Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of ≥ 3 g/dL serum M-protein and/or 10-60% bone marrow plasma cell infiltration with no myeloma-defining event (MDE). The Swedish Myeloma Registry reported that 14% of myeloma patients had evidence of SMM with a median age of 72 years [1]. The overall risk of progression from SMM to symptomatic myeloma is highly variable unlike MGUS and estimated to be 10% per year for the first 5 years, 3% per year for the next 5 years, and 1% per year for the last 10 years [2]. This feature suggests that SMM is a heterogeneous disorder and so the actual risk of progression to myeloma should be calculated by using various models proposed (Table 1) and should be classified and managed accordingly (Table 2). The Spanish myeloma group targeted only the high-risk SMM (HR-SMM) (Table 2) [5,6], unlike the previously failed studies, which included all risk classes. The Spanish study (n=119) compared early treatment with lenalidomide plus dexamethasone (Rd) as induction followed by lenalidomide maintenance versus observation [5,6]. After a median follow-up of 75 months, the median time to progression (TTP, primary endpoint) was significantly longer in patients in the early treatment group than in the observation arm (not reached, NR vs. 23 months; p<0.0001) with consequent improvement improvement in OS as well (not reached, NR vs. 117.6 months) [6]. The progression of SMM to myeloma occurred in 86% of patients in the observation arm as compared to 39% in the Rd arm. The safety profile was acceptable and most of the adverse events reported were grade 1 or 2. Apart from cytoreduction, lenalidomide was shown to have potential immunosurveillance effects against SMM in the Spanish study and possibly contributed to the reduced transformation to myeloma [7].
The present case belongs to the HR-SMM category according to the well-established Mayo/Spanish group criteria as well as other new criteria (Table 1) with an expected progression of approximately 50% at two years (Table 2). Interestingly, the PET/CT scan in the present case is negative for any focal lesions. In few recent studies, this predicts the probability of progression to be approximately 30-33% [8,9]. Importantly, it is independent of BM plasmacytosis and elevated SFLC ratio [9]. So apart from ruling out myeloma, PET/CT can be helpful deciding the management. To exclude the presence of osteolytic bone lesions in SMM, IMWG recommends MRI of spine and pelvis (or whole body preferably) in addition to skeletal survey or low-dose whole body CT, or PET/CT [4]. MRI was found to detect focal lesions in the axial skeleton in 18% of cases where PET/CT was negative in a study [8] and could re-classify them as myeloma [4].
In this young patient who is a candidate for a future autologous stem cell transplant (ASCT) should he develop myeloma, the decision to treat his SMM with Rd have potential concerns [10]. There had been concerns regarding the stem-cell collection with lenalidomide and an early mobilization is recommended within the first four cycles of lenalidomide-based induction, which is followed in the Spanish trial for SMM [11]. The median stem cell collection in the Spanish study (n=21, ~40%), with a target of 2×106 CD34+ cells per kg, was 3.1×106 per kilogram (range, 0.3 to 15.1) after a median of 2 apheresis procedures (range, 1 to 4). In two of these patients (~10%), the target number of CD34+ cells was not reached [12]. The stem cell collection was done after 4 cycles of Rd when the myeloma response was not that great (>VGPR in only ~30% after 9 cycles of Rd). Again in a resource-limited setting stem cell storage adds more cost (discussed in detail in the next vignette). The stem collection in this study is far from satisfactory.
So better induction strategies with respect to response (VGPR or better) like in myeloma need consideration especially in young SMM patients e.g. Carfilzomib-Lenalidomide-Dexamethasone based combination (CRd), where all patients achieved CR and most were in immunophenotypic CR [13]. The other way to look at SMM is, it provides us a ‘window of curability’ and we may succeed in this approach by treating it just like myeloma with an induction-consolidation (ASCT)-maintenance like strategy and a study is trying to address this hypothesis (CESAR study) [14]. So, at this point in a young SMM patient, though Rd has a lot of promise, it also has limitations more so in a resource-limited setting.
The incidence of second primary malignancies (SPM) was also found to be higher for patients with SMM receiving Rd versus observation (10% versus 2%) in the Spanish study after a median follow-up of 75 months [6] similar to myeloma (~7% at 5 years) [15], whether it is induced by Rd or not needs more clear answers [16] and is a question for the future. So, the benefit needs to be weighed against this risk. The requirement of appropriate thromboprophylaxis also needs consideration in these patients who are at high risk for development of venous thromboembolism when treated with Rd [17].
