Maximizing Prognostic Benefit: Risk-adaptive Approaches in Multiple Myeloma

Maximizing Prognostic Benefit: Risk-adaptive Approaches in Multiple Myeloma

Evangelos Terpos
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece

Introduction
Multiple myeloma (MM) is a clonal plasma cell disorder characterized by the secretion of a monoclonal protein in the majority of patients along with several clinical features including anemia, osteolytic bone disease, renal impairment, and infections. Life expectancy of MM patients has dramatically improved with the introduction of several novel agents including proteasome inhibitors (PIs) (bortezomib, carfilzomib, and ixazomib); immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide, and pomalidomide); histone deacetylase inhibitors (panobinostat); and monoclonal antibodies (daratumumab and elotuzumab).[1,2] Although there is an increase in overall survival (OS), MM remains a highly heterogeneous disease, with OS ranging from a few months (for 10% of patients) to more than 10 years among different cases. This variability results from the heterogeneity in the tumor genetics and the interactions of myeloma cells within the host bone marrow microenvironment.[3] Therefore, it is extremely important to identify both prognostic factors and predictive markers that will improve the management of patients with MM.

It is important to distinguish between prognostic and predictive factors. A prognostic factor is a clinical or laboratory variable that gives information regarding the outcome of the patients. A predictive factor is a marker that provides information regarding response to a specific therapy and the outcome of patients who receive this therapy.[4] Prognostic factors in MM can be patient- or tumor-related. Tumor factors include chromosomal abnormalities of myeloma cells, their gene expression profiles, and the overall tumor burden. Patient factors include age, performance status, and comorbidities.[4,5] Based on these factors, we can distinguish “standard” from “high” risk disease. Several questions still exist regarding risk stratification, however. Do we need risk stratification models? What is the value of distinguishing “standard” from “high” risk myeloma? Do we treat patients in these categories differently?

Tumor Factors
For many years, staging of myeloma was based on two markers that define tumor load: serum beta-2 microglobulin and serum albumin.[6] The International Staging System (ISS) has been widely used and is presented in Table 1, with a depiction of the differences in survival between the disease stages shown in Figure 1. Since 2005, when the ISS was first described, several prognostic factors have been reported. Chromosomal abnormalities are present in the myeloma cells of almost all patients with MM, although only 30% of cases have abnormal karyotypes due to the low proliferating index of the majority of plasma cells.[7] Thus, the International Myeloma Working Group (IMWG) and the European Myeloma Network (EMN) have recommended to test plasma cells at baseline using fluorescent in situ hybridization (FISH) by cytoplasmic immunoglobulin enhancement or performed on the nuclei from purified plasma cells using probes that could detect the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), t(11; 14)(q13;q32), 17p13 deletions, chromosome 13 deletion, and chromosome 1 abnormalities.[8,9] Several studies have demonstrated that translocations t(4;14) and t(14;16), as well as del(17p), are chromosomal abnormalities that carry very poor outcomes; add(1q) may also confer poor survival.[10-15] Furthermore, the serum level of lactate dehydrogenase (LDH), another marker of tumor load, also has independent prognostic factor for OS.[16,17] This is the reason that the IMWG has produced the Revised ISS (R-ISS) based on the previous ISS and the presence of high-risk cytogenetic features (t(4;14), t(14;16) and/or del17p) and elevated LDH (Table 2); the differences in OS based on the R-ISS stages for non-transplantation, transplant-based, immunomodulatory-containing and PI-based regimens are demonstrated in Figure 2.[18]

Table 1. International Staging System for multiple myeloma [6]



Table 2. Revised-ISS for multiple myeloma [18]


Myeloma cell heterogeneity has also been studied with gene expression profiling (GEP) in an attempt to identify poor prognostic myeloma patients. Based on such studies, two GEP risk models have emerged. The first was produced by the University of Arkansas for Medical Sciences (UAMS). It is a 70-gene model that identified genes involved in cell cycle regulation, cell adhesion, migration, proliferation and angiogenesis. Several of these genes (approximately 30%) are mapped in chromosome 1.[19] The second is a 15-gene model produced by the Intergroupe Francophone du Myélome (IFM) and included genes that control proliferation (high-risk patients) and genes included in hyperdiploid karyotypes (low-risk patients).[20] Notably, the two models share no common genes, reflecting possible differences in the treatment population, GEP techniques, and the complex biology of myeloma with heterogeneity in the patterns of growth and survival of myeloma cells. Studies that evaluated the two GEP models showed that GEP70-gene model had prognostic value in all datasets tested, but the 15-gene model had prognostic value only in trials with bortezomib-based regimens.[21] In other studies, hypermethylation of regulated genes, such as CD38, TGFB1, NCAM1/CD56, GPX3, PDK4, RBP1, RACD1 and SPARC correlated with shorter OS, independently of age, ISS or high-risk cytogenetic features.[22] Furthermore, a recent study in 463 newly-diagnosed patients with MM who participated in the MRC-XI trial showed that mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) were associated with a negative impact on survival.[23]

