Abstract
Introduction
mSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. We aimed to study the clinical profile and outcomes of patients with DH/THM detected at relapse in a real-world setting.
Methods
The case records of all relapsed multiple myeloma patients with DH/THM diagnosed between January 2018 and December 2020 were identified and information regarding baseline characteristics, therapy and outcomes was noted.
Results
Seventeen patients were diagnosed with DH/THM at relapse during the study period. Twelve patients (70.6%) were in first relapse, while 3 patients were diagnosed at second relapse and 1 patient each at 3rd and 5th relapse respectively. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q (seen in 10 patients; 58.8%). Ten patients (58.8%) died within the first 2 months of diagnosis and 16 patients (94.1%) died during follow up (range 0–16 months). The most common cause of death was progressive/active disease (9 patients, 56.3%).
Discussion
The outcome of DH/THM at relapse is associated with an aggressive presentation and poor outcomes in the real-world setting. These patients are candidates for early aggressive or novel therapy or clinical trials.
Keywords: Double Hit/Triple Hit Myeloma, Relapsed Refractory Multiple Myeloma, High-risk Multiple myeloma, Global Oncology
Introduction
Therapy in Multiple Myeloma is becoming precision-based and personalized. Whether it be the use of Daratumumab based quadruplet therapy in patients with newly diagnosed high-risk Multiple Myeloma, or the use of venetoclax in patients with t(11:14), cytogenetics not only help prognosticate patients, but also drive therapy [1–3]. The presence of two or more high-risk cytogenetic abnormalities in Multiple Myeloma patients (defined as Double Hit and Triple Hit Myeloma by the mSMART classification) has been shown to have an abysmal prognosis in multiple studies [4–7]. However, most of the Double Hit/Triple Hit Myeloma (DH/THM) outcome data is from newly diagnosed patients. Further, the impact of this ultra-high-risk cytogenetic profile in patients with relapsed/refractory multiple myeloma in the real-world setting has not been studied. Here we describe the profile and outcomes of patients with DH/THM detected at relapse in a real-world setting.
Methods
We retrospectively analysed all patients diagnosed with relapsed/refractory multiple myeloma who underwent a bone marrow at our institute between January 2018 and December 2020. The study was approved by the Institute Ethics Committee. The patients were classified as DH/THM if they possessed 2 and 3 or more of the following cytogenetic abnormalities: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion and additional copies of chromosome 1q. The method for FISH analysis and the cut-offs taken for positivity have been given elsewhere [7]. All patients with relapsed/refractory multiple myeloma who fulfilled the criteria for DH/THM were included for analysis. Patient case records were retrieved, and baseline characteristics, therapy, and outcomes were noted. Response to treatment was graded according to the IMWG response criteria for multiple myeloma. The cause of death was established using available medical records. Overall survival (OS) was defined as the time from diagnosis to death due to any reason.
Results
One hundred forty-six patients underwent a bone marrow examination for a diagnosis of relapsed/refractory multiple myeloma at our institute between January 2018 and December 2020. Seventeen patients (11.6%) were identified to have DH/THM in this cohort. The cohort’s median age was 59 years, with almost an equal number of male and female patients (M = 9; F = 8). Twelve patients (70.6%) were diagnosed at the first relapse, while three were diagnosed at the second relapse and one patient at the 3rd and 5th relapse each, respectively. The median follow-up before diagnosing DH/THM was 28 months (Range- 5–89 months). At presentation, 8 patients (47.1%) had renal failure (serum creatinine > 2gm/dl), 12 patients (70.6%) had anemia (Hb < 10gm/dl) and bony lesions, and 6 patients (35.3%) had hypercalcemia (Calcium > 11 mg/dl). Seven patients (41.2%) presented with secondary plasma cell leukemia. The baseline characteristics are highlighted in Table 1.
Table 1.
