Myeloma New Vision's current management methods for high-risk multiple myeloma

The median overall survival (OS) of multiple myeloma is close to 10 years, but nearly one-fifth of the patients still have a poor prognosis
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At present, patients with myeloma need individualized management, especially high-risk patients who need intensive and continuous treatment
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In 2021, a review of the management methods for high-risk multiple myeloma patients was published in the American Journal of Hematology, which analyzed the results of recent retrospective analysis and clinical trials, and looked forward to the future through ongoing trials
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Next, the editor will take you to understand the details of this review
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Research background Multiple myeloma (MM) is a malignant tumor of plasma cells
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In the past ten years, autologous stem cell transplantation (ASCT) has been widely used.
Significant progress has been made in the research and development of new drugs such as protease inhibitors (PI), immunomodulatory drugs (IMID) or monoclonal antibodies, and the median OS of MM has increased to more than 8 years
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The survival improvement of MM patients is inconsistent, and 15%-20% of progressive MM patients die within 3 years after diagnosis
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Identifying high-risk patients is essential to accurately locate and select the most effective treatment plan to maximize the treatment effect, and help establish a framework for further research directions
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High-risk MM patients need intensive treatment to maximize the depth of remission; progression-free survival (PFS) is significantly reduced, and the initial response cannot be maintained, and continuous treatment is required; high-risk MM patients have limited OS even with new treatment methods, and it is recommended to consider participating Risk-adaptive clinical trials
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Therefore, this review explores the definition of high-risk MM patients and the progress of recommended treatments for patients with poor prognosis
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Definition of high-risk patients A variety of prognostic factors affect the survival of MM patients.
The definition of high-risk patients is based on predictive OS.
Patients who meet ASCT have OS<3 years, and those who do not meet ASCT have OS<2 years
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In order to identify high-risk patients at the time of diagnosis, several prognostic factors that have a significant impact on survival have been found, among which cytogenetic factors are the most significant prognostic factors
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1.
Prognostic markers and tumor staging system prognostic factors can be divided into three categories: patient-related factors, tumor-related factors, and factors that reflect the impact of tumors on the host (Figure 1)
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Among patient-related factors, age is an important predictor of MM survival.
From age <50 years (median OS 5.
2 years) to ≥80 years (median OS 2.
6 years), the survival period decreases with every ten years of age; Among tumor-related factors, the cytogenetic abnormality of myeloma cells is the most important prognostic indicator.
Other factors include serum lactate dehydrogenase (LDH), serum free light chain ratio, serum albumin and serum β2-microglobulin ( β-2M), tumor microenvironment microvessel density, circulating plasma cell number, plasma cell proliferation index, bone marrow plasma cell immunophenotype; clinical manifestations related to poor prognosis include extramedullary disease and plasma cell leukemia
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The factors reflecting the interaction between the host and the tumor include renal function, which has a great influence on the prognosis
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Figure 1t(4; 14) ectopic is a feature of poor prognosis in patients with high-risk MM; ~10% of patients are diagnosed with (17p) gene deletion (del), compared with other high-risk patients with chromosomal aberrations, del(17p) is An important factor in the reduction of survival in high-risk MM patients; 35%-40% of MM patients present with gain(1q), which is the most common chromosomal aberration.
In the era of new drugs and ASCT, it is related to poor prognosis, and the risk of disease progression is related to 1q copy number Increase (≥4) is related; gain[1q] often coexists with del[1p], the prognosis of patients is worse
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High-risk patients usually have a variety of cytogenetic abnormalities.
Patients with two cytogenetic abnormalities have a median OS of 23.
4 months, and patients with three cytogenetic abnormalities have the worst median OS at 9.
1 months
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Gene expression profiling (GEP) is an important research and prediction tool for multiple myeloma.
Several unique GEP phenotypes have been identified (Table 1)
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About 10% of MM patients have ≥2 high-risk chromosomal aberrations and abnormal GEP high-risk expression profiles, and the prognosis is poor.
