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
|
[7]
|
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
|
[10]
|
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
|
[11]
|
Witzig et al.
|
Thalidomide plus zoledronic acid versus zoledronic acid alone
|
[12]
|
Korde et al.
and
Mailankody et al.
|
Carfilzomib, lenalidomide and dexamethasone followed by a lenalidomide extension
|
[13]
[16]
|
Ghobrial et al.
|
Elotuzumab versus lenalidomide and dexamethasone
|
[14]
|
Nooka et al.
|
PVX-410 multiseptated vaccine with or without lenalidomide
|
[17]
|
Landgren et al.
|
Daratumumab with extended intense, extended intermediate, or short dosing schedules
|
[18]
|
Lonial et al.
|
Lenalidomide single agent versus observation
|
[19]
|
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.