Tag: Multiple Myeloma

LYNOZYFIC® (Linvoseltamab-gcpt)

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The FDA on July 2, 2025, granted accelerated approval to LYNOZYFIC®, a bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. LYNOZYFIC® is a product of Regeneron Pharmaceuticals, Inc.

Late Breaking Abstract – ASH 2025: Teclistamab Plus Daratumumab Redefines Outcomes in Early Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI®), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX®), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med. Published December 9, 2025. DOI: 10.1056/NEJMoa2514663

 

 

 

 

FDA Approves BLENREP® Combination for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on October 23, 2025, approved Belantamab mafodotin-blmf (BLENREP®), a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor conjugate, with Bortezomib and Dexamethasone for adults with Relapsed or Refractory Multiple Myeloma (RRMM) who have received at least two prior lines of therapy, including a Proteasome Inhibitor and an immunomodulatory agent.

Context and Rationale

Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Patients with newly diagnosed multiple myeloma often receive triplet and quadruplet regimens that incorporate Proteasome Inhibitors, immunomodulators, and anti-CD38 antibodies as first line therapy, as these regimens are associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS). However, most patients relapse and frontline use of Lenalidomide therapy has increased the number of patients with Lenalidomide-refractory disease at the time of the first relapse. New novel combinations are needed for patients who have relapsed or refractory myeloma, after disease progression during frontline therapy.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and multiple myeloma. B-Cell Maturation Antigen is therefore an established target in myeloma.

Belantamab Mafodotin: A Multimodal Antibody-Drug Conjugate

Belantamab mafodotin is a BCMA-targeting antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. Auristatin F induces cytotoxicity, Antibody-Dependent Cellular Cytotoxicity and phagocytosis, and induction of immunogenic cell death. Early-phase data demonstrated sustained, deep responses in heavily pretreated populations, suggesting potential benefit when used earlier in the disease course in combination with established backbones.

Study Design: DREAMM-7

The Phase III DREAMM-7 trial (DRiving Excellence in Approaches to Multiple Myeloma) was an open-label, multicenter, randomized study comparing Belantamab mafodotin plus Bortezomib and Dexamethasone (BVd) versus Daratumumab plus Bortezomib and Dexamethasone (DVd) in patients with RRMM who had received at least one prior line of therapy. A total of 494 patients were randomized 1:1 to BVd (N=243) or DVd (N=251). Baseline characteristics were well balanced between arms: approximately half of participants (51%) had received one prior line of therapy, 52% had prior Lenalidomide exposure, 34% were Lenalidomide-refractory, and 28% harbored high-risk cytogenetic abnormalities. The Primary endpoint was PFS as assessed by an Independent Review Committee. Key Secondary endpoints included OS, Duration of Response (DOR), Minimal Residual Disease (MRD) negativity by Next-Generation Sequencing, Overall Response Rate (ORR), and safety.

Primary Analysis: Robust Progression-Free Survival Benefit

At a median follow-up of 28.2 months, the trial met its Primary endpoint. The median PFS was 36.6 months (95% CI, 28.4–not reached) in the BVd arm versus 13.4 months (95% CI, 11.1–17.5) in the DVd arm, corresponding to a 59% reduction in risk of progression or death (HR=0.41; 95% CI, 0.31–0.53; P<0.00001).

BVd achieved higher rates of Complete Response or better with MRD negativity (25% vs 10%) and a more favorable DOR distribution (P<0.001). Median DOR was 35.6 months with BVd compared to 17.8 months with DVd. Treatment benefits with BVd were preserved even after subsequent therapy (PFS2 HR= 0.56; 95% CI, 0.41–0.76). Although median OS was not reached at this time point, a strong trend favored BVd (HR=0.57; 95% CI, 0.40–0.80).

Second Interim Analysis: Statistically Significant OS Advantage

At the second interim analysis, conducted at a median follow-up of 39.4 months, BVd demonstrated a 42% reduction in the risk of death versus DVd (HR=0.58; 95% CI, 0.43–0.79; P=0.00023). Median OS was not reached in either arm, but projected estimates were striking, 84 months for BVd compared with 51 months for DVd. The 3-year OS rate was 74% with BVd versus 60% with DVd, with survival separation evident as early as 4 months and sustained over time.

