Treatment options for multiple myeloma patients with high-risk disease
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- Ailawadhi, S., Masood, A., Sher, T. et al. Med Oncol (2010) 27: 53. doi:10.1007/s12032-010-9521-4
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Multiple myeloma is a heterogeneous malignant disorder with a variable clinical course suggestive of diverse biological factors that have important prognostic implications. Despite development of several new therapeutic agents and substantially effective novel combination regimens, myeloma remains an incurable disease. There is an emphasis to define new biologic parameters to accurately identify patients with aggressive disease biology. This will allow more informed treatment decisions based on the biology of the disease, resulting in further optimization of management strategies in specific patient subgroups. Among biological parameters of risk stratification, cytogenetics has emerged as arguably the most important dependable and clinically convenient. These are being increasingly utilized to develop therapeutic stratification in newer clinical trials. Appraisal of current data suggests that patients with high-risk cytogenetics have a worse prognosis. However, treatment with novel agents has changed this variable. There is emerging evidence that patients with aggressive disease biology are fairing better with innovative treatment regimens utilizing a combination of conventional and novel agents. This review focuses on current and emerging data about defining high-risk disease in multiple myeloma and the various therapeutic options for this group of patients.
Multiple myeloma (MM) is a prototype of malignant clonal B-cell disorders with monoclonal protein production in more than 90% of patients. It accounts for 10% incidence and 20% mortality of all hematological malignancies . MM is a heterogeneous disease that ranges from an indolent phase, called monoclonal gammopathy of uncertain significance (MGUS), that requires no treatment to an aggressive symptomatic phase that is typically associated with bone marrow infiltration, lytic bone lesions, renal dysfunction, immune compromised state and a compromised survival. There have been several exciting advances in therapeutic options for MM patients in recent years, despite that it remains an incurable disease in the vast majority of patients.
Clinical heterogeneity in patients with MM translates into variable survival that ranges from a few months to several years . This implies a variable response to the different available therapeutic options—both conventional and novel. These findings may be indicative of diverse biological factors that are inherent to the malignant clone leading to important prognostic and therapeutic implications. Such observations have lead to a search for biomarkers to accurately identify patients with aggressive disease biology. Identification of patients with high-risk disease will allow more informed treatment decisions based on disease biology resulting in further optimization of management strategies in specific patient subgroups. Here, we review the current information on distinguishing MM patients with high-risk disease and the emerging data regarding the impact of various novel therapeutic options in management of these patients.
Defining high-risk disease in multiple myeloma
Several clinical and biological parameters have been observed that suggest aggressive disease characteristics in patients with MM. Some of these characteristics have been correlated to poor prognosis and adverse survival outcomes. This field is still maturing, and thus, all the potentially poor-risk characteristics have not yet been standardized. The standard prognostic factors as well as some of the emerging markers of high-risk MM are summarized here.
Several inherent patient and clinical characteristics at the time of diagnosis have been identified as markers of high-risk or aggressive disease, conferring a significant adverse prognostic risk. These include poor-performance status (ECOG ≥ 3),  advanced age (≥70 years),  significant bone disease as marked by advanced lytic lesions, advanced clinical stage (≥stage 1) of the disease either by the Durie Salmon staging system (DS)  or by the International Staging system (ISS),  presence of renal dysfunction, [6, 7] and increased bone marrow plasmacytosis (≥50%) . Despite a large body of literature available highlighting the significance of these factors in defining disease with a poor patient outcome, these parameters are not necessarily utilized to select specific therapeutic regimens for patient subgroups. Among these, patients with advanced age may be preferentially given certain therapeutic regimens mostly due to their ineligibility for high-dose therapy and autologous stem cell transplant (HDT/ASCT). Thus, the choice of treatment in elderly patients may be secondary to a risk–benefit ratio of various treatment modalities, rather than a specific regimen that clinically benefits this patient subgroup more.
Lenalidomide dose adjustment in patients with renal dysfunction
Creatinine clearance (Clcr)
Clcr ≥ 60 ml/min
No adjustment required
Clcr 30–59 ml/min
10 mg once daily
Clcr < 30 ml/min (non-dialysis dependent)
15 mg every 48 h
Clcr < 30 ml/min (dialysis dependent)
5 mg once daily (administer following each dialysis)
Serum beta-2 microglobulin (β2 M) is elevated in up to 75% of patients with active MM at the time of initial diagnosis and is arguably the single most important prognostic marker for such patients [3, 5]. β2 M in conjunction with serum albumin is incorporated into the ISS . Despite its prognostic importance, β2 M level is not utilized to direct specific treatment options for MM patients. Other biochemical markers like C-reactive protein (CRP) and lactate dehydrogenase (LDH)  have been reported to be associated with more aggressive disease, but have not shown a consistent association with poor overall survival (OS) as β2 M has .
