Tag: Multiple Myeloma

Late Breaking Abstract – ASCO 2026: CEL MoDs Significantly Extend Progression-Free Survival in Relapsed and Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 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.

Modern therapies,including Proteasome Inhibitors, Immunomodulatory drugs, and anti-CD38 antibodies, have extended survival to nearly a decade. However, patients whose disease becomes resistant to these treatments face poor outcomes with a median survival of less than 1 year. There is a critical need for novel, effective therapies with new mechanisms of action.

Targeted Protein Degradation

Cereblon is a key human protein encoded by the CRBN gene that acts as a primary target for immunomodulatory drugs (IMiDs) like Lenalidomide, Pomalidomide, and Thalidomide. It functions as a receptor that labels specific proteins for cellular destruction, driving tumor cell death and activating the immune system.

CELMoDs (Cereblon E3 Ligase Modulators) are a new class of highly potent oral medications designed primarily to treat multiple myeloma. They work as targeted “molecular glue” by binding to the cereblon protein, similar to immunomodulatory drugs. However, they bind with much higher affinity and induce a more active, “closed” conformation. This enhanced biochemical grip allows them to be effective even in patients whose disease has become resistant to standard IMiDs. Once cereblon is activated by the CELMoD, it acts as a garbage disposal signal (ubiquitin) to mark specific target proteins, most notably Ikaros (IKZF1) and Aiolos (IKZF3), for destruction by the cell’s proteasome.

Ikaros (IKZF1) and Aiolos (IKZF3) are zinc-finger transcription factors that regulate lymphocyte development. These transcription factors in many hematological malignancies such as multiple myeloma and leukemia act as rogue cancer-driving proteins, supporting cancer cell survival by repressing tumor suppressors and driving oncogene expression, and are heavily relied upon by myeloma cells to survive and multiply.

When CELMoDs destroy these proteins, it arrests the cancer cell’s growth cycle and actively triggers apoptosis (programmed cell death). Further, Destroying Ikaros and Aiolos removes the natural brakes that suppress immune function, allowing T cells and Natural Killer (NK) cells to better attack the tumor.

Prominent CELMoDs under study include Iberdomide and Mezigdomide, and are being investigated both as standalone therapies and in combination with other treatments like monoclonal antibodies for patients who have Relapsed/Refractory Multiple Myeloma (RRMM).

Mezigdomide, an investigational oral cereblon E3 ligase modulator (CELMoD), has been specifically engineered to promote rapid and potent degradation of the transcription factors Ikaros and Aiolos. Compared with earlier immunomodulatory agents, Mezigdomide demonstrates enhanced anti-myeloma activity and greater immune stimulation in preclinical studies, including restoration of T-cell function and reversal of immune exhaustion. The Phase 3 SUCCESSOR-2 trial evaluated whether adding Mezigdomide to Carfilzomib and Dexamethasone could improve outcomes in this difficult-to-treat patient population.

SUCCESSOR-2 Study Design

SUCCESSOR-2 (NCT05552976) is a global, randomized, open-label, Phase 3 trial enrolling adults with RRMM who had received at least one prior line of therapy, including both Lenalidomide and an anti-CD38 monoclonal antibody. The study used a seamless two-stage design, with the initial stage identifying the optimal Mezigdomide dose before proceeding to the confirmatory efficacy comparison.

Patients received Mezigdomide combined with weekly Carfilzomib and Dexamethasone (MeziKd), or Carfilzomib plus Dexamethasone (Kd). Following dose optimization, the 1.0-mg Mezigdomide dose was selected for the second stage of the study. The Primary endpoint was Progression-Free Survival (PFS), while Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, Minimal Residual Disease negativity, time to next treatment, and patient-reported Quality of Life.

Clinically Meaningful Improvement in Disease Control

The efficacy analysis included 479 patients, with 288 receiving MeziKd and 191 receiving Kd alone. Participants represented a heavily pretreated population with substantial treatment resistance. More than 92% had prior exposure to all three major therapeutic classes, nearly 86% were refractory to anti-CD38 therapy, and approximately 76% were refractory to Lenalidomide. Over one-third had previously received Pomalidomide, and a smaller proportion had been exposed to anti-BCMA therapy.

