Body Mass Index Trajectory during Triplet Induction Therapy: Clinical Implications in Newly Diagnosed Multiple Myeloma
Authors: Thirugnanasambandam Ram Prakash , Firestone Ross S , Derkach Andriy , Furberg Helena , Shekarkhand Tala , Rueda Colin , Maclachlan Kylee H , Hultcrantz Malin , Mailankody Sham , Patel Dhwani , Lahoud Oscar Boutros , Landau Heather J. , Chung David J. , Shah Gunjan L. , Scordo Michael , Hassoun Hani , Lesokhin Alexander M. , Giralt Sergio , Korde Neha , Usmani Saad Z. , Tan Carlyn Rose , Shah Urvi A. 
Published: December 2024

Background
Elevated body mass index (BMI) is a recognized risk factor for newly diagnosed multiple myeloma (NDDM), and extremes of BMI (underweight and obese) are associated with worse survival. Despite this, the clinical significance of BMI changes during induction therapy is poorly understood. The primary goal of this study was to identify patient-specific risk factors associated with extreme weight changes and to determine the clinical significance of a change in baseline BMI during induction therapy.
Methods
We conducted a retrospective analysis of 389 NDDM patients (pts) undergoing induction therapy with either carfilzomib, lenalidomide, and dexamethasone (KRd, N=191) or bortezomib, lenalidomide, and dexamethasone (VRd, N=198) from January 2016 to December 2022. Data on BMI, age, gender, Revised International Staging System (RISS), cytogenetics, cardiac history, and diabetes history were collected and reviewed from our electronic health records. Pts were classified into three BMI groups: underweight (BMI &lt; 18.5), normal (BMI 18.5-24.9), and overweight /obese (BMI &gt;25). Changes in baseline BMI following induction therapy were defined as weight stable (BMI change &lt;5%), weight loss (BMI decrease ≥5%), and weight gain (BMI increase ≥5%).
Associations between BMI change during induction and progression-free survival (PFS) and overall survival (OS) were analyzed using landmark analysis from the time of induction completion to disease progression or death. Multivariable Cox proportional hazards regression models were also used and were adjusted for baseline BMI, BMI change, age, gender, RISS, cytogenetics, and cardiac history. Exploratory analysis evaluated the association of anti-diabetic medications on PFS and OS.
Results
At the start of induction therapy, 1% of pts were underweight, 22% had normal BMI, 73% had elevated BMI, and 4% had missing records for BMI. No significant differences in age, cytogenetics, or RISS stage were noted across baseline BMI categories. During induction, 65% were weight stable, 19% gained weight, and 16% lost weight. Older age was associated with weight loss during induction, with an associated BMI change of -0.03kg/m2 per year increase in age (p=0.0005), while younger age was associated with weight gain. Compared to pts with RISS I disease, pts with RISS 2-3 disease showed a higher likelihood of weight loss (10% vs 20%) and weight gain (15% vs.20%). Pts with RISS 1 disease were more likely to be weight stable compared to RISS 2-3 (75% vs. 60%) (p=0.0075). When compared to pts with weight loss, pts with weight gain had an increased risk of disease progression (HR 2.12 p=0.028), and pts with stable weight had no difference in PFS (HR 1.45, p=0.211).
Elevated BMI was not associated with PFS at baseline (HR 1.02, p=0.29) and at the end of induction (HR 1.03, p=0.17). However, elevated BMI at both baseline (HR 1.05, p=0.02) and at the end of induction (HR 1.05, p=0.03) was associated with worse OS. These outcomes were adjusted for potential confounders, including high-risk cytogenetics, in a multivariate model. As expected, RISS3 (HR 2.5, p=0.01 and HR 4.2, p=0.01) and high-risk cytogenetics (HR 2.5, p=&lt;0.001 and HR 2.0, p=0.02) were associated with worse PFS and OS, respectively. Within this cohort, 14.1% were on medications for diabetes mellitus (DM) (oral/insulin), regardless of DM diagnosis status. Pts on diabetic medications had a higher likelihood of weight loss during induction (29.1% vs. 13.6%, p=0.01). Pts not on medications for diabetes may have a lower risk of progression compared to those on diabetic medications (HR 0.6, p=0.05).
Conclusions
In this study, most pts were overweight/obese and had stable weight during induction therapy. Younger pts were more likely to gain weight, while older pts were more prone to weight loss. Weight gain during induction was associated with a higher risk of disease progression compared to weight loss. These factors should be discussed during pts counseling, focusing on risk factors associated with weight changes during induction therapy.