Click to Enlarge: There are multiple factors of importance to MM patients regarding their treatment that impact on the effectiveness of that treatment in the real-world setting. Source: Blood Cancer Journal
DALLAS — Multiple myeloma (MM) remains treatable but not curable; however, the therapeutic landscape has changed dramatically over the past decade. Recently U.S. Food and Drug Administration–approved immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies have extended survival for many veterans with MM, enabling some patients to remain in remission for 5 or 10 years or more.
MM is a malignant neoplasm of plasma cells characterized by uncontrolled proliferation within the bone marrow, leading to impaired bone integrity, anemia, renal insufficiency and immunodeficiency. The malignancy primarily affects older patients for whom frailty may be an issue. At the VA, frailty affects at least 30% of U.S. veterans aged 65 years and older and is strongly associated with mortality, making treatment selection in VA settings particularly complex.
Despite these challenges, evolving evidence, including new data presented at the December 2025 American Society of Hematology (ASH) Annual Meeting, suggest that new regimens can deliver deeper responses and prolonged disease control in appropriately selected patients, such as veterans with higher-risk disease.
Treatment Goals and Supportive Care
The initial goals of MM therapy are to rapidly and safely reduce tumor burden, relieve symptoms and preserve quality of life. Clinicians aim to reduce monoclonal (M) protein levels or free light chains to the lowest possible level, eliminate malignant plasma cells from the bone marrow as assessed by minimal residual disease (MRD) testing, prolong the duration of response and ultimately extend overall survival.
Adjunctive therapies remain essential in care for veterans with MM. Bisphosphonates promote bone healing and reduce skeletal-related events such as fractures, spinal cord compression and hypercalcemia. Erythropoietin may be used to manage anemia, either alone or in conjunction with systemic therapy. Radiation therapy plays a valuable role in providing rapid pain relief, stabilizing weight-bearing bones, preventing neurologic compromise from plasmacytomas and treating solitary plasmacytomas, where it may serve as definitive therapy. Plasma exchange remains an important acute intervention for symptomatic hyperviscosity, while systemic therapy targets the underlying disease.
Evolving Treatment Options in the VA
Traditional MM therapies included chemotherapy, corticosteroids and hematopoietic cell transplantation (HCT). Today, treatment increasingly relies on combinations of proteasome inhibitors (PI), immunomodulating drugs (IMiDs), monoclonal antibodies, and, in later lines, B-cell maturation antigen (BCMA)–directed therapies, including CAR T-cell therapies and bispecific antibodies.
In a 20-year analysis of treatment patterns among veterans with MM, the investigators noted that disease heterogeneity, resistance to therapy, and relapse remain central challenges.1 Real-world data underscore the impact of modern agents: a retrospective study of U.S. veterans with MM conducted by VA researchers at the VA Long Beach, CA, found that IMiDs were associated with a 32% improvement in survival and CD-38 monoclonal antibodies with a 26% improvement.2
Proteasome inhibitor–based regimens remain foundational. The triplet combination of the PI bortezomib with lenalidomide and dexamethasone (VRd), for example, has become a standard regimen. However, frail patients with MM are more likely to experience treatment-related toxicity and shorter progression-free survival, raising concerns about tolerance for triplet therapy. 3
Notably, VA-based research has shown that more intensive triplet therapy can benefit even highly frail veterans. In a national VA analysis, veterans treated with VRd experienced superior outcomes compared with lenalidomide and dexamethasone alone.
“This benefit was even more pronounced in veterans with the highest levels of frailty, challenging the historical expert opinion-based recommendation to consider the doublet over the triplet in patients are frail,” lead author Clark DuMontier, MD, a researcher at VA Boston Healthcare System previously told U.S. Medicine. The finding challenges long-standing assumptions that frail patients should automatically receive less intensive therapy.4
Transplant-Eligible Veterans
The National Comprehensive Cancer Network (NCCN) Multiple Myeloma Guidelines (v5.2026) recommend quadruplet regimens as preferred induction therapy for transplant-eligible patients, reflecting improved depth of response and progression-free survival seen in clinical trials. Preferred regimens include VRd combined with daratumumab or isatuximab.
A recent study may prompt changes in the recommendations for preferred first-line treatment. In the COBRA trial presented at ASH in December, carfilzomib with dexamethasone and lenalidomide (KRd) significantly prolonged progression-free in newly diagnosed MM patients compared with VRd, with median progression-free survival not reached vs. 48.8 months, respectively.
