Octogenarian newly diagnosed multiple myeloma patients without geriatric impairments: the role of age >80 in the IMWG frailty score

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

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Role of liposomal doxorubicin as a first line agent with VTd regimen in newly diagnosed multiple myeloma

Annals of Oncology ◽

10.1093/annonc/mdy286.018 ◽

2018 ◽

Vol 29 ◽

pp. viii365

Author(s):

M. Khanderia ◽

G. Badarkhe ◽

S. Bj ◽

R. Naik

Keyword(s):

Multiple Myeloma ◽

Liposomal Doxorubicin ◽

Newly Diagnosed ◽

First Line

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N‐terminal fragment of the type‐B natriuretic peptide (NT‐proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma

American Journal of Hematology ◽

10.1002/ajh.24532 ◽

2016 ◽

Vol 91 (11) ◽

pp. 1129-1134 ◽

Cited By ~ 28

Author(s):

Paolo Milani ◽

S. Vincent Rajkumar ◽

Giampaolo Merlini ◽

Shaji Kumar ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Natriuretic Peptide ◽

Newly Diagnosed ◽

Type B ◽

Terminal Fragment ◽

Frailty Score

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COMPARISON OF FRAILTY SCORES IN NEWLY DIAGNOSED PATIENTS WITH MULTIPLE MYELOMA: A REVIEW

Journal of Frailty & Aging ◽

10.14283/jfa.2019.25 ◽

2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

H. Mian ◽

M. Brouwers ◽

C.T. Kouroukis ◽

T.M. Wildes

Keyword(s):

Multiple Myeloma ◽

Older Patients ◽

Treatment Options ◽

Clinical Settings ◽

Newly Diagnosed ◽

Future Directions ◽

Malignant Plasma Cell ◽

Co Morbidity ◽

Morbidity Index ◽

Frailty Score

Multiple myeloma is a malignant plasma cell disease, which typically affects older patients, with a median age at diagnosis of 70 years. The challenge in treating older patients is to accurately identify ‘fit’ patients that can tolerate more intensive treatment to maximize disease control, while simultaneously identifying vulnerable or ‘frail’ patients who may develop toxicity with significant morbidity and mortality, requiring different treatment options or dose modification. Multiple frailty scores have been devised for multiple myeloma over the years in newly-diagnosed patients. This paper gives an overview of the three common frailty measurements: the International Myeloma Working Group Frailty Score, Mayo Clinic Frailty Score and the Revised Myeloma Co-Morbidity Index. We will summarize the derivation, validation, usability and applicability of these scores in different clinical settings, emphasizing the main strengths and limitations for each index score. We will also highlight future directions in the operationalization of frailty in multiple myeloma.

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Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study

Blood ◽

10.1182/blood.v116.21.42.42 ◽

2010 ◽

Vol 116 (21) ◽

pp. 42-42 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Giulia Perrone ◽

Silvia Buttignol ◽

Elisabetta Calabrese ◽

Monica Galli ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Board Of Directors ◽

Induction Therapy ◽

Autologous Transplantation ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Significant Difference