Although this Spanish trial had made it clear that waiting till CRAB features to develop in HR-SMM as in the observation arm is a bad idea and detrimental and we need to intervene prior to that, the question remains what is the appropriate time point for intervention [18]. In the Spanish study, the evidence of asymptomatic biological progression before the development of CRAB was seen in 19% of patients in the observation arm [12]. In a preliminary study presented as an abstract, it was demonstrated that the evolving changes in hemoglobin, M-protein or immunoglobulins may further identify SMM with ultra-high risk features and may guide in management [19].
Proposed Treatment: The present case will be followed up carefully for evidence of myeloma every 2-3 months.
Myeloma is a disease of elderly. Hence, the treatment approach in myeloma has been based on whether a patient can tolerate the ASCT procedure and then the patient is classified as transplant-eligible. The objectives of an ideal induction regimen in a transplant-eligible patient of myeloma would be (i) aggressive cytoreduction for rapid symptomatic recovery, (ii) achieving deep responses, (iii) without compromising collection of stem cells and (iv) without causing significant toxicity to the patient [20]. The induction therapy in transplant-eligible patients has moved dramatically from conventional cytotoxics to novel biology-specific agents like proteasome inhibitors (PIs) or immunomodulators (IMiDs) because of their huge impact in improving survival [21,22]. These novel drugs combine well with conventional therapies and with one another to form a various doublet, triplet, and quadruplet regimens and have reasonable activity against myeloma (Table 1) [23]. The response rates increase as the number of active agents increases to 3 or 4 (Figure 1) and these responses further increase after ASCT.The synergism of a PI with IMiD in myeloma has been observed both in clinical [24] as well as pre-clinical studies [25]. The combination of bortezomib, thalidomide, and dexamethasone (VTD) [26] and bortezomib, lenalidomide, and dexamethasone (VRd) [27] demonstrated better response rates as well as survival when compared to TD and Rd respectively [26,27]. However, it is not known which IMiD is a better partner to Bortezomib. But in a comparative analysis of TD vs RD, RD was found to be more effective and better tolerated than TD [28]. In our own experience, we did not find any difference in response rates between Rd and Td (ORR 68% vs. 67%, VGPR or better 34% vs. 30%) in a phase III randomized study [29]. In another phase III trial comparing two triplet induction regimens before ASCT (VTD vs. bortezomib, cyclophosphamide, and dexamethasone or VCD) demonstrated that the rates of VGPR with VTD far outweighed those associated with VCD (66.3% vs. 56.24%; P = 0.05) [30]. So, this trial again underlines the synergism of PI-IMiD combination and the next step was to add a fourth drug to PI-IMiD-dexamethasone combination, which was either cyclophosphamide [31,32] or liposomal doxorubicin [33]. It was found that the efficacy of adding a fourth drug was associated with increased toxicity without any significant improvement in response [31–33].
Barlogie et al. developed the concept of a second or tandem ASCT that improved response as well as survival [34], but came at a cost of higher mortality [35], leave apart its economy. There was no additional benefit of a second ASCT in the subgroup of patients with at least VGPR as demonstrated by both French [36] as well as the Italian group [37]. So, VGPR remains an important as well as a desirable target for an induction regimen, so that a second ASCT can be avoided.
The optimal number of CD34+ hematopoietic stem cells to be collected from a transplant-eligible patient remains an important aspect of management. There are indications that these novel agents may impair stem cell mobilization in different studies which are more than that reported in the cytotoxic era especially VAD (Table no 3). Unlike thalidomide, lenalidomide is toxic to normal hematopoietic stem cells by suppression of their motility as well as angiogenesis and may impair the collection of stem cells [11,38].
The present case summarizes a young transplant-eligible patient with symptomatic myeloma, with ISS-II and normal cytogenetics and will fall into the low-risk category according to IMWG or MRC classification and intermediate-risk category according to German classification [48]. Before we classify this patient into a low or intermediate risk myeloma, serum LDH should also be assessed which can be elevated in approximately 10% of these cases [49] and predict poor prognosis in myeloma [49,50]. In a resource-limited setting, serum LDH is a readily available and inexpensive investigation and will further help in the management of these cases [50]. The treatment approach does not differ according to the risk status and in this modern era with highly active novel drugs being used in combination, a low-risk patient like the one described has the best chance of obtaining a long-term PFS and an operational cure.
