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Smoldering multiple myeloma current treatment algorithms

Smoldering multiple myeloma current treatment algorithms Blood Cancer Journal www.nature.com/bcj CURRENT TREATMENT ALGORITHM OPEN 1 1 2 3 S. Vincent Rajkumar , Shaji Kumar , Sagar Lonial and Maria Victoria Mateos © The Author(s) 2022 Smoldering multiple myeloma (SMM) is an asymptomatic condition that occupies a space between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) along the spectrum of clonal plasma cell proliferative disorders. It is not a biologic intermediate stage between MGUS and MM, but rather represents a heterogeneous clinically defined condition in which some patients (approximately two-thirds) have MGUS (pre-malignancy), and some (approximately one-third) have MM (biologic malignancy). Unfortunately, no single pathologic or molecular feature can reliably distinguish these two groups of patients. For purposes of practice and clinical trials, specific risk factors are used to identify patients with SMM in whom malignant transformation has already likely occurred (high risk SMM). Patients with newly diagnosed high risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials. Patients with low risk SMM should be observed without therapy every 3–4 months. Blood Cancer Journal (2022) 12:129 ; https://doi.org/10.1038/s41408-022-00719-0 INTRODUCTION as being a heterogenous clinically defined entity rather a than a The diagnostic criteria, staging system, response criteria, and true biologic intermediate stage between MGUS and MM. Thus management of multiple myeloma (MM) have evolved signifi- SMM as currently defined includes some patients with biological cantly in the last decade [1]. Almost all patients with MM evolve pre-malignancy (biological MGUS) and some with biologic from a pre-malignant stage termed monoclonal gammopathy of malignancy (multiple myeloma) [15, 16]. This is a major paradigm undetermined significance (MGUS) [2, 3]. MGUS is present in change, and over the last 10 years has initiated a cascading series approximately 5% of the population above the age of 50 [4–6], of changes in our strategic approach to both SMM and MM. One of and progresses to MM or related malignancy a rate of 1% per year the initial goals was to immediately identify the group of SMM [7, 8]. Smoldering multiple myeloma (SMM) is an intermediate patients who have biologic malignancy that will declare itself with asymptomatic condition that lies between MGUS and MM along clinical complications within 2 years. Three biomarkers were the spectrum of clonal plasma cell proliferative disorders. It is validated: bone marrow clonal plasma cells ≥60%, serum involved important from a clinical standpoint to distinguish SMM from to uninvolved free light chain (FLC) ratio ≥100 (provided involved MGUS because the risk of progression of SMM is 10 times higher FLC level is ≥100 mg/L), and more than 1 focal lesion (5 mm or than MGUS in the first 5 years following diagnosis. SMM more in size) on magnetic resonance imaging (MRI), each of which progresses to multiple myeloma at a rate of approximately 10% identified patients at high (approximately 80%) risk of progression per year over the first 5 years following diagnosis, 3% per year within 2 years. These biomarkers were considered myeloma over the next 5 years, and 1.5% per year thereafter [9]. Recent data defining events (MDE), and adopted in 2014 in the International confirm that the highest risk of progression is in the first 5 years, Myeloma Working Group (IMWG) Revised Diagnostic Criteria for with 2-, 5-, and 10-year risk of progression of 22%, 42%, and 64%, multiple myeloma and related plasma cell disorders [15]. When respectively [10]. Thus, the type of follow-up and counseling are using the FLC ratio ≥100 as a biomarker for the diagnosis of different for MGUS and SMM. myeloma, it is important to ensure that the urinary monoclonal SMM is present in approximately 0.5% of the population above protein is concordant, with a level of at least 200 mg per 24 h on the age of 40 years [11], and accounts for approximately 15% of all urine protein electrophoresis [17]. cases of newly diagnosed MM [12–14]. It is distinguished from The revised IMWG criteria protect patients from end-organ MGUS based on the M protein concentration and percentage of damage and has eliminated a “catch-22” where we did not want clonal BMPCs (Table 1)[15]. Light chain SMM is a unique subtype end-organ damage but were also not willing to treat before end- of SMM in which there is monoclonal free light chain (FLC) excess organ damage occurred. It allowed therapy to be initiated before with no expression of an intact immunoglobulin heavy chain M significant end-organ damage occurred. But it applied to a very protein such as IgG or IgA. It is characterized by the presence of small proportion of patients: the revised IMWG diagnostic criteria ≥500 mg/24 h of monoclonal FLC on urine protein electrophoresis. upstaged only about 10% of patients with SMM. The remaining Our recognition that the clinical course of SMM has a patients are still considered SMM. Thus, although patients with progression risk that decreases over time along with information imminent risk of progression were addressed by the 3 biomarkers from other laboratory studies has led us to better understand SMM considered MDEs in the revised IMWG diagnostic criteria, that still 1 2 Division of Hematology, Mayo Clinic, Rochester, MN, USA. Department of Hematology and Medical Oncology, Emory University School of Medicine Atlanta, Atlanta, GA, USA. Department of Hematology, and Center for Cancer Research, University Hospital of Salamanca, Salamanca, Spain. email: rajkumar.vincent@mayo.edu Received: 6 July 2022 Revised: 3 August 2022 Accepted: 10 August 2022 1234567890();,: S.V. Rajkumar et al. Table 1. International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma Cell Disorders. Disorder Disease Definition IgM Monoclonal gammopathy of undetermined All 3 criteria must be met: significance (IgM MGUS) � Serum IgM monoclonal protein <3 gm/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. Non-IgM monoclonal gammopathy of undetermined All 3 criteria must be met: significance (MGUS) � Serum monoclonal protein (non-IgM type) <3 gm/dL � Clonal bone marrow plasma cells <10% � 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 Light Chain MGUS All criteria must be met: � Abnormal free light chain (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 Smoldering multiple myeloma Both criteria must be met: � Serum monoclonal protein (IgG or IgA) ≥3 gm/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 Multiple Myeloma 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 per minute 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, computed 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 free light chain level must be ≥100 mg/L and urine monoclonal protein level at least 200 mg per 24 h on urine protein electrophoresis) ◦ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size) Modified from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–e548. A bone marrow can be deferred in patients with low risk MGUS (IgG type, M protein <1.5 gm/dL, normal free light chain ratio), in patients with uncomplicated suspected IgM MGUS < 1.5 gm/dl, and in patients with light chain MGUS who have a serum FLC ratio <8, in whom there are no clinical features concerning for myeloma, macroglobulinemia, or amyloidosis. left approximately one-third of patients who already had monoclonal proteins, including monoclonal gammopathy asso- malignant transformation to remain in the SMM category. These ciated peripheral neuropathy and proliferative glomerulonephritis patients comprise most of the patients currently classified as high- with immunoglobulin deposits [18, 19]. Similarly as with MGUS, risk SMM and account for the 50% or higher risk of progression to there may also be an increased risk of venous