The serum kappa/lambda free light chain (FLC) assay is used as a surrogate marker of clonal expansion of plasma cells, and presence of an abnormal FLC ratio may have prognostic value in patients with newly diagnosed symptomatic MM when used in conjunction with the ISS. Furthermore, there is some data that an abnormal FLC ratio can independently predict the risk of progression from smoldering myeloma (SMM) to active MM. In this analysis of 273 patients with SMM, the best breakpoint for predicting risk of progression was an FLC ratio of ≤0.125 or ≥8 (hazard ratio 2.3; 95% CI 1.6–3.2) . Snozek et al.  reported in their data that patients with an abnormal FLC ratio (<0.03 or >32) had a significantly shorter median survival when compared with patients with an FLC ratio within the normal parameters as per this study (30 vs. 39 months, respectively). The role of FLC ratio as well as a strict definition of abnormal values is still being defined further in patients with MM and has not yet been used in therapeutic stratification of patients.
Surface molecule expression: In addition to staining positively for cytoplasmic immunoglobulin, the malignant plasma cells in MM generally stain positive for CD38, CD56 and CD138 and are usually negative for surface immunoglobulin and the pan-B-cell antigen CD19 . A prospective series of 685 patients with newly diagnosed MM treated uniformly on a protocol found that patients with tumors that expressed CD19 or CD28 or lacked CD117 had significantly shorter progression-free and overall survival .
Plasma cell labeling index (PCLI): It is a double immunofluorescence technique performed on freshly obtained bone marrow cells to identify the plasma cell population . An elevated value in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death . In patients with symptomatic myeloma, the PCLI, obtained either before or after treatment, is an independent predictor of poor survival . In another study, PCLI was measured in 945 patients; those with a PCLI ≥1 percent had inferior survival compared to those with a PCLI < 1 percent (median survival 25 vs. 40 months; relative risk 1.5; 95% CI 1.3–1.7) . The major disadvantage of the PCLI, however, is that it is not widely available and thus is not practical at present despite its promising applications.
Amyloidosis: MM-associated amyloidosis is another independent high-risk prognostic factor in MM patients . In a report on 201 patients, MM-associated AL represented a poorer prognostic disease even in the absence of symptoms at diagnosis. Treatment options for such patients are not different from ones who do not have the presence of amyloid at the time of diagnosis.
Magnetic resonance imaging (MRI) is a non-invasive technique that can visualize large volumes of involved bone marrow in MM patients. The pattern of marrow involvement on MRI has been associated with survival in patients with MM . Our group has recently reported on the independent association of extent of marrow involvement on MRI with overall survival in patients with newly diagnosed MM (in press). This approach is non-invasive and can be implemented in the community effectively. These observations need further validation in a larger cohort of patients.
Conventional metaphase cytogenetics (karyotyping) and interphase fluorescence in situ hybridization (FISH) have emerged as one of the most important testing mechanisms that can be used for risk stratifying patients with MM. Results of many studies have shown that based on these tests, several genetic categories exist, defining subsets of MM with dissimilar outcome, unique clinicopathologic features and response to therapy [20, 21]. These techniques are widely available and are sufficiently standardized, so that they can be used routinely for therapeutic stratification of patients. Over 70 percent patients with MM may have genetic aberrations in the malignant clone, although conventional cytogenetics reveals karyotypic abnormalities only in approximately 40 percent patients with MM. Techniques using interphase FISH detect a higher frequency of abnormalities in patients with MM, even in those with otherwise normal karyotypes [22–26]. Specific molecular markers that have established significance, include hypodiploidy, deletion of chromosome 13q (del13q), deletion of 17p (del17p) and translocations 4;14 [t(4;14)] and 14; 16 [(14;16)] [23, 25, 27–29]. The two important distinctions based on numerical chromosomal abnormalities include the group with numerical gains—the hyperdiploid group—and the other with chromosomal rearrangements and loss of chromosomes—the non-hyperdiploid group. Patients with hyperdiploidy have a comparably favorable prognosis and include those with trisomies of chromosome 3, 5, 9, 11, 15, 19 and 21. The non-hyperdiploid group of MM patients includes those with the deletion of chromosome 1q, 1p, 8 and 13. The non-hyperdiploid group also encompasses translocations involving the immunoglobulin heavy chain locus on chromosome 14q32, t(4;14) (p16;q32), t(4;16) (q32;q23) or deletion 17p which embody the high-risk genetic category [30, 31].
