Detection of Double Hit and Triple Hit Cytogenetics at Relapse Identifies a Very High Risk Subset of Relapsed/Refractory Multiple Myeloma Patients
Authors: Singh Charanpreet , Sreedharanunni Sreejesh , Panakkal Vandana , Jandial Aditya , Jain Arihant , Lad Deepesh , Prakash Gaurav , Khadwal Alka , Malhotra Pankaj 
Published: November 2021

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. While cytogenetics at diagnosis helps in the decision-making process regarding initial therapy, their role in relapsed MM is not very well studied. 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 requiring active therapy between January 2018 and December 2020 were identified. All patients underwent bone marrow examination and repeat FISH cytogenetic analysis. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted.
RESULTS
A total of 17 patients were diagnosed with DH/THM at relapse during the study period. Median age of the cohort was 59 years with almost an equal number of male and female patients (M=9; F=8). Renal failure (serum creatinine &gt;2.0mg/dl) was seen in 8 patients (47.1%), while bone lesions, anemia (Hemoglobin &lt;10gm/dl) and hypercalcemia (serum calcium &gt;12mg/dl) were seen in 12 (70.6%), 12 (70.6%) and 6 (35.3%) patients respectively. Five patients (29.4%) fulfilled the criteria for plasma cell leukemia.
Twelve patients (70.6%) were in first relapse, while 3 patients were diagnosed at second relapse and 1 patient each at 3 rd and 5 th relapse respectively. All but 2 patients had received Bortezomib previously (N=15; 88.2%). Eleven patients (64.7%) had previous exposure to Lenalidomide and 8 patients (47.1%) had previous exposure to Thalidomide. Two patients had previously undergone autologous hematopoietic cell transplant. Median follow-up prior to diagnosing DH/THL was 28 months (Range- 5-89 months).
All patients had gain of 1q with at least 3 copies, while 12 patients (70.6%) had 4 or more copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q which was seen in 10 patients (58.8%). This was followed by co-occurrence of TP53 deletion with gain of 1q in 5 patients (29.4%). Two patients (11.8%) had triple hit myeloma.
Seven patients (41.2%) died within the first month of relapse and a further 3 patients died during the next month. Of the 10 patients who received at-least 1 cycle of therapy, 8 received triplet therapy with the combination of a proteasome inhibitor and an Immunomodulator, one patient received doublet with Lenalidomide and dexamethasone and one patient received Daratumumab based quadruplet therapy. Bortezomib based therapy was used in 5 patients and 4 patients received Carfilzomib based therapy. None of the patients underwent a 2 nd auto transplant. Two patients achieved VGPR or better with therapy. Of the 7 evaluable patients, 5 re-relapsed during follow up.
The follow up of entire cohort ranged from 0 to 29 months. Sixteen patients (94.1%) died during follow up. 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.
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.

Disclosures
No relevant conflicts of interest to declare.