The induction treatment apart from its favorable control of disease, it gives enough time to the patient for preparation for ASCT both mentally and more importantly economically. The cost of ASCT is approximately 300,000 INR (~6000 USD) in our hospital like our center, which is funded by the government [51]. The median time from diagnosis to ASCT at our center had been 10-12 months [52–55]. Once we admit the patient for ASCT after induction, we collect the stem cells in the same admission following G-CSF mobilization and store them at 4°C (can be stored up to 120 hours), then transfuse them back a day after high-dose melphalan which has a short elimination half-life. This approach of using non-cryopreserved stem cells is well-suited to myeloma transplants and at our center it saves 15% of the total cost of transplant [52].
The best regimen would be a triplet using bortezomib & dexamethasone (VTD, VRd/RVd, VCD) which helps in rapid symptomatic recovery and achieves high-quality responses [27,30]. The PI-IMiD combination (VTD or VRd) seems to be doing better than VCD with respect to achievement of deep responses [30,32]. VTD may be preferable regimen than VRd in a resource-limited setting because there is no need for early mobilization and collection of stem cells, as there is hardly any risk of poor mobilization when compared to VRd. Again VTD was demonstrated to have better stem cell yield as compared to VCD in a phase 3 study [30]. The cost of IMiD should also be taken into account while planning [51]. In India, Thalidomide (3000 INR = 45 USD) costs far less when compared to Lenalidomide (15000 INR =225 USD) [51].
As we look back in history we learn that ASCT in newly diagnosed myeloma was introduced at a point when nothing was really working beyond Melphalan-Prednisolone, the existing standard at that time [56] and ASCT demonstrated improvement in responses as well as survival when compared to conventional chemotherapy in the two landmark randomized studies by the French and UK group [56,58]. Even back then (cytotoxic era), the survival was not different when ASCT was deferred till relapse (median OS, 64 months vs. 64.6 months, p = 0.92) in a randomized trial, but the average time without symptoms, treatment, and treatment toxicity (TWiSTT) was longer in the group of patients undergoing early ASCT (median, 27.8 months vs. 22.3 months) [59].
In the present era where novel agents are included during induction, post-ASCT consolidation as well as maintenance, the beneficial role of ASCT is seen with a lot of skepticism. In two different randomized phase-III studies reported better PFS as well as OS for tandem ASCT compared with continued chemotherapy (Melphalan-RD [60] and Cyclophosphamide-RD lenalidomide [61]) after initial induction with Rd and lenalidomide (with or without prednisolone) maintenance following consolidation (ASCT or CRd) [60,61]. These trials tried to answer more than one question including the role of ASCT and maintenance. So, they may be relatively underpowered to answer precisely the benefit of early vs. late ASCT. They also did not use the current standard of IMiD-PI based combination therapy which is a major limitation [60–63]. In a recent phase-II IFM 2008-01 trial, RVd induction, ASCT (Single), short consolidation with RVd, and 1-year maintenance with lenalidomide in 31 patients yielded impressive 3-year PFS and OS rates of 77% and 100%, respectively [64]. The high-quality responses seen with RVd in newly diagnosed myeloma were remarkable [67,86,87] and few retrospective studies suggesting ASCT can be delayed when this combination is used [67,68]. So, in the IFM/DFCI 2009 study (The Determination Trial) RVd induction (3 cycles) followed by randomization to early vs. delayed ASCT that included 700 patients with myeloma [69]. At the second interim analysis of the IFM/DFCI 2009 study (The Determination Trial) where RVd induction (3 cycles) followed by randomization to early vs. delayed ASCT that included 700 newly diagnosed patients with myeloma, demonstrated a superior CR rates (58% vs. 46%, p<0.01) as well as 3-year PFS (61% vs. 48%) in the early ASCT arm [69]. The OS data does not reveal any difference between the two arms and require longer follow-up. The authors conclude that early ASCT should remain a standard of care for young patients with de novo myeloma, and suggest that RVd plus ASCT could be a future reference strategy in this setting [69].