and arterial overt end-organ damage from MM within 2 years seen in this thrombosis, infections, osteoporosis, and bone fractures even in group. It is this category of patients that is currently the target the absence of progression to overt malignancy [20]. population for early intervention. DIFFERENTIAL DIAGNOSIS CLINICAL FEATURES SMM must be distinguished from MGUS and MM using the criteria SMM is asymptomatic. It is recognized incidentally when patients listed in Table 1. Baseline laboratory studies should include are found to have a monoclonal protein during work up of a complete blood count, serum creatinine, serum calcium, skeletal variety of different symptoms and laboratory abnormalities. In imaging with whole body low dose CT or positron emission addition to the risk of progression to MM or AL amyloidosis, tomography-computed tomography (PET-CT), serum protein patients with SMM are also at risk of other systemic disorders electrophoresis (SPEP), serum immunofixation (IFE), 24 h urine besides overt malignancy that are causally associated with protein electrophoresis (UPEP), urine IFE, and serum FLC assay Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. [21]. An MRI of the spine and pelvis (or whole body MRI) should be RISK STRATIFICATION considered in patients with suspected high risk SMM if skeletal For clinical practice, the current goal of risk stratification is to identify imaging with CT or PET-CT is negative to ensure that focal patients with a 50% risk of progression within 2 years, since these are myeloma defining lesions are not missed [22]. Bone marrow the patients who are most likely to already have biologic malignant examination with fluorescent in situ hybridization (FISH) studies to transformation, and in clinical trials have shown the maximum detect high risk cytogenetic abnormalities (del 17p, t(4;14), gain benefit with early intervention. Multiple risk stratification models (eg. 1q, del 13) and plasma cell immunophenotyping by multi- Spanish and Mayo Clinic models) have been proposed by combining parametric flow cytometry is needed. prognostic factors [9, 23, 24, 28, 29, 33–36]. The Mayo 2018 criteria, also referred to as the 20-2-20 criteria, simplifies the identification of patients with high risk SMM using three variables: serum free light PROGNOSIS chain ratio >20, serum M protein level >2 gm/dL, bone marrow The risk of progression of SMM to MM or related malignancy is clonal plasma cells >20% [37]. Thepresenceof2or 3of these factors approximately 10% per year for the first 5 years, and then is associated with a median TTP to multiple myeloma of decreases over time. This rough estimate can be further refined approximately 2 years, and is considered high risk SMM (Table 2). using a variety of common variables, including the size and type These criteria have been validated in a separate cohort by the IMWG of monoclonal protein, and the extent of bone marrow involve- [10]. The IMWG validation study also provides a scoring system for ment [9]. For example, the time to progression was significantly more accurate estimation of prognosis. Importantly, a recent study shorter in patients with IgA M protein compared with IgG M has found the Mayo 2018 high risk criteria also applies during follow- protein, median 27 months versus 75 months, respectively, up when patients who are initially diagnosed as low risk SMM later P = 0.004 [9]. It is not clear whether this difference is driven by evolve with higher M protein, serum FLC ratio, or bone marrow isotype or underlying cytogenetic differences between the two involvement. Such patients should be considered as newly groups. Similarly the time to progression was 117 months for diagnosed high risk SMM at that point and are candidates for patients with <20% bone marrow involvement versus 26 months clinical trials or early intervention. for patients with bone marrow involvement by 20–50% clonal plasma cells, P < 0.001 [9]. A reduction in the level of uninvolved immunoglobulins is associated with increased risk of progression TREATMENT [9, 23]. The serum FLC ratio is also particularly valuable, and has Our current approach to management of SMM is provided in Fig. 1 been incorporated into risk stratification models [24]. [38]. For patients with low risk SMM by the 20-2-20 criteria, Imaging studies are important for accurate diagnosis of SMM and specifically to exclude MM. They are also of value in identifying patients who do not meet criteria for MM but are Table 2. Risk stratification of smoldering multiple myeloma (SMM). nevertheless at higher risk of progression in the future. Thus patients with one focal non-osteolytic lesion and those with Mayo 2018 Criteria (20-2-20 critieria) diffuse (non-focal) abnormalities on MRI are at increased risk of High risk SMM (2-year risk of progression 50%) progression to MM, and require more close follow-up and repeat Any 2–3 of the following high risk factors: imaging in 3–6months[25]. Similarly increased uptake on PET- CT without bone destruction is not adequate to be considered as Serum monoclonal protein > 2 gm/dL an MDE; but is indicative of a higher risk of progression. Zamagni Serum free light chain ratio (involved/uninvolved) >20 and colleagues found that the median time to progression was Bone marrow plasma cells >20% significantly shorter for patients with increased PET-CT uptake Intermediate risk SMM compared with patients with negative PET-CT, 1.1 years versus 4.5 years, P = 0.001. Progression occurred within 2 years in 58% Any 1 high risk factor of PET-CT positive patients versus 33% of PET-CT negative Low risk SMM patients [26]. No high risk factor Bone marrow studies provide significant prognostic information International Myeloma Working Group Scoring System for SMM beyond the extent of involvement. Immunophenotyping with multiparametric flow cytometry provides prognostic value by High Risk SMM (2-year risk of progression, 75%) accurately distinguishing and quantitating bone marrow plasma Score >12 cells with malignant potential (aberrant) from normal plasma cells High-Intermediate Risk SMM (2-year risk of progression, 50%) [27]. In a Spanish study, the median time to progression was Score 9–12 34 months when bone marrow plasma cells were ≥95% aberrant versus not reached when bone marrow plasma cells had less than Low-Intermediate Risk SMM (2-year risk of progression, 25%) 95% aberrancy, P < 0.001. Detection of t(4;14) translocation, Score 5–8 del(17p), and gain(1q) on FISH or other molecular studies is also Low Risk SMM (2-year risk of progression, 5%) associated with a higher risk of progression from MGUS or SMM to Score 1–4 multiple myeloma [28–30]. International Myeloma Working Group Scoring includes 4 components. Another important prognostic variable is change in one or more Serum free light chain assay: Score of 0, 2, 3, and 5 for serum free light chain of the above parameters over time. In one study, an evolving ratio 0–10, 11–25, 26–40, and >40, respectively; Serum protein electrophoresis: change in monoclonal protein (0.5 gm/dl increase in M-protein) Score of 0, 3, and 4 for monoclonal protein level (gm/dL) 0–1.5, 1.6–2.9, and along with an evolving change in hemoglobin (0.5 g/dl decrease >3,respectively; Bone marrow: Scoreof0,2,3, 5,and 6 for bone marrow in hemoglobin) over a 12-month period was associated with high plasma cell percentage 0–15, 16–20, 21–30, 31–40, and >40, respectively; risk of progression [31]. Among patients with bone marrow Fluorescent in situ hybridization: Score of 2 for presence any high risk plasma cells ≥20%, evolving M protein and evolving hemoglobin cytogenetic abnormality (del 17p, t(4;14), gain 1q, or del 13). were independent predictors of progression; the 2-year progres- Derived from Lakshman A, et al. Risk stratification of smoldering multiple sion rate was 90.5% in patients who had both an evolving M myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J protein and evolving hemoglobin. The risk with evolving M 2018;8:59; and Mateos MV, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J protein been confirmed by an independent study by the Spanish 2020;10:102. myeloma group [32]. Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. Potential Newly Diagnosed Myeloma or Smoldering Multiple Myeloma Presence of No Myeloma Defining Events (SMM) Myeloma Defining Events (MM) High Risk SMM Low Risk SMM Evolving change in M protein and hemoglobin Consider Lenalidomide Observation Treat as Myeloma or Rd early intervention Fig. 1 Approach to the management of smoldering multiple myeloma. Footnote for Fig. 1: SMM, smoldering multiple myeloma; MM, multiple myeloma; Rd, lenalidomide plus dexamethasone. Myeloma Defining Events: End organ damage felt to be related to myeloma (hypercalcemia, light chain cast nephropathy, anemia, osteolytic bone lesions), serum free light chain ratio ≥100 with involved serum free light chain level ≥100 mg/dL and urine monoclonal protein ≥200 mg per 24 h on urine protein electrophoresis, ≥60% clonal bone marrow plasma cells, >1 focal lesion on magnetic resonance imaging. High risk Smoldering Multiple Myeloma: Any 2 of the following: bone marrow plasma cells >20%, serum monoclonal protein >2 gm/dL, serum free light chain ratio >20. Or high risk score based on the International Myeloma Working Group Scoring System for Smoldering Multiple Myeloma. Evolving change: Increase in monoclonal protein of 0.5 gm/dl or more along with a concomitant decrease in hemoglobin of 0.5 g/dl or more over a 12-month period. observation remains the standard of care. In these patients, serum progression or survival after progression, arguing against any M protein, serum FLC levels, complete blood count, serum long-term deleterious effect of early intervention. More recently a calcium, and serum creatinine should be monitored every randomized trial conducted by the Eastern Cooperative Oncology 3–4 months. The interval for follow-up can be reduced to once Group (ECOG) found that early therapy with lenalidomide as a every 6 months after the first 5 years [38]. If during follow-up, low single agent prolongs time to symptomatic MM with end-organ risk SMM patients with 20% or greater bone marrow involvement damage in patients with high risk SMM [46]. Only 6 patients have develop an evolving change in monoclonal protein level died in this trial, 4 in the observation arm and 2 in the accompanied by an evolving change in hemoglobin (as discussed lenalidomide arm, making it difficult to assess the effect of early earlier), treatment should be considered. These recommendations therapy on overall survival. However, when the effect of early are based on data showing that such increase is associated with therapy is analyzed among patients meeting Mayo 2018 high risk >90% risk of progression within 2 years [31]. In patients with MRI criteria, both the Spanish trial and the ECOG trial show a striking showing diffuse infiltration, solitary focal lesion, or equivocal 90% reduction in time to end-organ damage. Based on the results lesions, follow-up radiographic examination in 3–6 months is of these two trials, we recommend that patients with newly recommended [25]. During follow-up, if low risk SMM patients diagnosed high risk SMM patients be considered for early meet criteria for high risk SMM based on the Mayo 2018 or IMWG intervention with lenalidomide or Rd for two years (Fig. 1). risk stratification model, early intervention similar to high risk SMM Between lenalidomide and Rd, the choice should be made taking described below should be considered. into account the patients age, comorbidities, and tolerance to For patients with newly diagnosed high risk SMM, we dexamethasone. Patients with high risk SMM who are treated with recommend therapy with lenalidomide or lenalidomide plus lenalidomide or Rd should have peripheral blood stem cells dexamethasone (Rd) for two years, or enrollment in a clinical trial collected for cryopreservation after approximately 4–6 cycles of testing early therapy. Early studies in SMM with alkylating agents therapy [47, 48]. Patients with high risk SMM are also candidates found no significant benefit[39–41]. A subsequent randomized for clinical trials testing intensive therapy with curative intent [49]. trial comparing thalidomide plus zoledronic acid versus zoledronic Our recommendation in favor of early intervention applies to acid alone in patients with SMM showed some promise [42]. Time patients recently diagnosed with high risk SMM. We recognize to monoclonal protein elevation was superior for patients treated that there are patients with high risk SMM who have been with thalidomide plus zoledronic acid (n = 35) versus zoledronic diagnosed years ago and have remained stable without therapy. acid alone (n = 33). However, there were no significant differences These patients represent a self-selected group with likely stable in time to end organ damage, 4.3 versus 3.3 years, and no pre-malignancy and can therefore continue to be observed closely difference in overall survival, 5-year survival 74% versus 73%, and considered for intervention only at time of evolving respectively. Further, thalidomide has long-term side effects that laboratory parameters. make not suitable for treatment of SMM [43, 44]. These early trials The role of bisphosphonates to delay bone events in SMM is not were also limited by lack of a risk-adapted strategy. fully settled. In a randomized trial, a reduction in skeletal-related Two randomized trials with lenalidomide in high risk SMM have events (SRE) has been seen with pamidronate (once a month for shown benefit. In the Spanish randomized trial in patients with 12 months) compared with observation [50]. However, no high risk SMM, time to progression to MM with end organ damage improvement in time to progression or survival was seen. In was significantly longer in patients treated with Rd compared with another randomized trial, a reduction in SREs was noted with observation, median TTP not reached versus 21 months, P < 0.001 zoledronic acid (once a month for 12 months), 56% versus 78%, [27, 45]. Overall survival was also longer, 3-year survival rate 94% respectively, P = 0.04 [51]. We recommend once-yearly bispho- vs. 80%, respectively, P = 0.03. Importantly, early intervention with sphonate similar to that used for the treatment of osteoporosis for Rd did not affect the impact of subsequent therapy after patients with SMM who have osteopenia or osteoporosis. Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. COMMON QUESTIONS AND CONTROVERSIES Why can we not observe patients closely for progression Can we remove the SMM category and merge it with MGUS or instead of starting on any form of therapy? MM? In our experience conducting retrospective and prospective Although biologically, there is only a clear distinction between studies on hundreds of patients with SMM [9, 10, 27, 31, 37, 42, MGUS (pre-malignancy, analogous to a polyp) and MM (malig- 52, 53], we have seen physicians reassure patients with high risk nancy), for clinical purposes SMM is an important entity to SMM that the disease is stable only to have progression occur in preserve. It is easy to distinguish from MGUS, SMM, and MM with between visits. In randomized trials conducted in specialized current clinical criteria, and the distinctions have major clinical centers we note 90% reduction in end organ damage with simple implications for the patient in terms of prognosis, management, lenalidomide or Rd therapy compared with observation alone. and for planning their life. A puristic focus based on biology does Thus, attempting to delay therapy until the last minute and not help in the clinic. Importantly, the diagnosis of SMM highlights intervene in time before end organ damage occurs is easier said the increased risk of progression and the need for closer follow-up than done and had not been shown to be possible in clinical trials compared to MGUS, a