A New Approach to Enhance Immunotherapy in Multiple Myeloma

Exploring new strategies to stimulate the immune system to fight multiple myeloma—an incurable hematologic malignancy—is the goal of the research supported by the “Giovani Ricercatori” grant from Fondazione Cariplo, led by Dr. Tommaso Perini, hematologist at the Hematology and Bone Marrow Transplantation Unit and researcher at the Aging Diseases Unit. His project, “Targeting the mitochondrial protease ClpP: a novel strategy to boost anti-cancer immunity in multiple myeloma,” recently resulted in a publication in Blood, a leading international scientific journal in the field of hematology.

Multiple myeloma is a cancer caused by the uncontrolled growth of malignant plasma cells in the bone marrow. Over time, the disease causes bone and kidney damage and impairs blood cell production, ultimately proving fatal.
Although therapies have advanced significantly in recent years, most patients still experience multiple relapses and eventually develop disease refractory to all available treatments.
As Dr. Perini explains, one of the main barriers to a cure is the tumor’s ability to weaken the immune system, rendering it unable to perform its natural defense function against malignant cells.

Dr. Perini’s research has developed an innovative perspective. Starting from the idea that mitochondria are not only the “powerhouses” of the cell but also key regulators of cellular metabolism and health, the study focused on the possibility of targeting ClpP, a mitochondrial protease that has proven essential for myeloma cells.

“We discovered that by inhibiting ClpP,” explains the researcher, “tumor cells stop proliferating because they can no longer produce polyamines—molecules crucial for their growth. But the most intriguing finding is that without ClpP, mitochondria begin to release fragments of DNA, triggering an alarm mechanism (the cGAS–STING pathway) that activates the immune system to better recognize and attack malignant cells.”

Preclinical models showed that blocking ClpP not only limits the growth of multiple myeloma cells but also enhances the efficacy of modern immunotherapeutic agents, such as bispecific antibodies already used in clinical practice.

The next steps of the research are clear: to develop a drug capable of targeting ClpP suitable for clinical trials, and to identify the most effective strategies to increase the immunogenicity of myeloma cells.

“Our hope,” adds Perini, “is to develop therapies that not only directly target tumor cells but also stimulate the immune system, enabling it to eradicate the disease definitively.”

For the researcher, the support of Fondazione Cariplo represented a key moment in his scientific career:

“The Cariplo grant provided the opportunity to develop an original and independent project. It is a great honor to have earned Cariplo’s trust—it allowed me to carry out crucial experiments and to explore the translational potential of my research. Moreover, leading a complex project and coordinating diverse and multidisciplinary teams has been an invaluable opportunity to grow as an independent translational scientist.”