore, dexamethasone was added to the lenalidomide maintenance period in case of progression during maintenance^[10]. Disease control was achieved in two-thirds of patients receiving this combination maintenance whereas 64% of patients receiving only lenalidomide maintenance progressed to MM^[10].

Mateos et al. (2019) used a treatment strategy called GEM-CESAR to treat high-risk SMM in a phase 2 trial^[11]. The strategy consisted of a combination treatment with carfilzomib, lenalidomide and dexamethasone (KRd)^[11]. Afterwards, the patients received high-dose therapy-autologous stem cell transplantation (HDT-ASCT), KRd consolidation and lenalidomide and dexamethasone (Rd) maintenance^[11]. 56% of patients that completed the whole treatment regimen achieved MRD negativity and 70% reached CR^[11].

In another phase 3 trial for SMM by Witzig et al. in patients with SMM^[12], thalidomide plus zoledronic acid was tested in comparison to zoledronic acid alone. Thalidomide is an immunomodulatory drug whereas zoledronic acid is a bisphosphonate that can be used to treat and prevent bone complications such as lytic lesions, which are common in patients with MM^[12]. The median TTP of patients receiving both drugs was significantly lower than the TTP of patients receiving only zoledronic acid^[12]. Interestingly, the 1-year response rate for patients receiving both drugs was 37%, whereas there was no confirmed response for zoledronic acid alone^[12]. The combination treatment with thalidomide and zoledronic acid might be able to prolong the TTP in SMM patients^[12]. However, the authors mention that this trial was designed before the availability of lenalidomide, which may be a more attractive preventive drug as it may be safer^[12].

Korde et al. investigated the safety and efficacy of treatment with carfilzomib, lenalidomide and dexamethasone followed by a lenalidomide extension on patients with newly diagnosed MM (NDMM) and high-risk SMM^[13]. The therapy was well tolerated in both patient groups and patients with high-risk SMM showed deeper responses of at least a near complete response (nCR) rate of 100% compared to NDMM patients with 62%^[13]. Interestingly, all SMM patients reached at least a very good partial response (VGPR) and minimal residual disease (MRD) was 95% when measured by FC and 75% when measures by NGS^[13]. In conclusion, this treatment might be suitable for treating high-risk SMM patients^[13].

A phase 2 trial by Ghobrial et al. aimed to determine the effect of elotuzumab in combination with lenalidomide and dexamethasone in high-risk SMM patients^[14]. Elotuzumab is an IgG monoclonal antibody that likely stimulates NK cells and that leads to MM cells being killed through antibody-dependent cellular cytotoxicity^[15]. The results of the study showed a clinical benefit rate of 97% and an overall response rate of 71%, which may indicate what this treatment could be a suitable treatment to treat high-risk SMM patients^[14].

Mailankody et al. treated patients with carfilzomib, lenalidomide and dexamethasone followed by a lenalidomide extension^[16]. This is the same treatment regimen treatment as Korde et al.^[13], mentioned in the paragraph above. The cohort was larger, and the median follow up was longer than in the previous study^[16]. The response rate was 100%, and 63% of patients reached MRD negativity^[16]. Furthermore, the genomic landscape of high-risk SMM was compared to NDMM^[16]. High-risk SMM showed a significantly lower frequency of mutations in the NFKB pathway genes as well as in significant myeloma genes^[16]. The authors suggest that these findings could indicate that high-risk SMM shows a better treatment-response biology than NDMM^[16]. This supports the early treatment of high-risk SMM patients instead of observation until progression to MM^[16].

A new avenue in the treatment of high-risk SMM was the use of a cancer vaccine, which was studied by Nooka et al.^[17]. In this phase 1/2 clinical trial, the effect of PVX-410 multiseptated vaccine with or without lenalidomide on moderate or high-risk SMM patients was investigated^[17]. The vaccine includes four synthetic peptides from three MM-associated antigens which stimulate cytotoxic T cells that can evoke a tumor-specific immune response^[17]. An immune response was observed in 95% of all patients^[17], which was higher in magnitude in patients receiving a combination therapy. All patients that received the PVX-410 vaccine alone reached stable disease (SD)^[17]. One patient in the combination group reached partial response, four reached SD, and four reached minimal response^[17]. The authors suggest that the modest clinical response rates were due to the short duration of the study (12 months)^[17]. The results suggest that the vaccine is safe and immunogenic in SMM patients, but further studies with a longer duration are needed to assess the clinical value of this treatment option^[17].