The OS rate at 48 months is 12.
5%
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Some MM patients without high-risk chromosomal aberrations still have a poor prognosis and can be regarded as high-risk patients.
These patients are refractory or early relapse (12-18 months after ASCT), and there is no cytogenetic abnormality or disease at the time of diagnosis Recurrence did not occur; therefore, high-risk patients can obtain early response, but the response cannot be sustained, and the remission rate has no effect on the outcome
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The depth of relief also plays a key role in prognostic evaluation
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The clearance of minimal residual disease (MRD) after induction therapy plays an important role in predicting the prognosis of MM patients
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The combined analysis of the three trials by PETHEMA/GEM found that patients with negative MRD had better outcomes than patients with complete remission, especially in high-risk patients; compared with the MRD-positive group, high-risk patients with negative MRD [t( 4; 14), t(14; 16) and del(17p)] have longer PFS and OS; the same research team recently confirmed that high-risk patients and standard-risk patients have similar reductions in the risk of disease progression when MRD is undetectable (PFS rate at 36 months: 91% vs.
97%, p = 0.
569); but when MRD is still detectable, PFS in high-risk patients is significantly lower than that in standard-risk patients (the PFS rate at 36 months is 60%, respectively vs.
37%; p＜0.
001)
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The role and application of MRD, or whether it can be used as a surrogate endpoint or determinant of treatment, still needs further data to confirm
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Table 1 Management of high-risk patients 1.
Induction therapy Table 2 shows the survival rates of high-risk patients with different initial treatment regimens, but compared with standard-risk patients, none of the studies have proven to completely improve the adverse survival associated with specific high-risk characteristics
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Due to differences in the definition of high-risk subgroups of patients, treatment strategies, study endpoints, follow-up time, and results analysis methods, it is difficult to draw clear conclusions from clinical trials of high-risk patients
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In general, the treatment plan that benefits standard-risk patients should also be effective for high-risk patients.
The relative improvement between the two groups of patients varies with different plans
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Ideally, interventions that have more relative improvements for high-risk patients than standard-risk patients will be given priority to high-risk patients
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The management principles for newly diagnosed high-risk MM patients are shown in Figure 2, based on the Mayo’s myeloma stratification and risk-adjusted treatment (mSMART) consensus recommendation
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Table 2 Figure 22.
Autologous stem cell transplantation-single vs.
series Even in the era of new drugs, including high-risk patients, ASCT is a standard treatment as a consolidation therapy suitable for first-line treatment of transplant patients
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Standard-risk patients need to postpone the first ASCT, high-risk patients recommend early ASCT
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There is no data to support the benefit of serial ASCT in the general MM population in the new drug era, but there are data showing the benefit in high-risk patients
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High-risk patients with MM suitable for transplantation should consider early ASCT
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Existing evidence remains controversial about the role of tandem ASCT in high-risk patients
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In view of the low survival rate of high-risk patients, especially those with double-strike or triple-strike MM, serial ASCT should be considered
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3.
Allogeneic SCT allogeneic stem cell transplantation (alloSCT) is not routinely performed in MM patients outside of clinical trials.
It is because there are matching donors, the relatively high mortality rate during the transplantation process, and the highly selected patients (young and other Health, with high-risk characteristics or relapsed MM) provides additional options
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Past data show that MM patients have high surgical-related mortality.
At present, alloSCT has not been extensively studied.
Especially in the era of the emergence of multiple new drugs, the risks and potential benefits of alloSCT have not been balanced
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The definition of high-risk patients is based on typical karyotype analysis, and there are few literatures on the application of alloSCT to high-risk patients
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4.
Consolidation/maintenance therapy At present, maintenance therapy is widely used in patients with myeloma.