distinction that will be lost if we clubbed even with monthly follow-up. the two together. The SMM category is similar to staging systems based on tumor Why do we recommend lenalidomide or lenalidomide plus volume, nodal spread, and cellular characteristics used in solid dexamethasone instead of myeloma-like therapy for high risk tumors. They may not be biologically different, but the clinical SMM? implications are different. In the plasma cell disorders field, we did We have data from randomized trials that lenalidomide or Rd is once refer to SMM as Stage I MM. But since the SMM terminology superior to observation in preventing end organ damage [45, 52]. has been in use for decades, we feel no reason to rename it at this One of these trials has shown a clear overall survival benefit[45]. point. If we come to a point where accurate tests to classify Although it is interesting to hypothesize that a myeloma-like patients with SMM into those with biologic pre-malignancy versus triplet or quadruplet regimen may be superior to lenalidomide or biologic malignancy are validated and widely available, and when Rd, we do not have randomized data to support that. Such a trial is we have data from randomized trials that treating high risk SMM ongoing (NCT03937635), and we are awaiting its results. For those similar to MM provides superior clinical benefit compared to concerned that lenalidomide or Rd may cause some delayed harm lenalidomide or Rd, we can reconsider. We are not there yet, and or drug resistance, that experiment has been done: the recent two we will not be there for a while. randomized trials with lenalidomide do not show any such adverse effect [45, 52]. This is therefore a theoretical risk that has been tested and found to be not true. For those who feel we Are the current risk stratification models adequate? should go straight to myeloma-like therapy it is also worth Current risk stratification models are not perfect, but they are considering that most patients cannot access such therapy readily available around the world, and identify patients with a without regulatory approval. In a disease where observation has 50% risk of progression within 2 years. The population so been the standard of care, we need to first demonstrate one drug identified has been treated in randomized trials with early works compared to no treatment, and then build on that. Making intervention, and a 90% reduction in risk of end organ damage a practice change without proof will provide myeloma therapy to has been demonstrated in both trials, with a survival advantage well insured patients in the United States but leave the vast in one trial. It is possible to do better and we will continue to majority in the world with no approved intervention. We are doing develop better models. Secondly, the fact that different models several clinical trial strategies in parallel including necessary capture different high-risk populations is not a negative. Each of regulatory trials (to show one drug works versus observation) our models is not very sensitive, and so we capture only a (NCT03301220), strategic trials (to see if myeloma like therapy is proportion of patients at risk. By using more models, we capture superior to Rd)(NCT03937635), and more aggressive trials (to see if more of the patients at risk, and lack of an overlap is actually early aggressive intervention at the SMM stage can be curative) advantageous in this regard. But whatever model is used, as (NCT02415413, NCT03289299). long as the population identified has at least a 50% risk of progressionin2 years, it is sufficient for clinical purposes both for management and counseling. Third, modern genomic FUTURE DIRECTIONS sequencing methods have not shown clear superiority in An ongoing ECOG randomized trial is testing whether a standard identifying patients for early intervention compared to more myeloma therapeutic triplet (DRd) will be superior to prophylactic conventional risk stratification models. Further, they are not doublet therapy with lenalidomide plus dexamethasone in standardized, with methods and techniques varying across patients with high risk SMM (NCT03937635) [54]. A similar laboratories, and are not widely available. When available, we randomized trial is comparing isatuximab plus Rd versus Rd in encourage their use in addition but not to the exclusion of patients with high risk SMM (NCT04270409). There are also clinical existing systems. In the future, assessment of circulating tumor trials testing intensive therapy with curative intent [49]. cells is another emerging technology that can be standardized and serve as a widely available metric for risk stratification and follow-up. DATA AVAILABILITY This is a current treatment algorithm, There are no new data generated for this Is early therapy justified without clear overall survival benefit? manuscript and data sharing is not applicable. In MM, end-organ damage includes osteolytic bone lesions and renal failure. At times, these are not reversible. They can cause significant morbidity to patients. 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Zamagni E, Nanni C, Gay F, Pezzi A, Patriarca F, Bello M, et al. 18F-FDG PET/CT 50. D’Arena G, Gobbi PG, Broglia C, Sacchi S, Quarta G, Baldini L, et al. Pamidronate focal, but not osteolytic, lesions predict the progression of smoldering myeloma versus observation in asymptomatic myeloma: final results with long-term follow- to active disease. Leukemia. 2016;30:417–22. up of a randomized study. Leuk Lymphoma. 2011;52:771–5. 27. Mateos M-V, Hernández M-T, Giraldo P, de la Rubia J, de Arriba F, Corral LL, et al. 51. Musto P, Petrucci MT, Bringhen S, Guglielmelli T, Caravita T, Bongarzoni V, et al. A Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma. multicenter, randomized clinical trial comparing zoledronic acid versus obser- N Engl J Med. 2013;369:438–47. vation in patients with asymptomatic myeloma. Cancer. 2008;113:1588–95. Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. 52. Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, et al. Randomized GSK; Janssen; Oncopeptides; Pfizer; Regeneron; Roche; Sanofi; Seagen; Takeda, trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin outside the submitted work. Oncol. 2020;38:1126–37. 53. Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. ADDITIONAL INFORMATION Leukemia. 2013;27:941–6. Correspondence and requests for materials should be addressed to S. Vincent 54. Lonial S, Dhodapkar MV, Rajkumar SV. Smoldering myeloma and the art of war. Rajkumar. J Clin Oncol. 2020:38:2363–5. Reprints and permission information is available at http://www.nature.com/ reprints ACKNOWLEDGEMENTS Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims Supported in part by grants CA 168762 and CA186781 from the National Cancer in published maps and institutional affiliations. Institute, Rockville, MD, USA, and the Marvin Family Grant. AUTHOR CONTRIBUTIONS Open Access This article is licensed under a Creative Commons All of the authors collectively conceived of the paper, researched the literature, and Attribution 4.0 International License, which permits use, sharing, wrote the manuscript. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party COMPETING INTERESTS material in this article are included in the article’s Creative Commons license, unless Dr. Rajkumar reports grants from NIH, outside the submitted work. Dr. Kumar reports indicated otherwise in a credit line to the material. If material is not included in the consultancy from BMS/Celgene, Takeda, and Janssen), and research funding from article’s Creative Commons license and your intended use is not permitted by statutory BMS/Celgene, Takeda, Novartis, AbbVie, Janssen, and Amgen. Dr. Lonial reports regulation or exceeds the permitted use, you will need to obtain permission directly personal fees from Celgene, personal fees from Takeda, personal fees from Amgen, from the copyright holder. To view a copy of this license, visit http:// personal fees from BMS, personal fees from GSK, personal fees from Novartis, creativecommons.org/licenses/by/4.0/. personal fees from ABBVIE, personal fees from Janssen, other from TG Therapeutics, outside the submitted work. Dr. Mateos reports personal fees from AbbVie; Adaptive Biotechnologies; Amgen; bluebird bio; Celgene, a Bristol-Myers Squibb Company; © The Author(s) 2022 Blood Cancer Journal (2022) 12:129 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Cancer Journal Springer Journals