Carfilzomib is a second-generation PI selectively and irreversibly binds to the proteasome, targets chymotrypsin-like activity [70]. The Chicago group led by Jakubowiak has also done pretty exciting work with CRd in upfront myeloma, and in a small phase 1/2 study (n=53) demonstrated exceptional response rates with stringent CR ~55% without ASCT which only got better in another phase 2 study (n=53) with the use of ASCT and extended CRd consolidation and maintenance to 86% (n=8) which further reinforces the importance of early ASCT in the present era with most effective novel agent combinations [71,72].
In a controlled environment of clinical trial, the patients who could be offered delayed ASCT was approximately 43% in one study [61] and 63% in another [60] despite prior stem cell collection, because of rapid worsening of their clinical condition or the patient’s decision to decline transplantation requires attention in community practice. Apart from these scientific evidence, it was also suggested that early ASCT could potentially be a relatively cost-effective treatment option compared with a delayed approach which can be more relevant in a resource constrained situations [73]. So, even in the present era ASCT performed early seems imperative in the management of young patients with myeloma, but there is scope for delayed ASCT, which needs to be individualized, needs a better understanding as well as careful discussion with the patient.
Proposed Treatment: The present case summarizes a young transplant-eligible patient with symptomatic myeloma, ISS-II with no high-risk cytogenetics and in MRD-positive CR post induction. In a meta-analysis, the presence of MRD-positive CR (n=134) had a 3-year and 5-year PFS of 50% and 29% respectively as compared to MRD-negative CR (n=362) which was 72% and 50% respectively [74]. Most of the myeloma patients with MRD-positive CR progressed by 6 years [74]. In the IFM/DFCI 2009 study, the PFS benefit persisted irrespective of the CR status [69]. So, this young patient should be offered consolidation with ASCT.
The present case summarizes a young patient with normal cytogenetics post-ASCT with CR and MFC (2nd generation) with a sensitivity of 1 in 105 does not reveal any evidence of MRD, which is good news for the patient and the physician. The expected median OS with MRD <10-4 in Medical Research Council Myeloma IX study was more than 7.5 years [75]. So, in the present case with MRD <10-5 the expected outcome seems excellent. Now we are in the era of next-generation novel agents (Carfilzomib etc.) as well as next-generation flow (NGF) and sequencing (NGS) [13].
Most of the available data on the prognostic value of MFC-based MRD assessment were obtained using “first generation” MFC (4-/6-color combinations), with a detection limit of 10−4. The next generation MFC (NGF) based on 8-color combinations has been introduced recently with a detection limit of 10−5 which has resulted in increased sensitivity in a study [76] and is comparable to NGS (10-6) in another study [13]. Barlogie and colleagues also highlighted the relevance of attaining MRD negativity by NGF in their cohort of long-term PFS (> 10 years), but did emphasize that achieving MRD may not be everything to achieve cure [77]. In a recent study, an absence of MRD by NGF in elderly myeloma patients enrolled in the PETHEMA/GEM2010MAS65 study was an independent prognostic factor for TTP (figure 2) as well as OS [76]. Attaining a deep remission does not declare victory over myeloma and it should not guide treatment. In the MRD-negative subgroup (after 9 cycles) of PETHEMA/GEM2010MAS65 study (Figure 2), we see that after completion of planned therapy the incidence of relapses is increasing. So, at this moment we do not know at what point we should stop treatment or what is the lowest level of no return for myeloma. Importantly, MRD by MFC only predicts about the tumor load in bone marrow and the extramedullary disease load is probably better assessed by imaging with PET/CT [78] and have been included in the definition of MRD negative Myeloma [79].
There is progressive deteoration of immune function from MGUS (normal immune function) [80] to SMM (mildly abnormal) [7] and to MM (grossly abnormal) [81] and the progression from MGUS or SMM is related to immune escape. In the Spanish trial treatment with Rd in SMM demonstrated that delay in progression is not entirely dependent on cytoreduction, immunomodulation by lenalidomide is partly responsible. In another study, myeloma patients with long-term disease control were demonstrated to have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance [82]. Similarly, in PETHEMA/GEM2010MAS65 study demonstrated a unique immune signature related to regeneration of mature B-lymphocytes, experience prolonged survival even though they are MRD-positive [76].
Proposed Treatment: As we discussed, attaining MRD-negativity is desirable but not a prerequisite in order to achieve long-term disease control, and with time to come we need to include imaging to further reconfirm the MRD-negativity. More accurate identification of such patients should is a research question for the future. This patient would need further treatment in form of maintenance with or without consolidation.