Disease characteristics of the patient cohort (N = 17)
| N (%) | |
|---|---|
| Male patients | 9 (52.9%) |
| Anemia (Hb < 10gm/dl) | 12 (70.6%) |
| Renal Failure (Creat > 2gm/dl) | 8 (47.1%) |
| Hypercalcemia (Ca > 11 meq/dl) | 6 (35.3%) |
| Bony Lesions | 12 (70.6%) |
| Circulating Plasma Cells | 9 (52.9%) |
| Plasma cell leukemia | 7 (41.2%) |
| Immature plasma cells in BM | 12 (70.6%) |
| Gain of 1q (≥ 3 copies) | 17 (100%) |
| Amplification of 1q (≥ 4 copies) | 12 (70.6%) |
| t (4:14) | 12 (70.6%) |
| t (14:16) | 0 |
| TP53 deletion | 7 (41.2%) |
| Triple Hit Myeloma | 2 (11.8%) |
FISH cytogenetics at the time of initial diagnosis were available for only 6 patients. Three patients had a normal FISH at baseline, 2 patients had a deletion of chromosome 13q, and one patient had an IgH-FGFR3 translocation with deletion of 13q. At relapse, all patients had a gain of chromosome 1q (defined as ≥ 3 copies), and 12 patients (70.6%) had amplification of chromosome 1q (defined as ≥ 4 copies). Twelve patients (70.6%) had IgH-FGFR3 translocation, and 7 patients (41.2%) had a TP53 deletion. The most common cytogenetic combination was IgH-FGFR3 translocation with an increase in chromosome 1q number, which was seen in 10 patients (58.8%). This was followed by the co-occurrence of TP53 deletion with an increase of chromosome 1q in 5 patients (29.4%). Two patients (11.8%) had triple hit myeloma.
All but two patients had received Bortezomib previously (N = 15; 88.2%). Eleven patients (64.7%) had previous exposure to Lenalidomide, and eight patients (47.1%) had prior exposure to Thalidomide. Two patients had previously undergone autologous hematopoietic cell transplants. Seven patients (41.2%) died within the first month of relapse and could not receive even one cycle of therapy. Out of ten patients who had received at least one cycle of therapy, eight received triplet therapy with a proteasome inhibitor and an Immunomodulator. One patient received doublet with Lenalidomide and dexamethasone, and one patient received Daratumumab-based quadruplet therapy. Bortezomib-based treatment was used in 5 patients, and 4 received Carfilzomib-based therapy. None of the patients underwent a 2nd auto-transplant. Two patients achieved VGPR or better with treatment. Of the seven evaluable patients, five re-relapsed during follow-up. The follow up for the entire cohort ranged from 0 to 29 months. Sixteen patients (94.1%) died during follow up, with ten patients (58.8%) dying within 2 months of diagnosis of relapse. The most common cause of death was progressive/active disease (9 patients, 56.3%), followed by a combination of active disease with sepsis (4 patients, 25%). Median OS was 1 month for the entire cohort. Subgroup analysis for the impact of individual cytogenetic abnormalities on outcome was not done due to the small number of patients in each subgroup.
Discussion
There are multiple clinical trials available in literature which have studied the effect of newer drugs in patients with relapsed/refractory Multiple Myeloma. However, the percentage of patients with high-risk cytogenetics varies in these studies from 19 to 38%. These studies also use different definitions to classify cytogenetic abnormalities as high risk [2, 8–12]. While the data on DH/THM at relapse is limited, studies have analysed the impact of individual cytogenetic abnormalities in patients with relapsed multiple myeloma. In the study by Reece et al., patients with del(17p) were shown to have significantly poorer outcomes with a median OS of just 4.67 months [13]. A similar study found that the presence of del(13) and t(4:14) was associated with lower response rates in patients with relapsed/refractory multiple myeloma[14]. Patients with relapsed/refractory myeloma with ≥ 2 cytogenetic abnormalities have been shown to have low response rates, and an inferior PFS and OS in comparison to patients with a single high-risk cytogenetic abnormality in the study by Jakubowiak et al. However, only 7 of the 19 patients with ≥ 2 high-risk cytogenetic abnormalities in this study would fulfil the criteria for DH/THM[15]. Most of the studies looking at outcomes of patients with relapsed/refractory Multiple Myeloma lack specific information regarding DH/THM. Further, real-world data regarding the impact of Double-Hit/Triple Hit cytogenetics at relapse is missing.
