Multiple Myeloma: A Modern Look at an Ancient Disease and 2025’s Therapeutic Breakthroughs

Multiple myeloma (MM) is a malignancy of plasma cells, which are a subset of white blood cells responsible for producing immunoglobulins. In MM, these plasma cells become neoplastic, proliferating uncontrollably in the bone marrow and secreting large amounts of monoclonal protein (M protein) that contribute to end-organ damage. This disease is associated with a constellation of symptoms known by the acronym “CRAB”: hypercalcemia, renal insufficiency, anemia, and bone lesions. MM accounts for roughly 10% of hematologic malignancies and 2% of all cancers in the United States, with an estimated 36,110 new diagnoses and approximately 12,030 deaths expected in 2025 alone.¹

Image Credit: © freshidea - stock.adobe.com

The roots of MM can be traced back centuries, with its first well-documented case described in the mid-19th century. Dr Samuel Solly's 1844 account of a man named Mr McBean marked the beginning of modern recognition of this condition.² The identification of Bence Jones proteins shortly thereafter by Henry Bence Jones was a seminal moment in hematologic oncology, setting the stage for future diagnostic advancements.³ For much of the 20th century, treatment options were limited, relying largely on alkylating agents like melphalan and corticosteroids.⁴ However, the therapeutic landscape of MM has dramatically evolved in the 21st century with the introduction of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. The year 2025 marked a significant leap forward in the treatment of MM, with multiple FDA approvals that have expanded both frontline and relapsed/refractory options.

In April 2025, the FDA approved 2 CD38-targeting monoclonal antibodies—daratumumab (Darzalex; Johnson & Johnson) and isatuximab (Sarclisa; Sanofi)—for patients with newly diagnosed MM who are eligible for autologous stem cell transplantation (ASCT).⁵ These approvals stemmed from robust clinical trial data showing improved depth of response and progression-free survival when the antibodies were added to existing induction regimens. Both agents are administered intravenously and work by engaging immune effector functions such as antibody-dependent cellular cytotoxicity and complement activation to eliminate malignant plasma cells. Daratumumab and isatuximab are now integrated into quadruplet induction therapies along with a proteasome inhibitor (eg, bortezomib [Velcade]), an immunomodulatory drug (eg, lenalidomide [Revlimid; Bristol Myers Squibb]), and dexamethasone. Adverse effects are generally manageable but may include infusion-related reactions, neutropenia, and an increased risk for infections due to immunosuppression.⁵

Another promising development in 2025 was the FDA’s acceptance of linvoseltamab (Lynozyfic; Regeneron) for priority review and eventual approval in relapsed/refractory MM.⁶ Linvoseltamab is a bispecific antibody that binds to B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, thereby redirecting the patient's own immune system to attack the cancer. This therapy represents the continued momentum behind BCMA-directed strategies, a hallmark of MM innovation in recent years. The regulatory decisions were supported by results from the LINKER-MM1 study, which demonstrated high overall response rates and durable remissions in patients who had exhausted prior lines of therapy.⁶ Linvoseltamab is notable for its off-the-shelf availability, which provides a key logistical advantage over autologous CAR T-cell therapies. Adverse effects include cytokine release syndrome (CRS), anemia, and fatigue. CRS was largely low grade and managed effectively with supportive care and IL-6 blockade agents like tocilizumab.⁶

In the realm of supportive care, the FDA approved a denosumab biosimilar, branded as Xbryk (denosumab-dssb), in February 2025 for the prevention of skeletal-related events in patients with MM who develop bone metastases.⁷ Denosumab, originally marketed as Xgeva, is a monoclonal antibody that inhibits receptor activator of nuclear factor kappa-Β ligand (RANKL), a key mediator of osteoclast activity. The introduction of XBryk represents an important milestone in expanding access to cost-effective bone health management in myeloma. Clinical studies demonstrated bioequivalence to the reference product, and its approval offers clinicians a more affordable alternative without compromising efficacy. Possible adverse effects of denosumab, and by extension XBryk, include hypocalcemia, musculoskeletal pain, and the risk of osteonecrosis of the jaw, especially when combined with invasive dental procedures.⁷

These 2025 approvals reflect a broader shift in MM treatment philosophy—from generalized cytotoxic therapy toward targeted, immune-based approaches that harness the body’s natural defense systems. Importantly, these advances also illustrate a commitment to personalizing therapy based on patient eligibility for transplant, prior treatment exposures, cytogenetic risk, and treatment goals. While ASCT remains a cornerstone of therapy in transplant-eligible individuals, the availability of novel antibodies and bispecific T-cell engagers is redefining frontline and salvage protocols.

The improved outcomes associated with these novel therapies are already being observed in clinical practice. According to Memorial Sloan Kettering Cancer Center, patients treated with modern triplet and quadruplet regimens are achieving deeper and more sustained remissions than ever before.⁸ Furthermore, these advancements are extending progression-free survival and improving quality of life, even in populations historically associated with poorer prognoses, such as older adults or those with high-risk cytogenetic profiles.

However, despite these breakthroughs, MM remains an incurable disease marked by inevitable relapse in most patients. Over time, many develop resistance to existing agents, underscoring the need for continued innovation. New targets, such as GPRC5D and FcRH5, are under investigation, and additional bispecific and CAR-T constructs are in clinical trials. The goal is not only to extend survival but also to eventually achieve functional cures, where patients can maintain remission without continuous therapy.

In conclusion, multiple myeloma has evolved from a fatal disorder with few treatment options to a chronic disease managed with a variety of advanced therapeutic modalities. The year 2025 was especially transformative, marked by the approval of daratumumab and isatuximab in newly diagnosed patients, linvoseltamab in relapsed/refractory settings, and a biosimilar to denosumab for bone protection. These approvals not only provide more choices but also signal a trend toward deeper responses, fewer toxicities, and better long-term outcomes. As research continues to push the boundaries of what is possible in MM care, patients and clinicians alike can remain hopeful that curative therapies are on the horizon.

REFERENCES

1. American Cancer Society. Key Statistics About Multiple Myeloma. February 28, 2025. Accessed June 20, 2025. https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html

2. Solly S. Cases of Mollities and Fragilitas Ossium. Med Chir Trans. 1844;27:435-498.

3. Bence Jones H. On a New Substance Occurring in the Urine of a Patient with Mollities Ossium. Philos Trans R Soc Lond. 1847;137:55-62.

4. MyMyelomaTeam. Multiple Myeloma: How Did It Begin? June 3, 2025. https://www.mymyelomateam.com

5. National Cancer Institute. FDA Approvals Expand Initial Treatment Options for Multiple Myeloma. April 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2025/fda-daratumumab-isatuximab-newly-diagnosed-myeloma

6. Targeted Oncology. FDA Reviews Linvoseltamab in Relapsed/Refractory Multiple Myeloma. March 2025. https://www.targetedonc.com/view/fda-reviews-linvoseltamab-in-relapsed-refractory-multiple-myeloma

7. HealthTree Foundation. Denosumab Biosimilar XBryk™ FDA Approved for Myeloma. February 13, 2025. https://healthtree.org/myeloma/community/articles/denosumab-biosimilar-xbryk-fda-approved-myeloma

8. Memorial Sloan Kettering Cancer Center. Multiple Myeloma: Improved Prognosis and Latest Treatments. 2025. https://www.mskcc.org/news/multiple-myeloma-improved-prognosis-latest-treatments