Subgroup Analysis and FDA Approval

In the subset of patients who had received two or more prior lines of therapy (the population used for regulatory evaluation, N=108 in the BVd and N=109 in the DVd groups), BVd maintained substantial efficacy. Median PFS was 31.3 months (95% CI, 23.5–NR) compared with 10.4 months (95% CI, 7.0–13.4) with DVd (HR, 0.31; 95% CI, 0.21–0.47). Median OS was not reached with BVd and 35.7 months with DVd (HR, 0.49; 95% CI, 0.32–0.76), representing a 51% reduction in risk of death.

Depth of Response and MRD Negativity

The BVd regimen achieved statistically significant improvements in MRD negativity, with rates more than 2.5 times higher than those observed with DVd (P<0.00001). Superior depth and durability of response were reflected in all major efficacy endpoints, including DOR and PFS2, underscoring the potential for more sustained disease control with the Belantamab-containing triplet.

Safety Profile and Ocular Events

Adverse events were consistent with prior experience for the individual agents. Grade ≥3 thrombocytopenia occurred in 56% of patients receiving BVd versus 35% with DVd; grade ≥3 anemia and neutropenia were comparable between groups. Ocular events, a known risk associated with Belantamab mafodotin, were manageable with dose modifications and rarely led to discontinuation. Only 10% of patients in the BVd arm discontinued therapy due to ocular toxicity.

Clinical Implications

The DREAMM-7 results represent the first head-to-head Phase III evidence of a statistically significant OS advantage for a BCMA-targeting therapy in RRMM compared with a Daratumumab-based regimen. The combination of Belantamab mafodotin with Bortezomib and Dexamethasone delivered a tripling of median PFS, a clinically meaningful OS benefit, and deeper MRD-negative responses, establishing a compelling new benchmark for patients experiencing their first relapse or later. These data reinforcing the OS benefit and may solidify BVd as a new standard of care for relapsed or refractory multiple myeloma.

Belantamab Mafodotin, Bortezomib, and Dexamethasone Vs Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Overall Survival Analysis and Updated Efficacy Outcomes of the Phase 3 Dreamm-7 Trial. Hungria V, Robak P, Hus M, et al. Blood (2024) 144 (Supplement 1): 772. https://doi.org/10.1182/blood-2024-200336

Innovating Multiple Myeloma Care: IRAKLIA Confirms On-Body Injector for Subcutaneous Isatuximab as a Safe, Effective Alternative to IV Delivery

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails.

With prevalence of multiple myeloma expected to climb further, disparities in care delivery remain a concern, often linked to treatment access, infusion-center capacity, and patient convenience. Advances in drug delivery technology, particularly subcutaneous (SC) administration, offer an opportunity to bridge these gaps. Compared with intravenous (IV) therapy, SC approaches can shorten administration time, improve comfort, and reduce healthcare resource demands.

However, conventional SC delivery of large-volume biologics can be challenging, often requiring high manual pressure over several minutes and the use of larger needles, both of which may cause discomfort and anxiety for patients and increase the physical burden for nurses. The IRAKLIA trial is the first Phase III study in multiple myeloma to evaluate an On-Body Injector (OBI) for delivering SC Isatuximab (Isa) in combination with Pomalidomide and Dexamethasone (Pd) in Relapsed/Refractory MM (RRMM).

Study Design
IRAKLIA was a global, open-label, randomized, noninferiority Phase III trial enrolling adults with 1 or more prior lines of therapy, including Lenalidomide and a Proteasome Inhibitor. A total of 531 patients were randomized (OBI, N=263; IV, N=268). Participants were assigned 1:1 to receive either:

  • Isa OBI: 1,400 mg SC via an OBI device (Enable Injections, Inc.)
  • Isa IV: 10 mg/kg IV infusion once weekly during cycle 1, then on days 1 and 15 of subsequent cycles.

Both arms received Pomalidomide 4 mg orally, days 1–21 and Dexamethasone 40 mg orally weekly and 20 mg if 75 years or older. Baseline characteristics were generally balanced, although the OBI group had slightly more patients ≥75 years, with higher rates of advanced disease features (soft-tissue plasmacytomas, ISS stage III, reduced renal function, and Lenalidomide-refractory status).

