Overview of Multiple Myeloma Treatment
Multiple myeloma is a hematologic malignancy characterized by clonal proliferation of plasma cells in the bone marrow. Treatment has evolved dramatically over the past two decades, transforming this once rapidly fatal disease into a chronic condition for many patients. Modern regimens combine multiple drug classes — proteasome inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, and increasingly CAR-T cell therapy and bispecific antibodies. Treatment selection depends on transplant eligibility, cytogenetic risk, prior therapies, and patient fitness.
Treatment Sequencing by Setting
🔬 Newly Diagnosed — Transplant Eligible
- Induction: Daratumumab + Bortezomib + Lenalidomide + Dexamethasone (D-VRd, PERSEUS)
- Autologous stem cell transplant (ASCT)
- Maintenance: Lenalidomide ± daratumumab
🔬 Newly Diagnosed — Transplant Ineligible
- Daratumumab + Lenalidomide + Dexamethasone (D-Rd, MAIA)
- Daratumumab + Bortezomib + Melphalan + Prednisone (D-VMP, ALCYONE)
- Isatuximab + VRd (IMROZ)
🔁 First Relapse
- Carfilzomib + Dexamethasone (Kd) or Carfilzomib + Lenalidomide + Dexamethasone (KRd)
- Isatuximab + Carfilzomib + Dexamethasone (Isa-Kd, IKEMA)
- Pomalidomide-based combinations if lenalidomide-refractory
🧬 Heavily Pretreated / Triple-Class Refractory
- CAR-T: Idecabtagene vicleucel (Abecma) or Ciltacabtagene autoleucel (Carvykti)
- Bispecific antibodies: Teclistamab (Tecvayli, BCMA×CD3), Talquetamab (Talvey, GPRC5D×CD3), Elranatamab (Elrexfio, BCMA×CD3)
- Selinexor (Xpovio) + dexamethasone ± bortezomib
Epidemiology & Impact
Multiple myeloma accounts for approximately 1.8% of all new cancer cases in the United States, with an estimated 35,730 new diagnoses and 12,590 deaths in 2024. It is the second most common hematologic malignancy after non-Hodgkin lymphoma. The median age at diagnosis is 69 years, and the disease is roughly twice as common in African Americans compared to Caucasians, with the racial disparity representing one of the largest for any cancer type. While historically considered incurable, survival has improved dramatically — five-year relative survival has risen from 33% in 2000 to over 59% today, driven by the introduction of novel agents across multiple drug classes. The precursor condition, monoclonal gammopathy of undetermined significance (MGUS), progresses to myeloma at a rate of approximately 1% per year, and smoldering myeloma represents an intermediate stage with higher progression risk. Efforts to identify high-risk smoldering myeloma for early intervention are an active area of research, with the AQUILA and DETER trials evaluating early treatment strategies.
Molecular Biology & Biomarkers
The molecular heterogeneity of multiple myeloma profoundly influences prognosis and treatment response. Cytogenetic risk stratification using fluorescence in situ hybridization (FISH) divides patients into standard-risk and high-risk categories. High-risk abnormalities include t(4;14), t(14;16), t(14;20), del(17p)/TP53, and gain(1q21), collectively present in approximately 25% of newly diagnosed patients. The International Staging System (ISS), revised in 2015 to incorporate serum lactate dehydrogenase and high-risk cytogenetics (R-ISS), remains the standard prognostic framework. Gene expression profiling, including the GEP70 and SKY92 signatures, provides additional prognostic information. The clonal architecture of myeloma is characterized by significant spatial and temporal heterogeneity, with branching evolutionary patterns that drive treatment resistance through subclonal selection. The bone marrow microenvironment — including interactions with osteoclasts, osteoblasts, stromal cells, and immune effectors — plays a critical role in disease progression and represents an emerging therapeutic target.
Evolving Treatment Landscape
The pace of drug development in multiple myeloma has been extraordinary. Since 2000, over 15 novel agents have been approved, spanning proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, CAR-T cell therapies, bispecific antibodies, nuclear export inhibitors, and cereblon E3 ligase modulators. The current first-line standard for transplant-eligible patients has evolved to daratumumab-VRd (D-VRd) quadruplet induction based on the PERSEUS trial, which demonstrated a significant improvement in stringent complete response and MRD-negativity rates. For transplant-ineligible patients, daratumumab-Rd (D-Rd) based on the MAIA trial has become standard. The relapsed/refractory space has been transformed by immunotherapy: BCMA-targeting agents — including the CAR-T products idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), and the bispecific antibodies teclistamab (Tecvayli) and elranatamab (Elrexfio) — have produced deep responses in heavily pretreated patients. The novel GPRC5D-targeting bispecific talquetamab (Talvey) offers an alternative target for BCMA-exposed patients. Measurable residual disease (MRD) assessment at 10⁻⁵ sensitivity is increasingly used to guide treatment duration decisions, with sustained MRD-negativity emerging as a potential surrogate for long-term outcomes.
Approved Multiple Myeloma Therapies
Treatment Paradigms & Sequencing
Newly Diagnosed Transplant-Eligible
Standard induction includes quadruplet therapy with D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) for 4-6 cycles, followed by autologous stem cell transplant and lenalidomide maintenance until progression. The GRIFFIN trial established D-VRd as superior to VRd alone.
Newly Diagnosed Transplant-Ineligible
Daratumumab-based triplet regimens are standard, including DRd (daratumumab, lenalidomide, dexamethasone) or D-VMP (daratumumab, bortezomib, melphalan, prednisone). Treatment continues until progression or unacceptable toxicity.
Relapsed/Refractory Disease
Treatment selection depends on prior therapies and duration of response. Options include daratumumab-based combinations (DKd, DVd, DPd), pomalidomide-based regimens, CAR-T cell therapy (Abecma, Carvykti), and bispecific antibodies (teclistamab, elranatamab). For triple-class exposed patients, CAR-T or BiTEs are preferred.