More sophisticated techniques are now available to further characterize tumor cells and predict aggressive biological behavior. These include gene expression profiling (GEP), comparative genomic hybridization, tumor-associated antigens, and multiparameter flow cytometry. While these techniques have generated a lot of interest and are able to dissect aggressive disease in a more sensitive manner, these evaluations are not readily available, are difficult to interpret in clinical practice and are still considered experimental [32–37]. The use of GEP has helped to delineate a high-risk molecular signature in MM [38, 39]. So far, there is lack of uniform platform and widespread availability of these tools. Despite the current shortcomings of these techniques and paucity of standardized data utilizing them, the initial indications are quite provocative. In the future, other methodologies may be used to aid the diagnosis, risk stratification and therapy in patients with MM.
Treatment options for high-risk cytogenetics—emerging evidence
Clinical studies of various chemotherapeutic options in high-risk multiple myeloma
Jagannath et al.
Bortezomib vs. Dex
San Miguel et al.a
t(4;14), t(14;16), del(17p)
Sonneveld et al.a
VAD vs. PAD
del (13/13q), t(4;14)
Rosinol et al.a
VTD vs. TD vs. V/VBMCP/VBAD
t(4;14), t(14;16), del(17p)
Kapoor et al.
Hypodiploidy, del (13/13q), t(4;14), t(14;16), del(17p)
t(4;14), t(14;16), del(17p)
Reece et al.
del (13/13q), t(4;14), del(17p)
Knop et al.
del (13q), t(4;14), del(17p)
Kumar et al.a
Barlogie et al.
Total therapy 2 (with Thalidomide)
Barlogie et al.a
Total therapy 3 (with Bortezomib)
Among the novel agents being utilized for management of MM, bortezomib was the first one noted to demonstrate clinical activity among patients with high-risk cytogenetics features of MM . This was noted in a retrospective analysis of R/R MM patients treated with bortezomib in large phase 2 (SUMMIT)  and 3 (APEX)  clinical trials. This report showed that in both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13). However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics . This data has lead to the acceptance of bortezomib or bortezomib-based regimens as the therapeutic option of choice for patients with del(13) abnormality on cytogenetics. Furthermore, there is emerging data that in the era of treatment with novel agents, del(13) may be a high-risk characteristic only in conjunction with other cytogenetic abnormalities like del(17p), t(4;14) or del(1q).
Based on this initial data, most of the newer clinical trials involving novel agents have reported subgroup analyses of response rates in high-risk cytogenetics. One such large randomized phase 3 clinical trial is the VISTA study that compares the combination of bortezomib, melphalan and prednisone (VMP) with melphalan and prednisone (MP) in previously untreated elderly patients with MM . A retrospective analysis of high-risk cytogenetics, as obtained by interphase FISH (t(4;14), t(14;16), del(17p)), was performed in these patients. There was no significant difference between the high-risk or standard-risk groups, treated on the VMP arm, with respect to time to progression (TTP) (19.8 months vs. 23.1 months; HR 1.297; 95% CI 0.55-3.06) or overall survival (OS) (not reached in either group; HR 1.104; 95% CI 0.44-2.74). This further supports the initial observation that bortezomib-based regimens might overcome the negative prognostic effect of high-risk cytogenetics in MM patients.
Two recent reports at the 2008 annual meeting of the American Society of Hematology (ASH) have noted the role of bortezomib-based regimens in the setting of ASCT (Table 2). The first of these is an interim analysis of the HOVON-65/GMMG-HD4 study presented by Sonneveld et al. The two regimens being studied on this trial are vincristine, adriamycin, dexamethasone (VAD) and bortezomib, adriamycin, dexamethasone (PAD) followed by high-dose melphalan and ASCT. The study population comprised only newly diagnosed MM patients. Number of patients with del(13/13q) or t(4;14), achieving a very good partial response (VGPR) or better, in the two arms were compared. Presence of t(4;14) adversely affected outcomes with both VAD and PAD, although better outcomes were noted with PAD in this patient subgroup. On the other hand, patients positive for del(13/13q) had superior response with PAD when compared with those treated with VAD (P < 0.01). This study is ongoing, and the duration of response or survival data is not yet available. Another analysis of the randomized phase 3 trial of the Spanish myeloma group (PETHEMA/GEM) incorporated thalidomide, dexamethasone (TD) vs. TD plus bortezomib (VTD) vs. bortezomib plus VBMCP/VBAD (V/VBMCP/VBAD) as pre-ASCT induction therapy in newly diagnosed MM patients (Table 2). Among a total of 183 patients randomized, 17, 25 and 17% were noted to have high-risk cytogenetics (t(4;14), t(14;16), del(17p)) in the three arms, respectively. In a subgroup analysis, overall response rates within this high-risk patient population were higher with VTD (69%) when compared with TD (45%) or V/VBMCP/VBAD (45%). Similar results were noted for the patients achieving a complete response (CR) as well (36 vs. 0 vs. 18%, respectively). The estimated overall survival at 2 years was 82% with no significant differences among the 3 arms, while the time to progression (TTP) and progression-free survival (PFS) were significantly shorter with TD (P = 0.05 and P = 0.012, respectively) when compared with the VTD arm.