After a median follow-up of 10.6 months, MeziKd significantly prolonged PFS compared with Kd alone. Median PFS reached 18.0 months with the Mezigdomide regimen versus 8.3 months for the control arm, corresponding to a 52% reduction in the risk of disease progression or death (HR=0.48; P<0.0001). Importantly, the benefit was consistently observed across clinically relevant subgroups, including patients treated at first relapse, those with more than two prior lines of therapy, individuals with high-risk cytogenetic abnormalities, patients with extramedullary disease, and those aged 75 years or older.

Treatment responses also favored the investigational regimen. The ORR increased to 80.2% with MeziKd compared with 53.4% for Kd alone, while Complete Responses or better were achieved in 26.7% and 8.9% of patients, respectively. Patients receiving MeziKd also remained on therapy longer than those receiving the standard regimen.

Safety Profile Remains Predictable

The safety findings were consistent with previous clinical experience using Mezigdomide and with the known toxicities of the individual treatment components. Grade 3 or 4 treatment-emergent adverse events occurred more frequently with MeziKd than with Kd alone, largely reflecting higher rates of neutropenia and infections. Grade 3-4 neutropenia was observed in 61.1% of patients receiving MeziKd compared with 9.1% in the control arm, while Grade 3-4 infections occurred in 34.0% and 15.6% of patients, respectively. Despite these differences, fatal infections remained uncommon in both treatment groups, and adverse events were generally considered manageable with appropriate supportive care and monitoring.

Clinical Perspective

SUCCESSOR-2 provides compelling evidence that Mezigdomide combined with Carfilzomib and Dexamethasone can substantially improve clinical outcomes in patients with RRMM previously exposed or refractory to Lenalidomide and anti-CD38 therapy. The nearly 10-month improvement in median PFS, together with higher response rates across multiple high-risk subgroups, highlights the potential of cereblon E3 ligase modulation as an important therapeutic strategy in contemporary myeloma management.

As treatment sequencing continues to evolve and more patients become refractory to frontline therapies, MeziKd has the potential to become an important option beginning at first relapse and may represent a future standard-of-care regimen pending regulatory review and longer-term survival follow-up.

Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 SUCCESSOR-2 trial. Richardson PG,  Schjesvold F, Fu C, et al. J Clin Oncol 44, LBA7506(2026)

Breakthrough Results from the CARTITUDE-4 Trial: A Major Step Forward in Multiple Myeloma Treatment

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 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.

Modern therapies,including Proteasome Inhibitors, Immunomodulatory drugs, and anti-CD38 antibodies, have extended survival to nearly a decade. However, patients whose disease becomes resistant to these treatments face poor outcomes with a median survival of less than 1 year. There is a critical need for novel, effective therapies with new mechanisms of action

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.

CAR T-Cell Therapy & BCMA Targeting

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells to upregulate cytokine production and promote the expansion of the engineered CAR T-cells.

Ciltacabtagene autoleucel (Cilta-cel; CARVYKTI®), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy indicated for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to Lenalidomide.

 CARTITUDE-4 Study

CARTITUDE-4 is an ongoing open-label, multicenter, randomized Phase III trial conducted to compare Cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with Lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of Cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the Cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and Cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single Cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the Cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

In the first interim analysis, a single Cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies

The researchers in this publication reported a prespecified second interim analysis of OS and an updated analysis of PFS in the intention-to-treat population. New data from the CARTITUDE-4 study highlight the significant clinical benefits of Cilta-cel in patients with Lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy.

Key Efficacy Findings

With a median follow-up of nearly 34 months patients receiving Cilta-cel experienced substantially longer disease control. Median PFS was not reached, compared with 11.8 months for those on standard therapy, representing a 71% reduction in the risk of progression or death.

Overall Survival outcomes also favored Cilta-cel. While median OS was not reached in either group, treatment with Cilta-cel led to a 45% reduction in the risk of death, a statistically significant improvement.

At 30 months, approximately 59% of Cilta-cel patients were alive and progression-free vs 26% with standard care. Around 66% remained treatment-free after a single infusion.

Cilta-cel achieved higher rates of sustained MRD negativity, indicating deeper and more durable responses.

Safety Overview

Safety outcomes were evaluated in 208 patients per group. Grade 3 Adverse Events (AEs) were 14% with Cilta-cel versus 37% with standard of care and Grade 4 AEs were 75% with Cilta-cel versus 56% with standard of care and was most commonly neutropenia in both groups. Treatment-Related Deaths was 3% with Cilta-cel and 2% with standard therapy. Most were linked to infections.