Other prognostic factors that reflect tumor burden include plasma cell proliferative rate, extramedullary disease and plasma cell leukemia. Plasma cell labeling index (PCLI) is a well-established prognostic factor[24]; however, the methodology is rather expensive and it is not available in all institutions. The presence of extramedullary plasmacytomas is also associated with poor prognosis; it is often accompanied by advanced disease features, such as high-risk cytogenetics, high LDH or poor-risk GEP.[25] The most common sites for extramedullary disease at diagnosis include the skin and soft tissues, while liver is often affected at disease relapse or progression.[26] In a UAMS study including patients enrolled in total therapy protocols, the presence of extramedullary disease identified by positron emission tomography/computed tomography (PET/CT) offered a 5-year OS probability of 31% versus 59% for patients who did not have extramedullary myeloma (Figure 3).[26] Finally, plasma cell leukemia, which is characterized by the presence of adverse genetic features such as del170, del13q and MYC translocations, has a very poor prognosis with a median survival of 16-18 months in the majority of studies.[27]

Host Factors
The more important prognostic factors associated with the patient include age, performance status (PS), and comorbidities present at diagnosis, along with response to previous therapies for patients with relapsed/refractory disease. Age is a well-established prognostic factor for MM. In our department series, 23% of newly diagnosed patients were older than 80 years of age; these patients had advanced ISS, lower PS and worse OS; the median OS was 22 months and 14% of patients died within 2 months of initial therapy.[28] A meta-analysis of 1,435 patients aged >65 years who participated in four European phase III trials with thalidomide and/or bortezomib showed that the risk for death was increased in patients >75 years of age (hazard ratio (HR) 1.44; 95% confidence interval (CI): 1.2-1.72; P<.001).[29] Older age is a poor prognostic factor; however, physical and psychological function is variable among patients of the same age. Therefore, PS, or the more detailed Comprehensive Geriatric Assessment (CGA) score that defines frailty are important tools for the management of older patients. The IMWG has suggested the use of a CGA score designed using three tools: the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI) (Table 3). This proposal was based on an analysis of data from three prospective trials for a total of 869 newly diagnosed elderly patients with MM. Using the three indices above, the authors created a score between 0-5 and managed to identify three groups of patients with different outcomes: fit (score: 0; 39% of patients), intermediate fitness (score: 1; 31% of patients), and frail (score ≥2; 30% of patients). The 3-year OS was 84% in fit, 76% in intermediate-fitness (HR 1.61; 95% CI: 1.02-2.56; P=.042), and 57% in frail (HR 3.57; 95% CI: 2.37-5.39; P<.001) patients (Figure 4A). The cumulative incidence of grade ≥3 non-hematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (P=.217) and 34.0% in frail (P<.001) patients (Figure 4D), while the incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (P=.052) and 31.2% in frail (P<.001) patients (Figure 4E).[30] Thus, the IMWG CGA score could predict mortality and toxicity risk in elderly myeloma patients and can be easily used in everyday clinical practice to drive treatment decisions.

Table 3. (A) Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL); (B) Charlson Comorbidity Index. The ADL scale includes six items (bathing, dressing, toileting, transferring, continence, and feeding), with a score for each item ranging from 0 (unable to perform the activity) to 1 (able to perform the activity). Total score ranges from 0 to 6. The IADL scale includes eight items (ability to use the telephone, shopping, cooking, housekeeping, doing laundry, taking own medication, making transports, and to handle finances), with a score for each item of 0 (low function, dependent) or 1 (high function, independent); the total score ranges from 0 to 8. The CCI estimates the number and the severity of comorbidities, including nineteen diseases with a score varying from 1 to 6 for each of them in accordance to their severity. The score can range from 0 to 37. [30]


(Enlarge Table 3A )



(Enlarge Table 3B )

Myeloma complications often affect OS. Renal impairment (RI) is a common clinical feature of myeloma, which affects 20-40% of patients at diagnosis and up to 60% of patients during the course of their disease. Several studies have shown that patients with end-stage renal failure have poor outcomes. Although the survival of myeloma patients with RI has been improved with the introduction of novel agents such as bortezomib, severe RI continues to be associated with a high risk of early death; the rate of death in patients with severe RI was 12%, compared to 7% and 3% in moderate and mild or no RI, respectively (P<.001). This is especially true among older patients, and has remained unchanged over time.[31]

