Multiple myeloma is a highly refractory and relapsing type of hematological malignancy in which cure is achievable only in a select patient population with low-risk disease. Predictive cure models used at University of Arkansas for Medical Sciences reveal that 6% to 31% of patients with multiple myeloma have the potential to achieve cure with the more intense Total Therapy treatment regimen.

 However, a vast majority of patients remain incurable and reveal refractory and relapsing course of disease over time.

Recently, suggestions were made to start systemic treatment in earlier stages of disease, when patients are clinically asymptomatic and not yet transformed to multiple myeloma. Smoldering myeloma, a stage preceding multiple myeloma, is defined by the presence of serum and/or urine monoclonal protein and/or clonal plasma cell infiltration between 10% and 60% in the absence of end-organ damage, such as anemia, hypercalcemia, renal insufficiency, and bone lesion.

 Until now, it was a general dogma among myeloma experts to employ a watch-and-wait strategy at this stage.

Refining Our Understanding of Smoldering Myeloma

Over the past couple of years, it was revealed that smoldering myeloma behaves in different ways with various dynamics of progression to multiple myeloma. Some patients transform within a short period, whereas others remain in a smoldering stage over years or decades without requiring treatment. In particular, patients with ≥10% plasma cell in the bone marrow and serum M-protein of ≥3 g/dL have a significantly higher transformation rate, indicating high-risk smoldering myeloma.

 The transformation rate from smoldering to multiple myeloma is approximately 10% per year for the first 5 years, 3% per year for years 5 to 10, and 1% per year for the following 10 years.

Our myeloma group has published a 4-gene signature that can reliably distinguish between high-risk and low-risk smoldering myeloma, revealing a 2-year transformation rate of 5% in patients with low-risk disease versus 86% in those with high-risk disease.

Other risk factors identified for high-risk smoldering myeloma include the presence of immunoglobulin A subtype, immunoparesis with reduction of 2 uninvolved immunoglobulin subtypes, progressive increase of M-protein levels by 25% on 2 successive evaluations within a 6-month period, clonal plasma cell involvement in the bone marrow between 50% and 60%, increased circulating plasma cells in peripheral blood, magnetic resonance imaging—defined diffusion abnormalities or 1 focal lesion, and presence of a focal lesion with increased uptake without underlying osteolytic bone destruction in the positron emission tomography– computed tomography. Moreover, cytogenetic abnormalities such as t(4;14), deletion 17p, and gain of 1q are indicative of high-risk smoldering myeloma.

Several studies have been conducted to treat patients with high-risk smoldering myeloma with either a doublet or triplet regimen in a more conservative approach. Data from the QUIREDEX study (NCT00480363), conducted by the Spanish Myeloma Group, demonstrated that patients treated with lenalidomide (Revlimid) and dexamethasone had a significantly lower transformation rate from smoldering to multiple myeloma compared with the observation group (39% vs 86%, respectively).

 In addition, the time to progression to myeloma was significantly delayed in the treatment arm compared with the observation arm at 47 months versus 23 months, respectively.

Lonial et al published similar results in a randomized clinical trial, in which patients with intermediate- or high-risk smoldering myeloma receiving lenalidomide as a single agent were compared with an observational group. After a 35-month follow-up, the progression free survival (PFS) was significantly longer with lenalidomide compared with the observational arm (HR, 0.28; 95% CI, 0.12-0.62; 

 In the treatment and observational groups, the 1-year, 2-year, and 3-year PFS rates were 98%, 93%, and 91% compared with 89%, 76%, and 66%, respectively.

 A triplet regimen consisting of carfilzomib (Kyprolis), lenalidomide, and dexamethasone also demonstrated significant efficacy in patients with highrisk smoldering myeloma, leading to minimal residual disease (MRD) negativity in 92% (11 of 12) of patients.

So far, conservative treatment concepts using doublet and triplet regimens have been introduced only for patients with high-risk smoldering myeloma. These regimens have demonstrated significant improvements in PFS, delay in transition to multiple myeloma, and achievement of MRD negativity.

Several unanswered questions remain for this patient population. For example, which dose and combination should be used to treat patients with high-risk smoldering myeloma and for how long? Additionally, how should a relapse, refractoriness, and progression of high-risk smoldering myeloma be approached? A cure concept has not yet been established for asymptomatic and untreated patients with high-risk smoldering myeloma, and debate needs to be initiated surrounding how these patients can be treated sustainably while also taking into account their age, comorbidities, fitness, personal preference, and adverse events of the therapeutic agents.

A long-term approach and perspective are lacking with the current available clinical trials for patients with high-risk smoldering myeloma. In particular, for patients who are younger and those considered fit without comorbidities, more intensive treatment concepts with up-front stem cell collection and high-dose chemotherapy with autologous stem cell transplantation need to be discussed. Additionally, further clinical trials have to be established to underline the importance of a cure concept from the beginning.

Nishimura KK, Barlogie B, van Rhee F, et al. Long-term outcomes after autologous stem cell transplantation for multiple myeloma. 

. 2020;4(2):422-431. doi: 10.1182/bloodadvances. 2019000524.

Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. 

. 2014;124(20):3043-3051. doi: 10.1182/ blood-2014-07-552059.

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. 

. 2015;125(20):3069-3075. doi: 10.1182/ blood-2014-09-568899.

Landgren O. Shall we treat smoldering multiple myeloma in the near future? 

. 2017;2017(1):194-204. doi: 10.1182/asheducation- 2017.1.194.

Khan R, Dhodapkar M, Rosenthal A, et al. Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120). 

. 2015;100(9):1214-1221. doi: 10.3324/haematol. 2015.124651.

Mateos MV, Hernández MT, Giraldo P, 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. 

. 2016;17(8):1127-1136. doi: 10.1016/S1470-2045(16)30124-3.

Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma [published online October 25, 2019]. 

Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. 

. 2015;1(6):746-754. doi: 10.1001/ jamaoncol.2015.2010.

Articles

A cure concept has not yet been established for asymptomatic and untreated patients with high-risk smoldering myeloma, and debate needs to be initiated surrounding how these patients can be treated sustainably while also taking into account their age, comorbidities, fitness, personal preference, and adverse events of the therapeutic agents.

Sharmilan Thanendrarajan, MD

Articles

Controversy Surrounds Treatment of High-Risk Smoldering Myeloma