In a phase 2 trial by Landgren et al. another monoclonal antibody was tested as a treatment for moderate to high-risk SMM^[18]. This study is the basis for an ongoing phase 3 trial of daratumumab on SMM patients. Daratumumab is an IgG monoclonal antibody that targets CD38^[18], which is highly expressed on MM cells. It is currently being used as a treatment for MM, and the authors hypothesize that it might help extend TTP in SMM patients^[18]. Patients were assigned either extended intense, extended intermediate, or short dosing schedules^[18]. One coprimary end point of CR > 15% was not met during the study^[18]. However, the authors specify that the other coprimary end point, which was met, of progressive disease (PD)/death rate and the ORR indicate that daratumumab has single- agent activity in SMM and should be investigated further^[18]. Furthermore, results showed that long term dosing of daratumumab delays progression in SMM^[18]. Interestingly, the authors support the use of evolving biomarkers for the prediction of risk in SMM and the identification of patients that could benefit from treatment^[18].

Lenalidomide has been investigated previously but not as a single agent drug. Lonial et al. performed a phase 3 trial of lenalidomide single agent versus observation with a large cohort of patients with either intermediate or high-risk SMM^[19]. The 1, 2, and 3-year PFS rates in the treatment group were significantly higher than in the observation group^[19]. The authors support the establishment of early treatment of high-risk SMM patients^[19]. Lonial et al. also clarify that the risk assessment should be done using the Lakshman ’s Mayo Clinic 2018 criteria that was validated by the Mateos et al. (2020)^[19]^[20]^[21].

Table 1 summarizes the clinical trials presented in this section. Observation of SMM still remains the standard of care up to today even for high-risk patients. Fortunately, the 2014 revised IMWG criteria now categorises a portion of these high-risk patients as having active MM. But why are high-risk SMM patients not treated? The heterogeneity of SMM poses a problem because current risk-stratification models are not completely accurate in identifying these ultra-high-risk patients. Furthermore, the discordance between the Mayo Clinic model and the Spanish model is another problem that must be addressed. Treating patients who are not actually high-risk may do more harm than good, so the correct identification of high-risk patients is essential.

Table 1. Summary of selected clinical trials.

Group	Treatment Tested	Reference
Lust et al.	Interleukin 1 (IL-1) with inhibitors	^[22]
Mateos et al. (2013)	Lenalidomide and dexamethasone followed by lenalidomide maintenance or observation	^[6]
Mateos et al. (2016)	Lenalidomide and dexamethasone followed by lenalidomide and dexamethasone maintenance or observation	^[23]
Mateos et al. (2019)	GEM-CESAR: combination treatment with carfilzomib, lenalidomide and dexamethasone (KRd), followed by high-dose therapy-autologous stem cell transplantation (HDT-ASCT) and KRd consolidation. Treatment continued with lenalidomide and dexamethasone maintenance	^[24]
Witzig et al.	Thalidomide plus zoledronic acid versus zoledronic acid alone	^[25]
Korde et al. and Mailankody et al.	Carfilzomib, lenalidomide and dexamethasone followed by a lenalidomide extension	^[26]^[27]
Ghobrial et al.	Elotuzumab versus lenalidomide and dexamethasone	^[28]
Nooka et al.	PVX-410 multiseptated vaccine with or without lenalidomide	^[29]
Landgren et al.	Daratumumab with extended intense, extended intermediate, or short dosing schedules	^[30]
Lonial et al.	Lenalidomide single agent versus observation	^[31]

Interestingly, recent trials have suggested the use of lenalidomide in combination with other drugs, such as carfilzomib and dexamethasone, as a possible avenue for treatment of high-risk SMM. One ongoing trial is aiming to confirm this possibility (NCT03673826). Moreover, the emerging of alternative drugs such as vaccines and immunotherapy showed very low toxicity and may be a promising start for the early intervention in high-risk SMM patients. Fortunately, many different avenues are currently being explored in ongoing trials. With the improvement of SMM risk stratification models and the identification of safer and more effective drugs, the standard of care for SMM may change from observation to treatment in the future.