Key coPrimary endpoints were Overall Response Rate (ORR) and steady-state trough concentration (Ctrough) at cycle 6 day 1. The trial also assessed ≥Very Good Partial Response (≥VGPR) rate, pharmacokinetics at week 4, incidence of Infusion-related Reactions (IRs), and patient-reported satisfaction.

Efficacy after 12 Month Median Follow-Up

  • ORR: 71.1% (OBI) vs 70.5% (IV); noninferiority demonstrated (RR 1.008; 95% CI, 0.903–1.126).
  • Ctrough: Higher with OBI (geometric mean ratio 1.532; 90% CI, 1.316–1.784), meeting noninferiority criteria.
  • ≥VGPR rate: Comparable-46.4% (OBI) vs 45.9% (IV).
  • Results were consistent across most subgroups, with a lower response in patients ≥75 years in the OBI arm, likely due to baseline disease imbalances.

Safety

  • Grade ≥3 treatment-emergent adverse events occurred in 81.7% (OBI) vs 76.1% (IV).
  • Infusion-related Reactions were dramatically reduced with OBI (1.5%) compared with IV (25%).
  • Injection site reactions with OBI were rare (0.4%, all grade 1–2).
  • No unexpected safety signals emerged; the profile aligned with prior Isa studies.

Patient Experience

  • Satisfaction rates were higher with OBI (70.0%) than IV (53.4%).
  • Nearly all OBI doses (99.9%) were completed without interruption.

Clinical Implications

Reduced Infusion Reactions and Improved Workflow
The marked drop in Infusion-related Reactions incidence with OBI is likely related to slower systemic absorption from interstitial tissue compared with rapid IV exposure. This improvement not only enhances patient comfort but also reduces infusion chair time and the need for monitoring, potentially enabling at-home administration by healthcare professionals in select patients.

Efficiency for Nursing Staff
OBI eliminates the sustained manual pressure required for large-volume SC pushes and replaces large-bore needles with a smaller, hidden 30-gauge needle. This reduces nurse fatigue, frees up clinical resources, and may lower patient anxiety during injections.

Potential for Home Administration and Broader Access
Given the convenience and safety profile, OBI administration could be extended beyond the infusion center. This aligns with ongoing efforts to decentralize cancer care, expand access to anti-CD38 therapy, and improve treatment adherence in multiple myeloma.

Future Directions
Isa OBI is being further evaluated in other multiple myeloma settings, including:

  • IZALCO: Isa-Kd in RRMM (NCT05704049)
  • IsaSoCut: Isa-VRd in transplant-ineligible NDMM (NCT05889221)
  • GMMG-HD8: Isa-VRd in NDMM (NCT05804032)

Upcoming analyses from IRAKLIA will also explore the feasibility of at-home dosing.

Conclusion
The Phase III IRAKLIA trial demonstrates that Isa SC delivered via OBI is noninferior to IV administration in RRMM, with equivalent efficacy, favorable pharmacokinetics, and a significantly lower Infusion-related reaction rate. This hands-free delivery method offers a practical, patient-preferred, and resource-efficient alternative to standard IV infusion, potentially transforming anti-CD38 therapy administration in multiple myeloma.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. Ailawadhi S,  Špička I, Spencer A, et al. J Clin Oncol. 2025;43:2527-2537.

 

 

Practice-Changing Insights in Myeloma Prevention: DARZALEX® Shows Landmark Results in High-Risk Smoldering Myeloma (AQUILA Trial)

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM.

Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. Smoldering Multiple Myeloma or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years.

The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3 g/dL, IgA M-spike of at least 2 g/dL or a urinary Bence Jones protein level of more than 1 g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Immunoparesis describes the reduction of normal/polyclonal immunoglobulin levels and is commonly seen in conditions such as MM, SMM, and MGUS. This phenomenon involves a decline in immunoglobulins not associated with the malignant clone-for instance, in IgG-type myeloma, levels of IgA and IgM are typically decreased. The severity of immunoparesis at diagnosis serves as an independent prognostic indicator in newly diagnosed multiple myeloma. Patients presenting with lower levels of uninvolved immunoglobulins tend to experience shorter Progression-Free Survival (PFS) and Overall Survival (OS).