The achievement of deep response to frontline therapy has a significant impact on OS. Several studies have shown that the achievement of complete response (CR) is associated with better outcomes compared to very good partial response (VGPR) or partial response (PR) in both newly diagnosed patients who are eligible and ineligible for autologous stem cell transplant (ASCT).[32,33] Furthermore, the achievement of stringent CR correlates with better OS, even compared to CR patients,[34] while patients who failed to maintain their CR have poorer outcomes than those who maintain CR.[35] Finally, CR patients who achieve minimal residual disease (MRD) negativity have prolonged OS compared to CR patients who are MRD positive.[36]

Treatment Decisions Based on Risk Stratification
Age is a major factor for treatment decisions. Thus, fit patients up to age 70 are eligible for induction treatment followed by ASCT. However, aging-associated frailty mandates calculation of the CGA score and documentation of a patient’s level of fitness (Table 4). Recently, suggestions for treatment strategies (Table 5) and dosing schedules (Table 6) for frail myeloma patients have been developed.[37]

Table 4. Definition of frailty based on IMWG GA score [30,37]


Table 5. Treatment strategy in frail myeloma patients [37]


(Enlarge Table 5)

Table 6. Treatment schedule for frail myeloma patients [37]


(Enlarge Table 6)

For the management of RI in patients with MM, the IMWG has produced recent recommendations. High fluid intake is indicated along with antimyeloma therapy based on bortezomib (triplets seem to offer better renal responses compared to doublets). High-dose dexamethasone should be administered for at least the first month of therapy. Regarding IMiDs, thalidomide is effective in patients with myeloma and RI, and no dose modifications are needed. Lenalidomide is effective and safe in patients with mild to moderate RI; however, patients with severe RI or on dialysis should be closely monitored for hematologic toxicity with appropriate dose reduction of lenalidomide as needed. High-dose therapy (melphalan 100 mg/m2 to 140 mg/m2) with ASCT is feasible in this setting. Carfilzomib can be safely administered to patients with glomerular filtration rate (GFR) >15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with GFR >30 mL/min.[38]

Regarding high-risk cytogenetics, the currently available data suggest that bortezomib and carfilzomib appear to improve CR, progression-free survival (PFS) and OS in t(4;14) and del(17/17p), whereas lenalidomide may only be associated with improved PFS in patients with these cytogenetic abnormalities. Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents[39] and thus, the introduction of novel agents such as daratumumab and pomalidomide, an agent which has shown encouraging results in del17p patients,[40] may provide additional tools for the managements of patients with high-risk cytogenetics. A recent meta-analysis showed that lenalidomide maintenance after ASCT offers approximately 2.5 OS advantage; however, patients with ISS-3 and high-risk cytogenetics had no benefit from lenalidomide maintenance.[41] For patients with del17p who are eligible for ASCT, bortezomib maintenance after PAD (bortezomib, doxorubicin, dexamethasone) induction and double tandem ASCT seems to be a reasonable option. However, this treatment scheme offered no survival benefit for patients with t(4;14) and add(1q).[42]

Finally, the Mayo Clinic has developed a risk-stratified classification system for patients with multiple myeloma based on parameters previously described in this text (Table 7). With this classification, standard-risk patients have a median OS of 8-10 years, while patients with intermediate- and high-risk disease have a median OS of 4-5 years and 3 years, respectively. Treatment recommendations for these three categories have been provided (Figure 5).[43]

Table 7. Mayo (mSMART) risk stratification for myeloma patients [43]


(Enlarge Table 7)




Figure 1. Training versus validation data set [6]  (Enlarge Slide)




Figure 2. Revised International Staging System and overall survival by type of treatment: (A) OS in regimens non-transplantation-based regimens; (B) OS in transplantation-based regimens; (C) OS in immunomodulatory-based regimens; (D) OS in proteasome inhibitor-based regimens [18]  (Enlarge Slide)




Figure 3. Extramedullary disease correlated with poor prognosis independently of the type of given therapy [26]  (Enlarge Slide)




Figure 4. Long-term outcomes using the frailty score suggested by IMWG. (A) OS, (B) PFS, and (C) cumulative incidence of hematologic adverse events, (D) non-hematologic adverse events, and (E) discontinuation in the intention-to-treat population [30]  (Enlarge Slide)




Figure 5. Mayo Treatment recommendations for frontline therapy based on mSMART risk stratification model: for transplant eligible (A) and transplant ineligible patients (B) [43]  (Enlarge Slide)



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