KRd also produced significantly higher MRD negativity rates at 12 months and a greater proportion of complete responses. Importantly, benefits were observed in standard-risk patients and in those eligible for transplant. Although overall survival data remains immature, these findings represent one of the first demonstrations of clear superiority of a KRd regimen over VRd in a randomized phase III setting.5
While Grade 3 and higher adverse events occurred more frequently with KRd, no new safety signals were identified. Peripheral neuropathy occurred far less frequently with KRd than with VRd—an important consideration for veterans with baseline neuropathy from diabetes or prior chemotherapy—though cardiac events were more common, underscoring the need for careful patient selection and monitoring in VA practice.
Additional research will be needed to determine how these findings affect recommendations for initial treatment with quadruple therapies.
Stem-cell harvesting is recommended after 4 to 6 months of induction in hematopoietic cell transplant (HCT)-eligible patients. Even in those initially deemed transplant-ineligible, stem-cell collection may be considered for potential future HCT. High-dose melphalan remains the recommended conditioning regimen for HCT, with collection of sufficient stem cells for two transplants due to its stem-cell toxicity.
Post-transplant maintenance therapy remains standard, with low-dose lenalidomide improving both progression-free and overall survival, albeit with an increased risk of secondary malignancies. For patients with high-risk disease features, the NCCN recommends combination maintenance strategies, including carfilzomib plus lenalidomide or daratumumab plus lenalidomide. These approaches may be particularly relevant in the VA, where patients often present with advanced-stage disease or adverse cytogenetics.
Transplant-Ineligible and Frail Patients
For transplant-ineligible or deferred patients, NCCN Category 1 preferred regimens include daratumumab with lenalidomide and dexamethasone, with quadruplet regimens of VRd plus either daratumumab or bisatuximab for nonfrail patients younger than 80 years.
Other NCCN recommended options include carfilzomib-based triplets such as KRd, particularly for patients who may benefit from deeper responses or who have contraindications to bortezomib. Other combinations of the approved proteasome inhibitors may be useful in certain circumstances. For instance, for veterans with renal insufficiency, a common comorbidity, carfilzomib- or bortezomib-based regimens combined with cyclophosphamide and dexamethasone may be appropriate.
Relapsed and Refractory Multiple Myeloma
Treatment selection at relapse, either following HCT or in patients ineligible for HCT, must consider prior therapies, depth and duration of response, comorbidities, frailty and patient preferences. Carfilzomib plays a central role in multiple relapse scenarios. For patients who are refractory to CD38 antibodies or bortezomib, NCCN ranks carfilzomib-based combinations including KRd and carfilzomib with pomalidomide and dexamethasone among the preferred options.
In subsequent lines, the combinations should not repeat a previously received drug or, at least, not one received in the immediately previous line. In fourth or later lines, CAR T-cell therapy and bispecific antibodies may be considered, though access, logistics and patient fitness may be considerations.
Implications for Veteran Care
For VA clinicians, these evolving data reinforce the importance of individualized therapy selection grounded in frailty assessment, comorbidity burden, and disease risk. Carfilzomib-containing regimens, supported by robust clinical trial evidence and new ASH data, offer an important option for achieving deeper and more durable responses in selected veterans with MM. As treatment options continue to expand, integrating guideline-based care with veteran-specific considerations will remain central to improving outcomes in this complex population.
- Kaur G, Sannareddy A, Perkins A, et al. Demographic Characteristics and Treatment Patterns in Veterans With Multiple Myeloma: A Comprehensive Analysis from the Veterans Affairs Database (2000-2020). Blood. 2023;142(S1):7370.
- Mahmood S, Gupta P, Ma H. A retrospective analysis of factors impacting survival in United States military veterans with multiple myeloma. Leuk Lymphoma. 2024 Apr;65(4):530-533. doi: 10.1080/10428194.2023.2295791. Epub 2023 Dec 26. PMID: 38148142.
- Aureli A, Marziani B, Sconocchia T, et al. Challenges in Multiple Myeloma Therapy in Older and Frail Patients. Cancers (Basel). 2025 Mar 11;17(6):944. doi: 10.3390/cancers17060944. PMID: 40149280; PMCID: PMC11940046.
- DuMontier C, La J, Bihn J, Corrigan J, et. Al. More intensive therapy as more effective treatment for frail patients with multiple myeloma [corrected]. Blood Adv. 2023 Oct 24;7(20):6275-6284. doi: 10.1182/bloodadvances.2023011019. Erratum in: Blood Adv. 2023 Nov 28;7(22):7100. PMID: 37582048; PMCID: PMC10589796.
- Dytfeld D, Kubicki T, Tyczynska A, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM)—interim results from the randomized Phase III COBRA trial. Presented at ASH 2025. December 6-9, 2025. Orlando, FL. Abstract 99.