References

Lust, J.A.; Lacy, M.Q.; Zeldenrust, S.R.; Dispenzieri, A.; Gertz, M.A.; Witzig, T.E.; Kumar, S.; Hayman, S.R.; Russell, S.J.; Buadi, F.K.; et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin. Proc. 2009, 84, 114–122.
Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; Lopez Corral, L.; Rosinol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N. Engl. J. Med. 2013, 369, 438–447.
Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; Corral, L.L.; Rosinol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): Long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016, 17, 1127–1136.
Mateos, M.V.; Martinez-Lopez, J.; Rodriguez Otero, P.; Gonzalez-Calle, V.; Gonzalez, M.S.; Oriol, A.; Gutierrez, N.C.; Paiva, B.; Tamayo, R.R.; Dachs, L.R.; et al. Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd. Blood 2019, 134, 781.
Witzig, T.E.; Laumann, K.M.; Lacy, M.Q.; Hayman, S.R.; Dispenzieri, A.; Kumar, S.; Reeder, C.B.; Roy, V.; Lust, J.A.; Gertz, M.A.; et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2013, 27, 220–225.
Korde, N.; Roschewski, M.; Zingone, A.; Kwok, M.; Manasanch, E.E.; Bhutani, M.; Tageja, N.; Kazandjian, D.; Mailankody, S.; Wu, P.; et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015, 1, 746–754.
Mailankody, S.; Kazandjian, D.; Korde, N.; Roschewski, M.; Manasanch, E.; Bhutani, M.; Tageja, N.; Kwok, M.; Zhang, Y.; Zingone, A.; et al. Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma. Blood Adv. 2017, 1, 1911–1918.
Ghobrial, I.M.; Badros, A.Z.; Vredenburgh, J.J.; Matous, J.; Caola, A.M.; Savell, A.; Henrick, P.; Paba-Prada, C.E.; Schlossman, R.L.; Laubach, J.P.; et al. Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. Blood 2016, 128, 976.
Nooka, A.K.; Wang, M.L.; Yee, A.J.; Kaufman, J.L.; Bae, J.; Peterkin, D.; Richardson, P.G.; Raje, N.S. Assessment of Safety and Immunogenicity of PVX-410 Vaccine With or Without Lenalidomide in Patients With Smoldering Multiple Myeloma: A Nonrandomized Clinical Trial. JAMA Oncol. 2018, 4, e183267.
Landgren, C.O.; Chari, A.; Cohen, Y.C.; Spencer, A.; Voorhees, P.; Estell, J.A.; Sandhu, I.; Jenner, M.W.; Williams, C.; Cavo, M.; et al. Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: A randomized, open-label, multicenter, phase 2 study (CENTAURUS). Leukemia 2020, 34, 1840–1852.
Lonial, S.; Jacobus, S.; Fonseca, R.; Weiss, M.; Kumar, S.; Orlowski, R.Z.; Kaufman, J.L.; Yacoub, A.M.; Buadi, F.K.; O’Brien, T.; et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J. Clin. Oncol. 2020, 38, 1126–1137.
Thomas E Witzig; K M Laumann; Martha Q Lacy; Suzanne R Hayman; Angela Dispenzieri; S Kumar; Craig B Reeder; Vivek Roy; John A Lust; Morie A Gertz; et al.Philip R GreippHeitham T HassounSumithra J MandrekarS. Vincent Rajkumar A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2012, 27, 220-225, 10.1038/leu.2012.236.
Neha Korde; Mark Roschewski; Adriana Zingone; Mary Kwok; Elisabet E. Manasanch; Manisha Bhutani; Nishant Tageja; Dickran Kazandjian; Sham Mailankody; Peter Wu; et al.Candis MorrisonRene CostelloYong ZhangDebra BurtonMarcia MulquinDiamond ZuchlinskiLiz LampingAshley CarpenterYvonne WallGeorge CarterSchuyler C. CunninghamVerena GoundenTristan M. SissungCody PeerIrina MaricKatherine R. CalvoRaul BraylanConstance YuanMaryAlice Stetler-StevensonDiane C. ArthurKatherine A. KongLi WengMalek FahamLiza LindenbergKaren KurdzielPeter ChoykeSeth M. SteinbergWilliam FiggOla Landgren Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncology 2015, 1, 746-754, 10.1001/jamaoncol.2015.2010.