Abstract Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p<0.0001), double autotransplantation (54% vs 42%, p=0.008) and consolidation therapy (60% vs 44%, p=0.001). Best confirmed overall CR/nCR rate was 71% in the VTD arm compared with 52% in the TD arm (p<0.0001); the corresponding values for VGPR or better were 89% vs 72%, respectively (p<0.0001). To evaluate the role of consolidation therapy we performed a per-protocol analysis of 323 patients, 161 treated with VTD and 162 with TD. Overall, upgraded responses with VTD and TD as consolidation therapy were observed in 55% vs 37% of patients, respectively (p=0.01; OR:1.15-3.77). Furthermore, the probability to improve responses from less than CR before consolidation to CR after consolidation was 28% with VTD vs 15% with TD (p=0.02; OR:1.07-4.57) (p=0.003 using the Mc Nemar's test). Post-consolidation molecular detection of minimal residual disease was the objective of a substudy; detailed results are reported in a separate abstract. Briefly, both qualitative and quantitative analyses confirmed the statistically significant superiority of VTD over TD in effecting higher rates of molecular remissions and reducing the burden of residual myeloma cells after ASCT. Any grade 3–4 non-hematologic adverse events were 10% with VTD (peripheral neuropathy: 1.3%, skin rash: 0.6%) vs 12% with TD. With a median follow-up of 31 months, median PFS was 42 months in the TD arm and was not yet reached in the VTD arm (44-month projected rate: 61%) (HR: 0.62 [CI: 0.45–0.87], p=0.006). Superior PFS in the VTD vs TD arm was retained across patient subgroups with poor prognosis, including those with t(4;14) and/or del(17p). Randomization to VTD overcome the adverse influence of t(4;14) on PFS (40-month projected rates: 69% vs 67% according to the presence or absence of this abnormality, respectively; p=0.6). By the opposite, in the TD arm corresponding median PFS values were 24.5 vs 41.5 months, respectively (p=0.01). The small numbers of patients with del(17p) in both arms of the study precluded a statistical comparison with del(17p)-negative group. In a multivariate analysis, variables favorably influencing PFS were beta2-m lower than 3.5 mg/L (HR:0.47; p=0.000), absence of t(4;14) and/or del(17p) (HR:0.52; p=0.000), randomization to VTD arm (HR:0.57; p=0.002), attainment of at least VGPR (HR:0.50; p=0.009) and CR (HR:0.8; p=0.01). No statistically significant difference between the overall treatment protocols was seen in terms of OS, although curves seemed to initially diverge after 40 months (44-month projected rates: 84% vs 74% for VTD and TD arms, respectively). A multivariate analysis showed the independent role of absence of t(4;14) and/or del(17p) (HR:0.42; p=0.003), ISS stage1-2 (HR:0.49; p=0.02) and randomization to VTD (HR:0.53; p=0.04) in prolonging OS. When time-dependent CR entered the model, absence of t(4;14) and/or del(17p) and less advanced ISS stage retained their positive prognostic value; attainment of CR (strictly related to VTD randomization) was an additional favorable variable. In conclusion, in comparison with the TD arm of the study, 1) VTD induction emerges as a new standard of care for maximizing the degree and speedy of tumor reduction in preparation for ASCT; 2) VTD consolidation effected significantly higher rates of upgraded responses, including CR, and of molecular remissions; 3) double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

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Phase 2 Trial of Concurrent Monosialotetrahexosylganglioside in the Prophylactic Treatment of Bortezomib-Induced Peripheral Neuropathy in Patients of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.5399.5399 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5399-5399

Author(s):

Liang Wang ◽

Zhongjun Xia ◽

Xiaoqin Chen

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Subcutaneous Injection ◽

Complete Response ◽

Phase 2 ◽

Newly Diagnosed ◽

Female Ratio ◽

Phase 2 Trial

Abstract Backgrounds Bortezomib is an important drug in the treatment of multiple myeloma (MM), and peripheral neuropathy (PN) is a significant dose-limiting toxicity of bortezomib. No effective prophylaxis has been defined for PN. Monosialotetrahexosylganglioside (GM), a nerve-protecting drug, is often used to promote growth of nerve and function restoration of damaged nerve. The role of GM in the prophylaxis of bortezomib-induced PN in MM patients has never been investigated. Methods A phase 2 clinical trial was conducted in newly diagnosed MM patients to evaluate the value of GM in the prophylaxis of bortezomib-induced PN. All eligible patients were treated with VD (bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,15,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) or CyBorD (cyclophosphamide 300mg/㎡,po,d1 ,8,15, bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,1 5,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) for at least 4 cycles. GM was used at a dosage of 100mg/day intravenously at d1 -2, 8-9, 15-16, 22-23. No other nerve-protective drugs or thalidomide-containing regimens were allowed. The primary endpoint was overall incidence rate of PN (the grade of PN was recorded according to CTCAE v3.0). The secondary endpoints included duration of PN, complete response rate after 4 cycles of treatment, 1-year PFS and OS rate. (This trial was registered in ClinicalTrial.gov, NCT02093910). Results From February 2014 to February 2015, 25 patients of newly diagnosed MM were enrolled. The median age was 55 years old (37-75), and male to female ratio was 19:6. 5 patients had ISS stage I disease, 6 patients with stage II, and the remaining 14 patients with stage III. All patients received a median of 4 cycles (range 2-9) of Bortezomibcontaining regimens. At the time of data analysis, 84% of patients had at least partial response, 48% had at least very good partial response, and 24% had complete response. 7 patients experienced PN after a median of 2 cycles (range 1-4) of treatment, resulting in the overall PN rate of 28%. Among these 7 patients, only 1 patient (4%) had grade 2 PN, leading to dose reduction of bortezomib, and all other patients had grade 1 PN. During treatment, 1 patient (4%) had grade 2 diarrhea, and another 1 patient (4%) had herpes zoster infection. The concurrent use of GM did not introduce new side effects and seemed not compromise the efficacy of bortezomib. At a median follow up time of 8 months, 1-year PFS rate and OS rate were speculated to be 69.8% and 100%, respectively. Conclusions The early-term analysis of this phase 2 trial found it feasible to concurrently use GM and bortezomib-containing regimens, and GM had the potential role of reducing bortezomib-induced PN rate and severity without compromising efficacy. This needs to be validated in future phase 3 randomized clinical trials. Disclosures No relevant conflicts of interest to declare.