Smoldering multiple myeloma current treatment algorithms

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Blood Cancer Journal www.nature.com/bcj CURRENT TREATMENT ALGORITHM OPEN 1 1 2 3 S. Vincent Rajkumar , Shaji Kumar , Sagar Lonial and Maria Victoria Mateos © The Author(s) 2022 Smoldering multiple myeloma (SMM) is an asymptomatic condition that occupies a space between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) along the spectrum of clonal plasma cell proliferative disorders. It is not a biologic intermediate stage between MGUS and MM, but rather represents a heterogeneous clinically defined condition in which some patients (approximately two-thirds) have MGUS (pre-malignancy), and some (approximately one-third) have MM (biologic malignancy). Unfortunately, no single pathologic or molecular feature can reliably distinguish these two groups of patients. For purposes of practice and clinical trials, specific risk factors are used to identify patients with SMM in whom malignant transformation has already likely occurred (high risk SMM). Patients with newly diagnosed high risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials. Patients with low risk SMM should be observed without therapy every 3–4 months. Blood Cancer Journal (2022) 12:129 ; https://doi.org/10.1038/s41408-022-00719-0 INTRODUCTION as being a heterogenous clinically defined entity rather a than a The diagnostic criteria, staging system, response criteria, and true biologic intermediate stage between MGUS and MM. Thus management of multiple myeloma (MM) have evolved signifi- SMM as currently defined includes some patients with biological cantly in the last decade [1]. Almost all patients with MM evolve pre-malignancy (biological MGUS) and some with biologic from a pre-malignant stage termed monoclonal gammopathy of malignancy (multiple myeloma) [15, 16]. This is a major paradigm undetermined significance (MGUS) [2, 3]. MGUS is present in change, and over the last 10 years has initiated a cascading series approximately 5% of the population above the age of 50 [4–6], of changes in our strategic approach to both SMM and MM. One of and progresses to MM or related malignancy a rate of 1% per year the initial goals was to immediately identify the group of SMM [7, 8]. Smoldering multiple myeloma (SMM) is an intermediate patients who have biologic malignancy that will declare itself with asymptomatic condition that lies between MGUS and MM along clinical complications within 2 years. Three biomarkers were the spectrum of clonal plasma cell proliferative disorders. It is validated: bone marrow clonal plasma cells ≥60%, serum involved important from a clinical standpoint to distinguish SMM from to uninvolved free light chain (FLC) ratio ≥100 (provided involved MGUS because the risk of progression of SMM is 10 times higher FLC level is ≥100 mg/L), and more than 1 focal lesion (5 mm or than MGUS in the first 5 years following diagnosis. SMM more in size) on magnetic resonance imaging (MRI), each of which progresses to multiple myeloma at a rate of approximately 10% identified patients at high (approximately 80%) risk of progression per year over the first 5 years following diagnosis, 3% per year within 2 years. These biomarkers were considered myeloma over the next 5 years, and 1.5% per year thereafter [9]. Recent data defining events (MDE), and adopted in 2014 in the International confirm that the highest risk of progression is in the first 5 years, Myeloma Working Group (IMWG) Revised Diagnostic Criteria for with 2-, 5-, and 10-year risk of progression of 22%, 42%, and 64%, multiple myeloma and related plasma cell disorders [15]. When respectively [10]. Thus, the type of follow-up and counseling are using the FLC ratio ≥100 as a biomarker for the diagnosis of different for MGUS and SMM. myeloma, it is important to ensure that the urinary monoclonal SMM is present in approximately 0.5% of the population above protein is concordant, with a level of at least 200 mg per 24 h on the age of 40 years [11], and accounts for approximately 15% of all urine protein electrophoresis [17]. cases of newly diagnosed MM [12–14]. It is distinguished from The revised IMWG criteria protect patients from end-organ MGUS based on the M protein concentration and percentage of damage and has eliminated a “catch-22” where we did not want clonal BMPCs (Table 1)[15]. Light chain SMM is a unique subtype end-organ damage but were also not willing to treat before end- of SMM in which there is monoclonal free light chain (FLC) excess organ damage occurred. It allowed therapy to be initiated before with no expression of an intact immunoglobulin heavy chain M significant end-organ damage occurred. But it applied to a very protein such as IgG or IgA. It is characterized by the presence of small proportion of patients: the revised IMWG diagnostic criteria ≥500 mg/24 h of monoclonal FLC on urine protein electrophoresis. upstaged only about 10% of patients with SMM. The remaining Our recognition that the clinical course of SMM has a patients are still considered SMM. Thus, although patients with progression risk that decreases over time along with information imminent risk of progression were addressed by the 3 biomarkers from other laboratory studies has led us to better understand SMM considered MDEs in the revised IMWG diagnostic criteria, that still 1 2 Division of Hematology, Mayo Clinic, Rochester, MN, USA. Department of Hematology and Medical Oncology, Emory University School of Medicine Atlanta, Atlanta, GA, USA. Department of Hematology, and Center for Cancer Research, University Hospital of Salamanca, Salamanca, Spain. email: rajkumar.vincent@mayo.edu Received: 6 July 2022 Revised: 3 August 2022 Accepted: 10 August 2022 1234567890();,: S.V. Rajkumar et al. Table 1. International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma Cell Disorders. Disorder Disease Definition IgM Monoclonal gammopathy of undetermined All 3 criteria must be met: significance (IgM MGUS) � Serum IgM monoclonal protein <3 gm/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. Non-IgM monoclonal gammopathy of undetermined All 3 criteria must be met: significance (MGUS) � Serum monoclonal protein (non-IgM type) <3 gm/dL � Clonal bone marrow plasma cells <10% � 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 Light Chain MGUS All criteria must be met: � Abnormal free light chain (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 Smoldering multiple myeloma Both criteria must be met: � Serum monoclonal protein (IgG or IgA) ≥3 gm/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 Multiple Myeloma 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 per minute 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, computed 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 free light chain level must be ≥100 mg/L and urine monoclonal protein level at least 200 mg per 24 h on urine protein electrophoresis) ◦ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size) Modified from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–e548. A bone marrow can be deferred in patients with low risk MGUS (IgG type, M protein <1.5 gm/dL, normal free light chain ratio), in patients with uncomplicated suspected IgM MGUS < 1.5 gm/dl, and in patients with light chain MGUS who have a serum FLC ratio <8, in whom there are no clinical features concerning for myeloma, macroglobulinemia, or amyloidosis. left approximately