High-risk SMM has long posed a therapeutic dilemma—patients face a substantial risk of progression to symptomatic disease, yet no standard treatment has been approved. Traditionally, observation has remained the mainstay approach, despite the documented risk of end-organ damage. Daratumumab (DARZALEX®), a CD38-targeting monoclonal antibody already approved for multiple myeloma, has now been evaluated in this pre-malignant population through the pivotal Phase 3 AQUILA trial.

Study Design: The AQUILA Trial
AQUILA was a global, multicenter, open-label, randomized Phase 3 study, evaluating the efficacy of subcutaneous Daratumumab monotherapy versus active monitoring in patients with high-risk SMM. Conducted across 124 sites in 23 countries, the trial enrolled 390 patients, randomized 1:1 to receive either subcutaneous Daratumumab 1800 mg with recombinant Hyaluronidase PH20 weekly during cycles 1–2, biweekly during cycles 3–6, and monthly thereafter for 39 cycles for 36 months, or until disease progression (N=194), or active monitoring (N=196).

Eligibility criteria included:

  • 10% or more clonal plasma cells in bone marrow
  • At least one high-risk feature, such as:
    • Serum M-protein 30 g/L or more
    • IgA subtype
    • Immunoparesis (2 or more uninvolved Ig isotypes)
    • FLC ratio between 8 and 100
    • Clonal plasma cells more than 50% but less than 60%

The Primary end point was Progression-Free Survival (PFS) defined as progression to active multiple myeloma as assessed by an Independent Review Committee in accordance with International Myeloma Working Group (IMWG) diagnostic criteria.

Efficacy Outcomes
After a median follow-up of 65.2 months, results demonstrated a clear and significant benefit for Daratumumab over observation:

  • Progression-Free Survival (PFS):
    • 5-year PFS: 63.1% with Daratumumab vs 40.8% with active monitoring
    • Hazard ratio (HR): 0.49 (95% CI: 0.36–0.67; P<0.001)
  • Overall Survival (OS):
    • 5-year OS: 93.0% with Daratumumab vs 86.9% with active monitoring
    • HR for death: 0.52 (95% CI: 0.27–0.98)

These results support a 51% reduction in risk of progression to active multiple myeloma or death with early Daratumumab intervention.

Safety Profile
Daratumumab was well tolerated:

  • Grade 3–4 hypertension was the most frequent serious AE (5.7%)
  • Treatment discontinuation due to AEs occurred in only 5.7%
  • No new safety signals were observed
  • Quality of life was maintained throughout treatment and comparable to active monitoring

Clinical Interpretation
The AQUILA trial provides the strongest evidence to date supporting early therapeutic intervention in high-risk SMM. Unlike prior trials (e.g., QuiRedex, ECOG E3A06), which demonstrated benefit with Lenalidomide-based regimens but did not lead to regulatory approval, AQUILA offers compelling long-term survival and disease control data using a well-tolerated, single-agent regimen. Importantly, patient-reported outcomes indicated no decline in quality of life, reinforcing the feasibility of early intervention.

Context & Historical Comparison

  • In QuiRedex (Rd vs monitoring), median time to progression was prolonged (9.5 vs 2.1 years), but approval was not pursued
  • ECOG E3A06 (Lenalidomide vs monitoring) showed improved PFS but no OS benefit
  • AQUILA uniquely demonstrates both PFS and OS advantages with a favorable safety profile, positioning Daratumumab as a potential new standard for early treatment of high-risk SMM

Conclusion
The AQUILA study marks a paradigm shift in the management of high-risk Smoldering Multiple Myeloma. Subcutaneous Daratumumab monotherapy not only halved the risk of progression or death but also preserved quality of life, supporting its consideration as the first active treatment option for this high-risk population. Oncologists should engage in shared decision-making with high-risk SMM patients regarding early therapeutic intervention, particularly in the context of these compelling new data.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. Dimopoulos MA, Voorhees PM,  Schjesvold F, et al. for the AQUILA Investigators. N Engl J Med 2025;392:1777-1788

SARCLISA® with VRd Regimen for Transplant Ineligible Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024, and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails. Additionally, Isatuximab infusions are less cumbersome.

