Polypharmacy Linked to Improved Outcomes in Lymphoma, CLL, and Multiple Myeloma

More Pills, Worse Prognosis: Polypharmacy a Key Indicator for Lymphoid Cancer Patients

New research published in Hemasphere suggests that the number of medications a patient takes before a lymphoid cancer diagnosis could be a significant predictor of their overall survival, hospitalization rates, and risk of severe infection.

A study by Brieghel and colleagues analyzed medication histories from over 46,000 newly diagnosed patients with lymphoma, chronic lymphocytic leukemia (CLL), or multiple myeloma (MM) in Denmark. Leveraging the country’s thorough prescription registry, where most medications require a prescription, the researchers examined the prognostic value of polypharmacy – the use of multiple prescription medications.

The findings revealed a clear correlation: the more medications patients were taking at diagnosis, the poorer their expected outcomes. Patients on zero to three medications had a baseline hazard ratio (HR) of 1.0 for overall survival, hospitalization, and severe infection. This HR increased with the number of medications:
4 to 7 medications: HR of 1.2
8 to 11 medications: HR of 1.4
More than 11 medications: HR of 1.9

This trend was also observed for hospitalization and severe infection rates.

Beyond the sheer number of medications, the types of drugs prescribed also held prognostic meaning. Immunostimulants and blood substitutes were associated with a negative impact on overall survival. Conversely, gynecologicals and sex hormones were linked to more favorable outcomes. The researchers suggest that the former group may represent patients already undergoing supportive therapy for other conditions, while the latter patients were more likely to be younger and female. Notably, even after adjusting for age and sex, sex hormones maintained a positive prognostic value.

The study’s authors emphasize that while their research was not designed to establish causality,the findings strongly suggest that the selection of patients who require multiple medications,indicative of underlying multimorbidity,is a key factor influencing outcomes rather than a direct causal effect of the medications themselves.

Furthermore, for patients with Hodgkin lymphoma, mantle cell lymphoma, and MM, the analysis indicated that an increased number of medications correlated with a shorter time to the next treatment.

Brieghel and colleagues propose that the number of medications a patient is taking can serve as a robust, independent prognostic indicator for lymphoid cancer patients.They recommend that this “key baseline characteristic” should be routinely considered in both randomized clinical trials and everyday clinical practice to better stratify patient risk and guide treatment decisions.This research builds upon previous findings that have linked polypharmacy to increased risks of mortality, adverse drug reactions, and longer hospitalizations in older adults.

References:

1. Brieghel C, Lacoppidan T, Packness E, et al. Polypharmacy independently predicts survival, hospitalization, and infections in patients with lymphoid cancer. Hemasphere. 2025;9(7):e70172. doi:10.1002/hem3.70172
2. li Y, Zhang X, Yang L, et al. Association between polypharmacy and mortality in the older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr*. 2022; 100: 104630. DOI: 10.1016/J.Archger.2022.104630

How does the increasing recognition of polypharmacy as a potential strategy challenge traditional views of managing medications in hematologic cancers?

Understanding Polypharmacy in Hematologic Malignancies

Polypharmacy, traditionally defined as the concurrent use of five or more medications, is increasingly recognized not simply as a risk factor, but as a potential strategy to enhance treatment efficacy in hematologic cancers like lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma.This shift in perspective stems from a growing body of evidence demonstrating synergistic effects when combining targeted therapies, immunomodulators, and conventional chemotherapy. The focus is moving beyond simply managing multiple medications to strategically utilizing them for optimal patient outcomes. key terms related to this include “combination therapy,” “treatment regimens,” and “drug interactions.”

The rationale Behind Combination Regimens

Historically, treatment for these cancers ofen involved single-agent chemotherapy or limited combinations. Though, the inherent heterogeneity of these diseases – variations in genetic mutations, disease stage, and patient-specific factors – necessitates a more nuanced approach.

Overcoming Resistance: Cancer cells are adept at developing resistance to single therapies. Polypharmacy attacks multiple pathways simultaneously, reducing the likelihood of resistance emerging.

Synergistic Effects: Certain drug combinations exhibit synergy, meaning the combined effect is greater than the sum of their individual effects. This can lead to more profound remissions.

Targeting Multiple Disease Drivers: Lymphoma, CLL, and multiple myeloma are complex diseases driven by multiple factors. Polypharmacy allows clinicians to address these diverse drivers concurrently.

Personalized Medicine: The rise of genomic profiling allows for tailoring polypharmacy regimens to individual patient characteristics, maximizing efficacy and minimizing toxicity. This is a core tenet of precision oncology.

Polypharmacy in Lymphoma Treatment

Lymphoma,encompassing Hodgkin lymphoma and various non-Hodgkin lymphomas (NHL),benefits significantly from polypharmacy.

Diffuse Large B-Cell lymphoma (DLBCL)

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains a standard first-line treatment. However, research is exploring adding novel agents like:

BTK inhibitors (ibrutinib, acalabrutinib): Demonstrated improved progression-free survival when added to R-CHOP in relapsed/refractory DLBCL.

PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab): Showing promise in specific DLBCL subtypes, particularly those with PD-L1 expression.

Bispecific Antibodies (Glofitamab, Mosunetuzumab): These innovative therapies directly engage T cells to target and destroy lymphoma cells, frequently enough used in relapsed/refractory settings.

Follicular Lymphoma

While frequently enough indolent,follicular lymphoma can transform into more aggressive forms. Polypharmacy strategies include:

Rituximab plus chemotherapy: The cornerstone of treatment.

Maintenance rituximab: Prolongs remission duration.

PI3K inhibitors (copanlisib): Used in relapsed/refractory cases,frequently enough in combination with rituximab.

Polypharmacy in Chronic Lymphocytic Leukemia (CLL)

The treatment landscape for CLL has been revolutionized by targeted therapies, leading to more complex polypharmacy regimens.

Bruton’s Tyrosine Kinase (BTK) Inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib): Often used as first-line therapy, particularly in patients with IGHV unmutated CLL.

BCL-2 Inhibitors (Venetoclax): Highly effective, often combined with BTK inhibitors for a fixed-duration treatment approach.

Chemoimmunotherapy (Fludarabine, Cyclophosphamide, Rituximab – FCR): Still utilized in select cases, but increasingly replaced by targeted therapies.

CAR T-cell Therapy: for relapsed/refractory CLL, offering a perhaps curative option.

Polypharmacy in Multiple Myeloma

Multiple myeloma treatment has evolved from traditional chemotherapy to incorporating proteasome inhibitors,immunomodulatory drugs (IMiDs),and monoclonal antibodies.

Proteasome inhibitors (bortezomib, Carfilzomib, Ixazomib): Target the proteasome, a cellular machinery involved in protein degradation.

IMiDs (Lenalidomide, Pomalidomide): modulate the immune system and inhibit myeloma cell growth.

Monoclonal Antibodies (Daratumumab,Isatuximab): Target specific proteins on myeloma cells,enhancing immune-mediated killing.

CAR T-cell Therapy (Ide-cel, Cilta-cel): Demonstrates high response rates in relapsed/refractory myeloma.

* selinexor: A first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, frequently enough used in combination for heavily pre-treated patients.

Managing the Challenges