one-third of patients who already had monoclonal proteins, including monoclonal gammopathy asso- malignant transformation to remain in the SMM category. These ciated peripheral neuropathy and proliferative glomerulonephritis patients comprise most of the patients currently classified as high- with immunoglobulin deposits [18, 19]. Similarly as with MGUS, risk SMM and account for the 50% or higher risk of progression to there may also be an increased risk of venous and arterial overt end-organ damage from MM within 2 years seen in this thrombosis, infections, osteoporosis, and bone fractures even in group. It is this category of patients that is currently the target the absence of progression to overt malignancy [20]. population for early intervention. DIFFERENTIAL DIAGNOSIS CLINICAL FEATURES SMM must be distinguished from MGUS and MM using the criteria SMM is asymptomatic. It is recognized incidentally when patients listed in Table 1. Baseline laboratory studies should include are found to have a monoclonal protein during work up of a complete blood count, serum creatinine, serum calcium, skeletal variety of different symptoms and laboratory abnormalities. In imaging with whole body low dose CT or positron emission addition to the risk of progression to MM or AL amyloidosis, tomography-computed tomography (PET-CT), serum protein patients with SMM are also at risk of other systemic disorders electrophoresis (SPEP), serum immunofixation (IFE), 24 h urine besides overt malignancy that are causally associated with protein electrophoresis (UPEP), urine IFE, and serum FLC assay Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. [21]. An MRI of the spine and pelvis (or whole body MRI) should be RISK STRATIFICATION considered in patients with suspected high risk SMM if skeletal For clinical practice, the current goal of risk stratification is to identify imaging with CT or PET-CT is negative to ensure that focal patients with a 50% risk of progression within 2 years, since these are myeloma defining lesions are not missed [22]. Bone marrow the patients who are most likely to already have biologic malignant examination with fluorescent in situ hybridization (FISH) studies to transformation, and in clinical trials have shown the maximum detect high risk cytogenetic abnormalities (del 17p, t(4;14), gain benefit with early intervention. Multiple risk stratification models (eg. 1q, del 13) and plasma cell immunophenotyping by multi- Spanish and Mayo Clinic models) have been proposed by combining parametric flow cytometry is needed. prognostic factors [9, 23, 24, 28, 29, 33–36]. The Mayo 2018 criteria, also referred to as the 20-2-20 criteria, simplifies the identification of patients with high risk SMM using three variables: serum free light PROGNOSIS chain ratio >20, serum M protein level >2 gm/dL, bone marrow The risk of progression of SMM to MM or related malignancy is clonal plasma cells >20% [37]. Thepresenceof2or 3of these factors approximately 10% per year for the first 5 years, and then is associated with a median TTP to multiple myeloma of decreases over time. This rough estimate can be further refined approximately 2 years, and is considered high risk SMM (Table 2). using a variety of common variables, including the size and type These criteria have been validated in a separate cohort by the IMWG of monoclonal protein, and the extent of bone marrow involve- [10]. The IMWG validation study also provides a scoring system for ment [9]. For example, the time to progression was significantly more accurate estimation of prognosis. Importantly, a recent study shorter in patients with IgA M protein compared with IgG M has found the Mayo 2018 high risk criteria also applies during follow- protein, median 27 months versus 75 months, respectively, up when patients who are initially diagnosed as low risk SMM later P = 0.004 [9]. It is not clear whether this difference is driven by evolve with higher M protein, serum FLC ratio, or bone marrow isotype or underlying cytogenetic differences between the two involvement. Such patients should be considered as newly groups. Similarly the time to progression was 117 months for diagnosed high risk SMM at that point and are candidates for patients with <20% bone marrow involvement versus 26 months clinical trials or early intervention. for patients with bone marrow involvement by 20–50% clonal plasma cells, P < 0.001 [9]. A reduction in the level of uninvolved immunoglobulins is associated with increased risk of progression TREATMENT [9, 23]. The serum FLC ratio is also particularly valuable, and has Our current approach to management of SMM is provided in Fig. 1 been incorporated into risk stratification models [24]. [38]. For patients with low risk SMM by the 20-2-20 criteria, Imaging studies are important for accurate diagnosis of SMM and specifically to exclude MM. They are also of value in identifying patients who do not meet criteria for MM but are Table 2. Risk stratification of smoldering multiple myeloma (SMM). nevertheless at higher risk of progression in the future. Thus patients with one focal non-osteolytic lesion and those with Mayo 2018 Criteria (20-2-20 critieria) diffuse (non-focal) abnormalities on MRI are at increased risk of High risk SMM (2-year risk of progression 50%) progression to MM, and require more close follow-up and repeat Any 2–3 of the following high risk factors: imaging in 3–6months[25]. Similarly increased uptake on PET- CT without bone destruction is not adequate to be considered as Serum monoclonal protein > 2 gm/dL an MDE; but is indicative of a higher risk of progression. Zamagni Serum free light chain ratio (involved/uninvolved) >20 and colleagues found that the median time to progression was Bone marrow plasma cells >20% significantly shorter for patients with increased PET-CT uptake Intermediate risk SMM compared with patients with negative PET-CT, 1.1 years versus 4.5 years, P = 0.001. Progression occurred within 2 years in 58% Any 1 high risk factor of PET-CT positive patients versus 33% of PET-CT negative Low risk SMM patients [26]. No high risk factor Bone marrow studies provide significant prognostic information International Myeloma Working Group Scoring System for SMM beyond the extent of involvement. Immunophenotyping with multiparametric flow cytometry provides prognostic value by High Risk SMM (2-year risk of progression, 75%) accurately distinguishing and quantitating bone marrow plasma Score >12 cells with malignant potential (aberrant) from normal plasma cells High-Intermediate Risk SMM (2-year risk of progression, 50%) [27]. In a Spanish study, the median time to progression was Score 9–12 34 months when bone marrow plasma cells were ≥95% aberrant versus not reached when bone marrow plasma cells had less than Low-Intermediate Risk SMM (2-year risk of progression, 25%) 95% aberrancy, P < 0.001. Detection of t(4;14) translocation, Score 5–8 del(17p), and gain(1q) on FISH or other molecular studies is also Low Risk SMM (2-year risk of progression, 5%) associated with a higher risk of progression from MGUS or SMM to Score 1–4 multiple myeloma [28–30]. International Myeloma Working Group Scoring includes 4 components. Another important prognostic variable is change in one or more Serum free light chain assay: Score of 0, 2, 3, and 5 for serum free light chain of the above parameters over time. In one study, an evolving ratio 0–10, 11–25, 26–40, and >40, respectively; Serum protein electrophoresis: change in monoclonal protein (0.5 gm/dl increase in M-protein) Score of 0, 3, and 4 for monoclonal protein level (gm/dL) 0–1.5, 1.6–2.9, and along with an evolving change in hemoglobin (0.5 g/dl decrease >3,respectively; Bone marrow: Scoreof0,2,3, 5,and 6 for bone marrow in hemoglobin) over a 12-month period was associated with high plasma cell percentage 0–15, 16–20, 21–30, 31–40, and >40, respectively; risk of progression [31]. Among patients with bone marrow Fluorescent in situ hybridization: Score of 2 for presence any high risk plasma cells ≥20%, evolving M protein and evolving hemoglobin cytogenetic abnormality (del 17p, t(4;14), gain 1q, or del 13). were independent predictors of progression; the 2-year progres- Derived from Lakshman A, et al. Risk stratification of smoldering multiple sion rate was 90.5% in patients who had both an evolving M myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J protein and evolving hemoglobin. The risk with evolving M 2018;8:59; and Mateos MV, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J protein been confirmed by an independent study by the Spanish 2020;10:102. myeloma group [32]. Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. Potential Newly Diagnosed Myeloma or Smoldering Multiple Myeloma Presence of No Myeloma Defining Events (SMM) Myeloma Defining Events (MM) High Risk SMM Low Risk SMM Evolving change in M protein and hemoglobin Consider Lenalidomide Observation Treat as Myeloma or Rd early intervention Fig. 1 Approach to the management of smoldering multiple myeloma. Footnote for Fig. 1: SMM, smoldering multiple myeloma; MM, multiple myeloma; Rd, lenalidomide plus dexamethasone. Myeloma Defining Events: End organ damage felt to be related to myeloma (hypercalcemia, light chain cast nephropathy, anemia, osteolytic bone lesions), serum free light chain ratio ≥100 with involved serum free light chain level ≥100 mg/dL and urine monoclonal protein ≥200 mg per 24 h on urine protein electrophoresis, ≥60% clonal bone marrow plasma cells, >1 focal lesion on magnetic resonance imaging. High risk Smoldering Multiple Myeloma: Any 2 of the following: bone marrow plasma cells >20%, serum monoclonal protein >2 gm/dL, serum free light chain ratio >20. Or high risk score based on the International Myeloma Working Group Scoring System for Smoldering Multiple Myeloma. Evolving change: Increase in monoclonal protein of 0.5 gm/dl or more along with a concomitant decrease in hemoglobin of 0.5 g/dl or more over a 12-month period. observation remains the standard of care. In these patients, serum progression or survival after progression, arguing against any M protein, serum FLC levels, complete blood count, serum long-term deleterious effect of early intervention. More recently a calcium, and serum creatinine should be monitored every randomized trial conducted by the Eastern Cooperative Oncology 3–4 months. The interval for follow-up can be reduced to once Group (ECOG) found that early therapy with lenalidomide as a every 6 months after the first 5 years [38]. If during follow-up, low single agent prolongs time to symptomatic MM with end-organ risk SMM patients with 20% or greater bone marrow involvement damage in patients with high risk SMM [46]. Only 6 patients have develop an evolving change in monoclonal protein level died in this trial, 4 in the observation arm and 2 in the accompanied by an evolving change in hemoglobin (as discussed lenalidomide arm, making it difficult to assess the effect of early earlier), treatment should be considered. These recommendations therapy on overall survival. However, when the effect of early are based on data showing that such increase is associated with therapy is analyzed among patients meeting Mayo 2018 high risk >90% risk of progression within 2 years [31]. In patients with MRI criteria, both the Spanish trial and the ECOG trial show a striking showing diffuse infiltration, solitary focal lesion, or equivocal 90% reduction in time to end-organ damage. Based on the results lesions, follow-up radiographic examination in 3–6 months is of these two trials, we recommend that patients with newly recommended [25]. During follow-up, if low risk SMM patients diagnosed high risk SMM patients be considered for early meet criteria for high risk SMM based on the Mayo 2018 or IMWG intervention with lenalidomide or Rd for two years (Fig. 1). risk stratification model, early intervention similar to high risk SMM Between lenalidomide and Rd, the choice should be made taking described below should be considered. into account the patients age, comorbidities, and tolerance to For patients with newly diagnosed high risk SMM, we dexamethasone. Patients with high risk SMM who are treated with recommend therapy with lenalidomide or lenalidomide plus lenalidomide or Rd should have peripheral blood stem cells dexamethasone (Rd) for two years, or enrollment in a clinical trial collected for cryopreservation after approximately 4–6 cycles of testing early therapy. Early studies in SMM with alkylating agents therapy [47, 48]. Patients with high risk SMM are also candidates found no significant benefit[39–41]. A subsequent randomized for clinical trials testing intensive therapy with curative intent [49]. trial comparing thalidomide plus zoledronic acid versus zoledronic Our recommendation in favor of early intervention applies to acid alone in patients with SMM showed some promise [42]. Time patients recently diagnosed with high risk SMM. We recognize to monoclonal protein elevation was superior for patients treated that there are patients with high risk SMM who have been with thalidomide plus zoledronic acid (n = 35) versus zoledronic diagnosed years ago and have remained stable without therapy. acid alone (n = 33). However, there were no significant differences These patients represent a self-selected group with likely stable in time to end organ damage, 4.3 versus 3.3 years, and no pre-malignancy and can therefore continue to be observed closely difference in overall survival, 5-year survival 74% versus 73%, and considered for intervention only at time of evolving respectively. Further, thalidomide has long-term side effects that laboratory parameters. make not suitable for treatment of SMM [43, 44]. These early trials The role of bisphosphonates to delay bone events in SMM is not were also limited by lack of a risk-adapted strategy. fully settled. In a randomized trial, a reduction in skeletal-related Two randomized trials with lenalidomide in high risk SMM have events (SRE) has been seen with pamidronate (once a month for shown benefit. In the Spanish randomized trial in patients with 12 months) compared with observation [50]. However, no high risk SMM, time to progression to MM with end organ damage improvement in time to progression or survival was seen. In was significantly longer in patients treated with Rd compared with another randomized trial, a reduction in SREs was noted with observation, median TTP not reached versus 21 months, P < 0.001 zoledronic acid (once a month for 12 months), 56% versus 78%, [27, 45]. Overall survival was also longer, 3-year survival rate 94% respectively, P = 0.04 [51]. We recommend once-yearly bispho- vs. 80%, respectively, P = 0.03. Importantly, early intervention with sphonate similar to that used for the treatment of osteoporosis for Rd did not affect the impact of subsequent therapy after patients with SMM who have osteopenia or osteoporosis. Blood Cancer Journal (2022) 12:129 S.V. Rajkumar et al. COMMON QUESTIONS AND CONTROVERSIES Why can we not observe patients closely for progression Can we remove the SMM category and merge it with MGUS or instead of starting on any form of therapy? MM? In our experience conducting retrospective and prospective Although biologically, there is only a clear distinction between studies on hundreds of patients with SMM [9, 10, 27, 31, 37, 42, MGUS (pre-malignancy, analogous to a polyp) and MM (malig- 52, 53], we have seen physicians reassure patients with high risk nancy), for clinical purposes SMM is an important entity to SMM that the disease is stable only to have progression occur in preserve. It is easy to distinguish from MGUS, SMM, and MM with between visits. In randomized trials conducted in specialized current clinical criteria, and the distinctions have major clinical centers we note 90% reduction in end organ damage with simple implications for the patient in terms of prognosis, management, lenalidomide