In our study, 12 patients were detected to have t(4:14) at relapse but only 1 patient was detected to have this abnormality at diagnosis. Since t(4:14) represents a primary cytogenetic abnormality, it is possible that it was missed at baseline in some patients. Our study highlights the aggressive presentation (highlighted by significant early mortality) and poor outcomes seen at relapse in this subgroup of patients. Better representation in clinical trials and the use of newer drugs and treatment strategies is required to improve outcomes in this group of ultra-high-risk patients.
Acknowledgment and Author Declaration
The manuscript was presented as a poster at the ASH 2021 meeting entitled “Detection of Double Hit and Triple Hit Cytogenetics at Relapse Identifies a Very High Risk Subset of Relapsed/Refractory Multiple Myeloma Patients” doi: 10.1182/blood-2021-152810.
Declarations
Conflict of Interest
The Authors have no conflict of interest to declare.
Footnotes
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References
- 1.Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. The Lancet. 2019;394:29–38. doi: 10.1016/S0140-6736(19)31240-1. [DOI] [PubMed] [Google Scholar]
- 2.Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020;21:1630–1642. doi: 10.1016/S1470-2045(20)30525-8. [DOI] [PubMed] [Google Scholar]
- 3.Voorhees PM, Investigators for the GT, Kaufman JL, Laubach J, Investigators for the GT, et al (2020) ;136:936–45. 10.1182/BLOOD.2020005288
- 4.Shah V, Sherborne AL, Walker BA, Johnson DC, Boyle EM, Ellis S, et al. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia. 2018;32:102–110. doi: 10.1038/LEU.2017.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Baysal M, Demirci U, Umit E, Kirkizlar HO, Atli EI, Gurkan H et al Concepts of Double Hit and Triple Hit Disease in Multiple Myeloma, Entity and Prognostic Significance. Scientific Reports 2020;10. 10.1038/S41598-020-62885-0 [DOI] [PMC free article] [PubMed]
- 6.Jin F, Kumar S, Dai Y. The adverse double-hit effect of combining cytogenetic abnormalities and ISS stage III on the outcome of patients with newly-diagnosed multiple myeloma. Clin Lymphoma Myeloma Leuk. 2019;19:e68. doi: 10.1016/J.CLML.2019.09.107. [DOI] [Google Scholar]
- 7.Singh C, Panakkal V, Sreedharanunni S, Jandial A, Jain A, Lad D et al Presentation and Impact of Double and Triple hit Cytogenetics in Patients With Multiple Myeloma in the Real World. Clin Lymphoma Myeloma Leuk 2022. 10.1016/J.CLML.2022.03.005 [DOI] [PubMed]
- 8.Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34:1875–1884. doi: 10.1038/S41375-020-0711-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Richardson PG, Oriol A, Larocca A, Bladé J, Cavo M, Rodriguez-Otero P, et al. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2021;39:757–767. doi: 10.1200/JCO.20.02259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398:314–324. doi: 10.1016/S0140-6736(21)00933-8. [DOI] [PubMed] [Google Scholar]
- 11.Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361–2371. doi: 10.1016/S0140-6736(21)00592-4. [DOI] [PubMed] [Google Scholar]
- 12.Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396:186–197. doi: 10.1016/S0140-6736(20)30734-0. [DOI] [PubMed] [Google Scholar]
- 13.Reece D, Song KW, Fu T, Roland B, Chang H, Horsman DE, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114:522–525. doi: 10.1182/BLOOD-2008-12-193458. [DOI] [PubMed] [Google Scholar]
- 14.Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C, et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexaméthasone. Leuk 2010. 2010;24:3. doi: 10.1038/leu.2009.273. [DOI] [PubMed] [Google Scholar]
- 15.Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, et al. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leuk 2013. 2013;27:12. doi: 10.1038/leu.2013.152. [DOI] [PMC free article] [PubMed] [Google Scholar]