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Role of oral examination in newly diagnosed multiple myeloma patients: A safe and simple way to detect light chain amyloidosis

Oral Diseases ◽

10.1111/odi.12901 ◽

2018 ◽

Vol 24 (7) ◽

pp. 1343-1348 ◽

Cited By ~ 1

Author(s):

Merav Leiba ◽

Suha Jarjoura ◽

Waseem Abboud ◽

Arnon Nagler ◽

Ran Yahalom ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Oral Examination ◽

Newly Diagnosed ◽

Light Chain Amyloidosis

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Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-130092 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5593-5593

Author(s):

Andrey Garifullin ◽

Sergei Voloshin ◽

Vasily Shuvaev ◽

Irina Martynkevich ◽

Elizaveta Kleina ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Risk Stratification ◽

Risk Group ◽

High Risk Group ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Genetic Abnormalities ◽

Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

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Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients

Cancers ◽

10.3390/cancers13246348 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6348

Author(s):

Samrat Roy Choudhury ◽

Cody Ashby ◽

Fenghuang Zhan ◽

Frits van Rhee

Keyword(s):

Dna Methylation ◽

Multiple Myeloma ◽

Dna Sequences ◽

Critical Length ◽

Newly Diagnosed ◽

Genome Wide ◽

Healthy Donors ◽

Binding Factor ◽

G Quadruplex

High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R2 ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.

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Role of autologous stem cell transplant after induction therapy with bortezomib-lenolidomide or bortezomib-thalidomide in newly diagnosed multiple myeloma patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8596 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8596-8596

Author(s):

N. Shah ◽

D. Weber ◽

R. Orlowski ◽

M. Wang ◽

S. K. Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Induction Therapy ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Newly Diagnosed ◽

Highly Active

8596 Background: The introduction of novel therapeutic options with bortezomib and immunomodulatory agents in the up-front management of multiple myeloma (MM) has significantly improved induction response rates. However, the role of high dose chemotherapy and autologous stem cell transplant (ASCT) after induction with these highly active agents is not known, especially in patients with only a partial response to induction therapy. Methods: We conducted a retrospective review of 95 newly diagnosed MM patients treated with induction bortezomib-lenolidomide-dexamethasone (BLD) or bortezomib-thalidomide-dexamethasone (BTD) prior to ASCT. Responses were graded according to IMWG criteria. Results: 19 patients received BLD and 76 patients received BTD. All patients were conditioned with a melphalan-based regimen. Of the 19 patients who underwent induction with BLD, complete response (CR), very good partial response (VGPR) and partial response (PR) were achieved in 2 (11%), 8 (42%) and 9 (47%) respectively for an overall response rate (ORR) of 19/19 (100%). After ASCT, CR, VGPR and PR were achieved in 9 (47%), 5 (26%) and 5 (26%) respectively for a continued ORR of 21/21 (100%). Notably, 4/8 (50%) of patients with a VGPR after induction therapy with BLD improved to a CR after ASCT. 3/9 (33%) of patients with an initial PR to BLD improved to a CR and 1/9 (11%) with a PR improved to VGPR after ASCT. Of the 76 patients who underwent induction with BTD, CR, VGPR and PR were achieved in 6 (8%), 37 (49%) and 31(41%) respectively for an ORR of 74/76 (97%). 1 patient had stable disease and 1 patient had progressive disease. After ASCT, 27/76 (36%) achieved a CR, 30/76 (39%) a VGPR and 18/76 (24%) a PR for an ORR of 75/76 (99%). Of the patients who initially had a VGPR to BTD 16/37 (43%) improved to a CR while 5/32(16%)of PR patients improved to a CR and 9/32 (28%) of PR patients improved to a VGPR. Conclusions: Of the 40 patients who only achieved a PR after induction therapy with BLD or BTD, 16 (40%) had further improvement to a CR or VGPR after ASCT. Thus there is a significant benefit of ASCT in these patients who initially demonstrate relative resistance to induction therapy with highly active regimens. [Table: see text]

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