The application of maintenance therapy for high-risk patients requires consideration of specific drug categories, increasing the duration of maintenance therapy, and consolidation therapy before maintenance therapy
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MRC Myeloma IX trial, thalidomide maintenance therapy vs.
no maintenance therapy, thalidomide maintenance therapy has benefit in the general population, but in the high-risk group (gain[1q], t[4; 14], t[ 4; 16], t[14; 20], del[17p], del[1p32] ), thalidomide reduces OS and has no effect on PFS
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Consolidated analysis of MMY3012 and MMY3013 trials, bortezomib consolidation therapy vs.
observation after ASCT, with high-risk characteristics (del[13q], t[4; 14] del[17p]) patients who obtained better PFS after bortezomib consolidation treatment (HR, 0.
66; 95%CI, 0.
41-1.
05)
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TOURMALINE-MM3 trial, ASCT after induction therapy, oral ixazomib maintenance therapy vs.
placebo, ixazomib can prolong PFS compared with placebo, but the difference is not significant in high-risk patients (defined as del[17p], t[4; 14], t[4; 16]; HR, 0.
62; 95%CI, 0.
38-1.
02)
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There are no studies confirming that lenalidomide single-agent maintenance therapy benefits high-risk patients, and there are no reports of adverse reactions
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Long-term maintenance treatment with lenalidomide improved PFS in patients with t[4; 14] and/or del[17p] (median PFS 15 months vs.
27 months, median PFS 14 months vs.
29 months )
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In the Myeloma trial, lenalidomide or thalidomide combined with cyclophosphamide and dexamethasone induction therapy, if the best remission is not achieved, switch to PI-containing therapy, ASCT and subsequent nanalidomide maintenance therapy or only observation; high-risk patients are defined as gain[1q], t[4; 14], t[4; 16], t[14; 20], or del[17p], ultra-high-risk patients with two or more abnormalities
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Lenalidomide maintenance treatment patients have a longer PFS than placebo, and can be extended in both high-risk and ultra-high-risk patients (high-risk HR, 0.
50; 95%CI, 0.
37-0.
67; ultra-high-risk HR, 0.
52; 95%CI, 0.
31-0.
87 )
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High-risk patients should not use thalidomide-based consolidation/maintenance therapy
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High-risk patients who are suitable for transplantation or not suitable for transplantation should receive PI combined with lenalidomide maintenance therapy in time, or PI maintenance therapy alone, until drug resistance or disease progression
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5.
The risk stratification and disease stage of relapsed/refractory MM are very important for the first or multiple relapses
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According to IMWG standards, aggressive recurrence is characterized by cytogenetic abnormalities (t[4;14], Del[17p], [1q21] increased, hypodiploid), high β2M levels (>5.
5g/L), low Albumin (<3.
5g/dL), extramedullary disease, high LDH value, short duration of remission (<12 months) or primary refractory disease, circulating plasma cells, ISS-Ⅲ stage at relapse, isotype transformation ( Light chain escape, oligosecretory diseases) and aggressive clinical manifestations (including rapid symptoms, other diseases found in laboratory, imaging or pathology, diseases related to organ damage)
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The mSMART guideline also includes the occurrence of t(14;16), t(14;20) and GEP high-risk expression profile abnormalities
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Several recent clinical trials have involved a subgroup of patients with high-risk, relapsed MM
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Pomalidomide seems to be particularly effective in patients with del[17p]
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In the MM-003 trial, pomalidomide combined with low-dose dexamethasone vs.
high-dose dexamethasone monotherapy, the pomalidomide group treated all high-risk patients significantly prolonged PFS compared with the dexamethasone group, including del[17p] ( 4.
6 vs.
1.
1 months, p<0.
001) and t[4; 14] (2.
8 vs.
1.
9 months, p = 0.
028), the del[17p] group also benefited from OS (12.
6 vs.
7.
7 months, p = 0.
008)
.

In the ENDEAVOR study, carfilzomib combined with dexamethasone in the treatment of the general population has a better OS than the VD regimen (47.
6 months vs.
40.
0 months), but in high-risk patients (t[4; 14], t[4; 16] and del[17p]; n = 230) No improvement in OS was observed (HR, 0.