Recent reports have looked at the combination of lenalidomide plus dexamethasone (LD) with or without other chemotherapy agents for the treatment of patients with MM with high-risk cytogenetics. Kapoor et al.  reported the impact of risk stratification on outcome among patients with MM receiving initial therapy with LD. Data was analyzed from 100 patients; 16% were classified as high-risk which was defined as hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), immunoglobulin heavy chain (IgH) translocations of t(4;14) or t(14;16) by FISH or cytogenetics, or plasma labeling index (PCLI) ≥3%. The high-risk characteristics utilized in this analysis are mentioned in Table 2. Response rates were 81 vs. 89% in the high-risk and standard-risk groups, respectively. The median PFS was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Despite a less durable response with LD in high-risk compared with standard-risk patients in this study, the TTP and PFS observed with lenalidomide in high-risk patients are comparable to those achieved with other therapies in similar clinical settings.
Similar analyses have been performed in previously treated MM patients with relapsed/refractory disease as well. The Canadian investigators evaluated the influence of cytogenetics in patients with relapsed or refractory MM (n = 130) treated with LD in a multicenter, open-labeled phase 2 clinical trial . Whereas patients with either del(13q) (n = 54) or t(4;14) (n = 24) experienced a median TTP and OS comparable with those without these cytogenetic abnormalities, patients with del(17p13) (n = 12) had a significantly worse outcome, with a median TTP of 2.22 months (HR, 2.82; P < .001) and median OS of 4.67 months (HR, 3.23; P < .001). In this study, the median TTP of 8.0 months in patients with t(4;14) is encouraging but needs to be interpreted with caution considering the relatively short follow-up (19.7 months). Thus, relapsed/refractory MM patients with del (17p13) specifically did not benefit from treatment with LD in this study, while patients with t(4;14) may experience durable responses with this regimen. A combination of LD with doxorubicin (RAD) has recently been reported by the German Myeloma Study Group DSMM in patients with relapsed and refractory MM . In a subgroup analysis of this study, response was not significantly different for patients displaying del (13q) (ORR 67%) compared with those lacking this abnormality (ORR 82%; P = .4). ORR for t(4;14)-positive patients (ORR 50%) was also not significantly different compared with patients without t(4;14) (ORR 73%; P = .176). Although the absolute number of patients was low, presence of del (17p) was identified as an adverse prognostic factor with respect to response (20 vs. 87%; P = .001) and median TTP (20 vs. 45.5 weeks; P = .025). These reports of lenalidomide-based regimens in high-risk patients with relapsed or refractory MM consistently show adverse outcomes in patients with del (17p), while patients with del (13q) or t(4;14) apparently had an outcome similar to standard-risk patients in both these studies. This suggests that lenalidomide may be an effective therapy for patients with high-risk cytogenetics except those with del (17p). It is to be noted that the number of patients in these studies was relatively small, and prior therapies may also influence the impact the outcome reported. Furthermore, this data must be validated in larger, prospective studies.
Subgroup analyses of patients with high-risk cytogenetics in another phase 2 clinical trial utilizing lenalidomide-based regimen was presented at the 2008 annual ASH meeting by Kumar et al. (Table 2). LD with cyclophosphamide was given to previously untreated MM patients. Among patients considered high risk (n = 14), response rates were comparable to those at standard risk (n = 39). This study was limited by description of the criteria used for risk stratification and for high-risk disease. Thus, with respect to the role of lenalidomide in patients with high-risk cytogenetics, the data is still emerging and warrants further careful evaluation in this group of high-risk MM.