The FDA in September 2024, approved Isatuximab with Bortezomib, Lenalidomide, and Dexamethasone for adults with newly diagnosed multiple myeloma who are not eligible for Autologous Stem Cell Transplant (ASCT). This approval was based on the IMROZ trial (NCT03319667), which was an international, multicenter, open-label, Phase 3, randomized, controlled trial, designed to evaluate the efficacy and safety of Isatuximab in combination with the established regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRd) compared to VRd alone. This study aimed to address a critical gap in treatment options for patients with newly diagnosed multiple myeloma who are ineligible for ASCT, a situation often faced by older patients or those with significant comorbidities. A total of 446 patients, aged 18 to 80 years, with symptomatic, previously untreated multiple myeloma were randomly assigned in a 3:2 ratio to receive either the Isatuximab-VRd regimen (N=263) or the standard VRd regimen alone (N=181). The Induction phase of the treatment consisted of 4 cycles, with each cycle lasting 6 weeks. Patients in the Isatuximab-VRd Group received Isatuximab 10 mg/kg IV weekly during Cycle 1, then every 2 weeks for subsequent cycles. Patients received subcutaneous Bortezomib (1.3 mg/m²) on specified days, along with oral Lenalidomide (25 mg daily for 14 days) and Dexamethasone (20 mg on specified days). The VRd group received the same VRd regimen without Isatuximab. Following the induction phase, both groups continued treatment with a regimen consisting of Lenalidomide and Dexamethasone. For the Isatuximab-VRd group, Isatuximab was given every 2 weeks, transitioning to monthly administration starting at Cycle 18. The median patient age was 72 years and treatment groups were well balanced. The Primary endpoint of the trial was Progression-Free Survival (PFS), assessed by an Independent Review Committee in accordance with International Myeloma Working Group criteria. Secondary endpoints included Complete Response (CR) or better, Minimal Residual Disease (MRD) negativity in patients achieving a Complete Response, assessed at a sensitivity level of 10⁻⁵ using Next-Generation Sequencing, Overall Survival (OS) and Quality of Life measures.

The results from the interim analysis at a median follow-up of 59.7 months demonstrated a significant improvement in PFS for the Isatuximab-VRd group compared to the VRd group. The 60-month PFS was estimated at 63.2% in the Isatuximab-VRd group versus 45.2% in the VRd group (HR=0.60; P<0.001), indicating a 40% reduction in the risk of disease progression or death for the Isatuximab group. Approximately 75% of patients in the Isatuximab-VRd group achieved a Complete Response or better compared to 64.1% in the VRd group (P=0.01). Higher rates of MRD negativity (55.5% vs. 40.9%; P=0.003) were also observed in the Isatuximab group. The safety profile of the Isatuximab-VRd combination mirrored that of established regimens, with no new safety signals identified. Incidences of serious adverse events were comparable between the two groups, though a slight increase in infections and neutropenia was noted with the addition of Isatuximab.

In conclusion, the results from the IMROZ trial clearly indicate that the addition of Isatuximab to the VRd regimen provides significant benefits in terms of Progression-Free Survival and Response Rates in patients with newly diagnosed multiple myeloma who are ineligible for transplantation, addressing an important unmet need. Further follow-up and analyses will continue to elucidate the long-term benefits and safety of this promising therapeutic strategy.

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Facon T, Dimopoulos M-A, Leleu XP, et al. for the IMROZ Study Group. N Engl J Med 2024;391:1597-1609.

Measuring Lymphocyte Count May Predict Response to CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median Progression-Free Survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with relapsed or refractory myeloma often have disease that is refractory to multiple drugs.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase III studies involving patients with relapsed or refractory myeloma.

The researchers conducted an insightful study aimed at identifying predictive biomarkers to enhance the efficacy of CAR T-cell therapy for patients with relapsed or refractory multiple myeloma (MM). While CAR T-cell therapy has revolutionized treatment for B-cell malignancies and other blood cancers, the high cost of therapy and variability in patient response highlight the need for precise biomarkers that could guide clinicians in selecting the best candidates for this therapy. This research delves into the factors that affect patient response, specifically focusing on the role of the Absolute Lymphocyte Count (ALC) in predicting treatment success and disease progression.