83; 95%CI, 0.
58- 1.
19)
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Erotuzumab combined with lenalidomide can effectively treat patients with high-risk relapsed/refractory MM
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In the ELOQUENT-2 trial, compared with the RD group alone, the PFS of the Erotuzumab-RD group was found in del[17p] patients (HR, 0.
65; 95%CI, 0.
45 -0.
94) and t[4; 14] patients ( HR, 0.
53; 95%CI, 0.
29-0.
95) all benefited; OS benefited only in del[17p] patients (median OS, 50.
1 months vs.
36.
4 months; HR, 0.
71; 95%CI, 0.
50 -1.
00 )
.

POLLUX trial, daratumomab-RD in the treatment of high-risk relapsed/refractory MM patients (del[17p], t[4; 14] or t[4; 16]) PFS is better than RD group (median PFS 26.
8 Months vs.
8.
3 months; HR, 0.
34; 95%CI, 0.
16-0.
72)
.

In the ICARIA-MM trial, anti-CD38 monoclonal antibody isatuximab combined with pomalidomide and dexamethasone (PD) in the treatment of refractory MM patients resistant to lenalidomide and PI prolonged PFS compared with PD monotherapy, but at high risk The benefit was not obvious in patients (HR, 0.
66; 95%CI, 0.
33-1.
28)
.

Selinexor combined with dexamethasone in the previous treatment of triple refractory MM patients can obtain a relatively ideal treatment remission rate (partial remission or better, 26%), high-risk subgroup (53% of patients have high-risk characteristics, partial remission or better, 18%)
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The management of high-risk patients with relapsed MM includes the following principles.
If available, priority should be given to treatments in well-designed clinical trials
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When choosing a drug, you should choose a drug or drug category that the patient has never used; if the first-line treatment remission lasts more than 12 months, you can use the same drug or other combined programs; for patients with lenalidomide that is not difficult to treat, the RD program can be combined with Combination of daretuzumab, carfilzomib, ixazomib or erotuzumab; for patients refractory to lenalidomide, the treatment plan should include at least pomalidomide, PI or monoclonal antibody Two drugs
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Patients with aggressive recurrence and good health should choose a powerful triple or quadruple treatment plan, and continue treatment until aggressive recurrence appears to be resistant to treatment or lose early response
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Patients who have not received ASCT and are suitable for transplantation may consider receiving ASCT when they relapse; or if they have received one ASCT, they may consider a second ASCT
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Young patients may consider Allo-SCT, preferably in the context of clinical trials as a research method
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  New perspectives As high-risk MM patients' needs for effective treatment and long-term response have not yet been met, a large number of new trials focus on the first-line treatment of high-risk MM patients with new drugs (Table 3)
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These trials focus on new drugs that have been approved to intensify induction therapy, or the application of new drugs in induction therapy
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Ongoing trials may help answer the following questions: the role of daratumomab and carfilzomib in the first-line treatment based on triple therapy, the efficacy of cetuximab in the first-line treatment, and new drugs Maintain the therapeutic effect after ASCT
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The results of research on chimeric antigen receptor genetically modified T cells (CAT-T) are expected.
Targeting B cell mature antigens and combining with ASCT as a consolidation treatment is expected to see research results in the next ten years, which is expected to be extended A milestone drug for the survival of high-risk MM patients
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Table 3 Conclusion For the management of high-risk MM patients, it is important to fully diagnose and stratify the patients as soon as possible, provide appropriate consultation and choose the most effective treatment plan
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Patients with high-risk MM are best given intensive and continuous treatment
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The survival of high-risk MM patients is still very poor, and randomized studies for high-risk MM patients are needed.
Future research needs to focus on the development of innovative methods and effective drugs for high-risk MM patients
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References: [1] Goldman-Mazur S, Kumar S K.
Current approaches to management of high-risk multiple myeloma[J].
Am J Hematol, 2021,96 (7) :854-871.
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