Irene M. Ghobrial; Ashraf Z Badros; James J. Vredenburgh; Jeffrey Matous; Bs Aaron M. Caola; Alexandra Savell; Patrick Henrick; Claudia E. Paba-Prada; Robert L. Schlossman; Jacob P. Laubach; et al.Jacalyn RosenblattAndrew YeeJeffrey S. WischMD Charles M. FarberRodrigo O. MaegawaMd Facp Saad Z UsmaniJoseph CappuccioBs Bradley RivottoNp Kimberly NoonanDnp Kaitlen ReyesNikhil C. MunshiKenneth C. AndersonPaul Richardson Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. Blood 2016, 128, 976-976, 10.1182/blood.v128.22.976.976.
Karen M. Fancher; Elizabeth J. Bunk; Elotuzumab: The First Monoclonal Antibody for the Treatment of Multiple Myeloma. Journal of the Advanced Practitioner in Oncology 2016, 7, 542-547, 10.6004/jadpro.2016.7.5.6.
Sham Mailankody; Dickran Kazandjian; Neha Korde; Mark Roschewski; Elisabet Manasanch; Manisha Bhutani; Nishant Tageja; Mary Kwok; Yong Zhang; Adriana Zingone; et al.Laurence LamyRene CostelloCandis MorrisonMalin HultcrantzAustin ChristoffersonMegan WashingtonMartin BoatengSeth M. SteinbergMaryAlice Stetler-StevensonWilliam D. FiggElli PapaemmanuilWyndham H. WilsonJonathan J. KeatsOla Landgren Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma. Blood Advances 2017, 1, 1911-1918, 10.1182/bloodadvances.2017005934.
Ajay K. Nooka; Michael (Luhua) Wang; Andrew J. Yee; Jonathan L. Kaufman; Jooeun Bae; Doris Peterkin; Paul G. Richardson; Noopur S. Raje; Assessment of Safety and Immunogenicity of PVX-410 Vaccine With or Without Lenalidomide in Patients With Smoldering Multiple Myeloma. JAMA Oncology 2018, 4, e183267-e183267, 10.1001/jamaoncol.2018.3267.
C. Ola Landgren; Ajai Chari; Yael C. Cohen; Andrew Spencer; Peter Voorhees; Jane A. Estell; Irwindeep Sandhu; Matthew W. Jenner; Catherine Williams; Michele Cavo; et al.Niels W. C. J. Van De DonkMeral BeksacPhilippe MoreauHartmut GoldschmidtSteven KuppensRajesh BandekarPamela L. ClemensTobias NeffChristoph HeuckMing QiCraig C. Hofmeister Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS). Leukemia 2020, 34, 1840-1852, 10.1038/s41375-020-0718-z.
Sagar Lonial; Susanna Jacobus; Rafael Fonseca; Matthias Weiss; Shaji Kumar; Robert Orlowski; Jonathan Kaufman; Abdulraheem M. Yacoub; Francis K. Buadi; Timothy O’Brien; et al.Jeffrey V. MatousDaniel M. AndersonRobert V. EmmonsAnuj MahindraLynne I. WagnerMadhav V. DhodapkarS. Vincent Rajkumar Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. Journal of Clinical Oncology 2020, 38, 1126-1137, 10.1200/jco.19.01740.
Arjun Lakshman; S. Vincent Rajkumar; Francis K. Buadi; Moritz Binder; Morie A. Gertz; Martha Q. Lacy; Angela Dispenzieri; David Dingli; Amie L. Fonder; Suzanne R. Hayman; et al.Miriam A. HobbsWilson I. GonsalvesYi Lisa HwaPrashant KapoorNelson LeungRonald S. GoYi LinTaxiarchis V. KourelisRahma WarsameJohn A. LustStephen J. RussellSteven R. ZeldenrustRobert A. KyleShaji K. Kumar Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer Journal 2018, 8, 1-10, 10.1038/s41408-018-0077-4.
María-Victoria Mateos; Shaji Kumar; Meletios A. Dimopoulos; Verónica González-Calle; Efstathios Kastritis; Roman Hajek; Carlos Fernández De Larrea; Gareth J. Morgan; Giampaolo Merlini; Hartmut Goldschmidt; et al.Catarina GeraldesAlessandro GozzettiCharalampia KyriakouLaurent GarderetMarkus HanssonElena ZamagniDorotea FantlXavier LeleuByung-Su KimGraça EstevesHeinz LudwigSaad UsmaniChang-Ki MinMing QiJon UkropecBrendan M. WeissS. Vincent RajkumarBrian G. M. DurieJesús San-Miguel International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer Journal 2020, 10, 1-11, 10.1038/s41408-020-00366-3.

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1. Introduction

2. Treatment of Smoldering Multiple Myeloma

References