The researchers analyzed data from 156 patients with relapsed or refractory multiple myeloma, treated with two BCMA-targeting CAR T-cell therapies: Ciltacabtagene autoleucel (CARVYKTI®) and Idecabtagene vicleucel (ABECMA®). These patients, who were treated between 2017 and 2023, had previously undergone several lines of therapy, rendering them refractory to conventional treatments. The research team collected and analyzed Absolute Lymphocyte Counts (ALC), a key immune marker, from 5 days before the CAR-T infusion for up to 15 days post-infusion, to determine if ALC could be used as a predictive biomarker for patient outcomes. The focus on this early post-infusion window was based on the hypothesis that the expansion of T cells, which is critical for the effectiveness of CAR T-cell therapy, would be reflected in the ALC levels. This study sought to correlate early ALC levels with long-term outcomes such as depth of response, Progression-Free Survival (PFS), and overall Duration of Response (DoR).

The findings demonstrated that ALC is a strong predictor of response to CAR T-cell therapy, with higher ALC values correlating with deeper responses and longer PFS. Specifically, patients who had an ALC maximum (ALCmax) above 1.0 x 103/µL during the first 15 days after infusion experienced a significant improvement in PFS, more than five times greater, compared to those with lower ALC counts. Patients with ALCmax above 1.0 x 103/µL had a median PFS of 33.1 months, while those with counts at or below 0.5 x 103/µL had a significantly shorter PFS of 6 months. The high-risk group, with an ALCmax of 0.5 or less x 103/µL, showed over three times the likelihood of early disease progression compared to their counterparts with higher ALC counts, making them a vulnerable population within the study cohort. The analysis also took into account a variety of potential confounding factors, such as patient age, previous therapies, high-risk cytogenetics, and the specific CAR T-cell product used. Even when these factors were considered, ALC remained an independent prognostic indicator, making it a reliable marker for predicting the depth and duration of response in this setting.

The researchers also explored the biological mechanisms underlying this phenomenon. CAR T-cell therapy relies heavily on the expansion of the infused T cells within the patient’s body. ALC, which includes a count of lymphocytes such as T cells, may serve as a surrogate marker for this expansion. Patients with higher ALC are likely to experience more robust CAR T-cell proliferation, leading to deeper and more durable anti-tumor responses. This aligns with previous findings that T-cell expansion after infusion is closely linked to treatment success. Additionally, the study noted that patients with higher ALC levels were also more likely to experience Cytokine Release Syndrome (CRS), a common side effect of CAR T-cell therapy that results from the rapid activation and expansion of T cells. While CRS can be a challenging complication to manage, its occurrence might also be a marker of effective CAR T-cell therapy.

The identification of ALC as a biomarker has significant implications for clinical practice. Physicians can now use ALC levels measured within the first 15 days post-infusion to guide treatment decisions. For patients with low ALC counts, this early biomarker could signal the need for alternative treatment approaches or additional therapeutic interventions to manage potential relapse. Given the limited options for patients who relapse after CAR T-cell therapy, having this early warning could be vital for planning the next steps in their treatment journey. Conversely, patients with high ALC levels can be reassured that they are more likely to achieve a deep and sustained response, allowing clinicians to optimize follow-up care and monitoring accordingly.

The researchers are further investigating the biological factors that influence ALC levels after CAR T-cell infusion. By analyzing patient samples and conducting deeper biological studies, they aim to uncover why some patients experience robust lymphocyte expansion while others do not. Understanding these underlying mechanisms could lead to new interventions that enhance CAR T-cell expansion, ultimately improving outcomes for a broader range of patients. Identifying potential pre-infusion markers that could predict whether a patient will have a favorable ALC response may be relevant. If such biomarkers can be identified, clinicians might be able to intervene even earlier, adjusting treatment plans before CAR T-cell therapy begins.

Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Saldarriaga MM, Pan D, Unkenholz C, et al. Blood Adv (2024) 8 (15): 3859–3869. https://doi.org/10.1182/bloodadvances.2023012470