or Rd therapy compared with observation alone. and for planning their life. A puristic focus based on biology does Thus, attempting to delay therapy until the last minute and not help in the clinic. Importantly, the diagnosis of SMM highlights intervene in time before end organ damage occurs is easier said the increased risk of progression and the need for closer follow-up than done and had not been shown to be possible in clinical trials compared to MGUS, a distinction that will be lost if we clubbed even with monthly follow-up. the two together. The SMM category is similar to staging systems based on tumor Why do we recommend lenalidomide or lenalidomide plus volume, nodal spread, and cellular characteristics used in solid dexamethasone instead of myeloma-like therapy for high risk tumors. They may not be biologically different, but the clinical SMM? implications are different. In the plasma cell disorders field, we did We have data from randomized trials that lenalidomide or Rd is once refer to SMM as Stage I MM. But since the SMM terminology superior to observation in preventing end organ damage [45, 52]. has been in use for decades, we feel no reason to rename it at this One of these trials has shown a clear overall survival benefit[45]. point. If we come to a point where accurate tests to classify Although it is interesting to hypothesize that a myeloma-like patients with SMM into those with biologic pre-malignancy versus triplet or quadruplet regimen may be superior to lenalidomide or biologic malignancy are validated and widely available, and when Rd, we do not have randomized data to support that. Such a trial is we have data from randomized trials that treating high risk SMM ongoing (NCT03937635), and we are awaiting its results. For those similar to MM provides superior clinical benefit compared to concerned that lenalidomide or Rd may cause some delayed harm lenalidomide or Rd, we can reconsider. We are not there yet, and or drug resistance, that experiment has been done: the recent two we will not be there for a while. randomized trials with lenalidomide do not show any such adverse effect [45, 52]. This is therefore a theoretical risk that has been tested and found to be not true. For those who feel we Are the current risk stratification models adequate? should go straight to myeloma-like therapy it is also worth Current risk stratification models are not perfect, but they are considering that most patients cannot access such therapy readily available around the world, and identify patients with a without regulatory approval. In a disease where observation has 50% risk of progression within 2 years. The population so been the standard of care, we need to first demonstrate one drug identified has been treated in randomized trials with early works compared to no treatment, and then build on that. Making intervention, and a 90% reduction in risk of end organ damage a practice change without proof will provide myeloma therapy to has been demonstrated in both trials, with a survival advantage well insured patients in the United States but leave the vast in one trial. It is possible to do better and we will continue to majority in the world with no approved intervention. We are doing develop better models. Secondly, the fact that different models several clinical trial strategies in parallel including necessary capture different high-risk populations is not a negative. Each of regulatory trials (to show one drug works versus observation) our models is not very sensitive, and so we capture only a (NCT03301220), strategic trials (to see if myeloma like therapy is proportion of patients at risk. By using more models, we capture superior to Rd)(NCT03937635), and more aggressive trials (to see if more of the patients at risk, and lack of an overlap is actually early aggressive intervention at the SMM stage can be curative) advantageous in this regard. But whatever model is used, as (NCT02415413, NCT03289299). long as the population identified has at least a 50% risk of progressionin2 years, it is sufficient for clinical purposes both for management and counseling. Third, modern genomic FUTURE DIRECTIONS sequencing methods have not shown clear superiority in An ongoing ECOG randomized trial is testing whether a standard identifying patients for early intervention compared to more myeloma therapeutic triplet (DRd) will be superior to prophylactic conventional risk stratification models. Further, they are not doublet therapy with lenalidomide plus dexamethasone in standardized, with methods and techniques varying across patients with high risk SMM (NCT03937635) [54]. A similar laboratories, and are not widely available. When available, we randomized trial is comparing isatuximab plus Rd versus Rd in encourage their use in addition but not to the exclusion of patients with high risk SMM (NCT04270409). There are also clinical existing systems. In the future, assessment of circulating tumor trials testing intensive therapy with curative intent [49]. cells is another emerging technology that can be standardized and serve as a widely available metric for risk stratification and follow-up. DATA AVAILABILITY This is a current treatment algorithm, There are no new data generated for this Is early therapy justified without clear overall survival benefit? manuscript and data sharing is not applicable. In MM, end-organ damage includes osteolytic bone lesions and renal failure. At times, these are not reversible. They can cause significant morbidity to patients. 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Randomized GSK; Janssen; Oncopeptides; Pfizer; Regeneron; Roche; Sanofi; Seagen; Takeda, trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin outside the submitted work. Oncol. 2020;38:1126–37. 53. Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. ADDITIONAL INFORMATION Leukemia. 2013;27:941–6. Correspondence and requests for materials should be addressed to S. Vincent 54. Lonial S, Dhodapkar MV, Rajkumar SV. Smoldering myeloma and the art of war. Rajkumar. J Clin Oncol. 2020:38:2363–5. Reprints and permission information is available at http://www.nature.com/ reprints ACKNOWLEDGEMENTS Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims Supported in part by grants CA 168762 and CA186781 from the National Cancer in published maps and institutional affiliations. Institute, Rockville, MD, USA, and the Marvin Family Grant. AUTHOR CONTRIBUTIONS Open Access This article is licensed under a Creative Commons All of the authors collectively conceived of the paper, researched the literature, and Attribution 4.0 International License, which permits use, sharing, wrote the manuscript. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party COMPETING INTERESTS material in this article are included in the article’s Creative Commons license, unless Dr. Rajkumar reports grants from NIH, outside the submitted work. Dr. Kumar reports indicated otherwise in a credit line to the material. If material is not included in the consultancy from BMS/Celgene, Takeda, and Janssen), and research funding from article’s Creative Commons license and your intended use is not permitted by statutory BMS/Celgene, Takeda, Novartis, AbbVie, Janssen, and Amgen. Dr. Lonial reports regulation or exceeds the permitted use, you will need to obtain permission directly personal fees from Celgene, personal fees from Takeda, personal fees from Amgen, from the copyright holder. To view a copy of this license, visit http:// personal fees from BMS, personal fees from GSK, personal fees from Novartis, creativecommons.org/licenses/by/4.0/. personal fees from ABBVIE, personal fees from Janssen, other from TG Therapeutics, outside the submitted work. Dr. Mateos reports personal fees from AbbVie; Adaptive Biotechnologies; Amgen; bluebird bio; Celgene, a Bristol-Myers Squibb Company; © The Author(s) 2022 Blood Cancer Journal (2022) 12:129

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