Thalidomide was the first agent with mild immunomodulatory activity approved for the treatment of MM. As previously mentioned, in the PETHEMA/GEM study, the outcome of patients in high-risk MM was better when bortezomib was added to the thalidomide plus dexamethasone combination. Other studies that have looked at the role of thalidomide in such patients are the Total Therapy 2 (TT2) trial by the group in Arkansas . Eligible newly diagnosed patients were randomly assigned to a control arm or an experimental arm that included thalidomide during all phases of treatment. Treatment included 4 induction cycles, followed by melphalan-based tandem ASCT, 4 cycles of chemotherapy consolidation, and maintenance therapy with interferon-alpha-2b to which dexamethasone was added in pulsed fashion during the first year . With a median follow-up of 72 months, survival plots segregated 5 years after initiation of therapy in favor of thalidomide (P = .09), reaching statistical significance for the subgroup of patients exhibiting cytogenetic abnormalities (P = .02). The duration of CR was also superior in the cohort presenting with cytogenetic abnormalities such that, at 7 years from onset of CR, 45% remained relapse-free as opposed to 20% in the control arm (P = .05). These observations were confirmed when examined by multivariate analysis suggesting that thalidomide reduced the hazard of death by 41% among patients with cytogenetic abnormalities (P = .008). Subsequent clinical trial conducted by the Arkansas Group incorporated bortezomib in the treatment schema (total therapy 3; TT3). The TT3 incorporated gene expression profiling (GEP) and cytogenetic abnormalities to delineate high-risk disease. Initial results reported at the 2008 annual ASH meeting suggest that TT3 improved outcomes over TT2 in all patients with t(4;14) and a subgroup of patients with del (17p) who had a low-risk GEP. More definitive data from this clinical trial is still awaited (Table 2).
High-dose therapy and autologous stem cell transplant
Despite current controversies regarding the role of ASCT in patients with MM, it still remains an important therapeutic modality for these patients. In the past, it was considered that more aggressive approaches including ASCT would be the management of choice for patients with high-risk disease. However, several large studies have shown that patients defined as genetically high risk do not derive durable responses to HDT/ASCT strategies as currently practiced, and many relapse soon after undergoing such treatment [20, 50, 51]. Of these, one group shown to benefit from HDT are patients with t(4;14) and low β2 M, who achieved durable responses with this modality . Furthermore, the role of delayed HDT/ASCT compared with upfront for patients with high-risk MM remains unknown . Emerging data has suggested that incorporation of novel agents into the HDT/ASCT process in the form of induction regimens as well as maintenance strategies may actually overcome these shortcomings . Data from such studies is still not mature, and these results are eagerly awaited.
Allogeneic stem cell transplant
For MM patients, allogeneic stem cell transplant remains a modality to be further explored in clinical trial settings. The relatively higher risk of treatment-related morbidity and mortality makes it a choice to be better defined prior to a more widespread application. The IFM reported a study comparing non-myeloablative allogeneic stem cell transplant (NM-SCT) with tandem HDT/ASCT in patients with high-risk MM . This study failed to show superiority for the allogeneic strategy in such patient subgroups. More recently, a randomized study comparing NM-SCT with tandem HDT/ASCT showed the superiority of the former technique, but included all comers in the analysis, irrespective of risk stratification . However, this issue needs further clarification and larger intergroup studies (BMT CTN 0102 and EBMT study) are currently ongoing that will likely address this better.
Treatment for MM has undergone several advancements in the recent past with a progressive improvement in overall survival. The credit for this tremendous progress goes unarguably to the novel therapeutic agents being utilized, improved patient management techniques, and better understanding of the characteristics and biological behavior of the disease. Another aspect of this fast changing field is the understanding of variability in clinical behavior, which among others, is related to the differences in disease biology. Based on these findings, risk stratification of patients with MM is of paramount importance to develop personalized therapeutic options that are likely to benefit patient subgroups the most. Although there is an increasing understanding of the high-risk disease subtype in MM, a uniform, risk stratification criteria needs to be developed. Prospective clinical trials targeting patients with high-risk MM that compare the various conventional and novel therapeutic strategies are likely to help understand this important clinical question better. The data presented here outlines some of the current clinical advancements and the need for future efforts in developing targeted prospective research in patients with high-risk MM.
Conflict of interest statements
Sikander Ailawadhi: Speaker’s Bureau—Celgene, Millennium, Ortho BioTech; Advisory board—Millennium; Aisha Masood: No disclosures to report; Taimur Sher: Advisory board for Millennium; Kena C. Miller: Speakers bureau for Celgene, Millennium, Cephalon, Medtonic/Kyphon; Advisory Board for Celgene and Millennium; Margaret Wood: No disclosures to report; Kelvin Lee: No disclosures to report; Asher Chanan-Khan: Speakers bureau—Celgene, Millennium; Advisory board—Celgene, Millennium. All authors received an honorarium for their participation in this supplement.