Why This Matters

CARTITUDE-4 is the first Phase 3 trial to demonstrate a significant Overall Survival benefit with CAR T-cell therapy in multiple myeloma. These findings reinforce the potential of Cilta-cel as an earlier-line treatment option. Even as newer therapies continue to emerge, Cilta-cel shows competitive, and in many cases superior outcomes, including notably higher MRD-negative response rates compared with other modern regimens.

Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Einsele H, San-Miguel J, Dhakal B et al. The Lancet Oncology, 2026;27:254-268

New Treatment Guidelines for Multiple Myeloma

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 patients are expected to die of the disease.

Recommendations on the treatment of multiple myeloma, was first published jointly by ASCO and Cancer Care Ontario in 2019. These two organizations jointly updated these recommendations to provide guidance, following the introduction of new therapies and review of 161 relevant randomized trials.

This clinical practice guideline update focused on four topics.

Smoldering Multiple Myeloma:
1.1. Patients with high-risk smoldering multiple myeloma may be offered active monitoring or Daratumumab (for up to 36 months). Lenalidomide is not routinely recommended.

Qualifying Statements for Recommendation 1.1:
In the AQUILA trial, high-risk smoldering multiple myeloma was defined as ≥10% clonal plasma cells in bone marrow and at least one of the following: (1) a serum M-protein level of at least 3 g/dl; (2) IgA smoldering multiple myeloma; (3) immunoparesis with reduced levels of two uninvolved immunoglobulin isotypes; (4) a ratio of involved FLCs to uninvolved FLCs (FLC ratio) in serum of 8 to <100; (5) a percentage of clonal plasma cells in bone marrow of more than 50% to <60%.
It should be noted that this definition differs from other contemporary criteria for high-risk smoldering multiple myeloma and that using the AQUILA definition of high-risk may classify some patients as high-risk who would not meet high-risk criteria in other classification systems. Therefore, careful discussion and consideration of individual patient factors is essential when evaluating management options.

1.2. Therapy is not recommended for patients with smoldering multiple myeloma who are not at high risk

1.3. Active multiple myeloma should be excluded using current diagnostic algorithms and procedures for smoldering multiple myeloma.


Transplant-Eligible MM: Evaluation of Eligibilty
2.1.1. Unless clearly ineligible, patients should be referred to a transplant center at time of diagnosis to determine transplant eligibility.

2.1.2. Eligibility for Autologous Stem Cell Transplantation (ASCT) should not be based solely on a patient’s chronological age or renal function. Instead, a comprehensive assessment of overall health, performance status, frailty, and comorbidities should guide the decision.

Transplant-Eligible MM: Initial Therapy
2.2.1. Transplant-eligible patients should be offered 4 months of induction therapy with either Daratumumab or Isatuximab, each in combination with Bortezomib, Lenalidomide, and Dexamethasone.

Qualifying Statement for Recommendation 2.2.1: In areas where Lenalidomide may be difficult to obtain, Thalidomide is a reasonable substitute in Daratumumab-containing regimens. At least four cycles of therapy should be considered the baseline, but patients can receive more cycles if they must wait for transplant.

2.2.2. For patients who received Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone and planned to receive post-transplant consolidation, two cycles of Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone can be offered following induction therapy and stem cell transplantation.

2.2.3. Carfilzomib can be used as a substitute for Bortezomib in the recommended induction and consolidation regimens, if toxicity is a concern.

Transplant-Eligible MM: Conditioning and Transplant
2.3.1. Up-front transplantation should be offered to all transplant-eligible patients.

2.3.2. Agents associated with stem-cell toxicity such as Melphalan should be avoided in patients who are potential candidates for ASCT.

2.3.3. Regardless of transplant intent, ample stem cells (sufficient for at least two ASCT) should be collected following 4-6 months of induction therapy to allow for potential stem cell transplants later.

2.3.4. High-dose Melphalan is the recommended conditioning regimen for ASCT.

Transplant-Eligible MM: Maintenance
2.4.1. Lenalidomide should be offered as maintenance therapy.

2.4.2. Carfilzomib or Daratumumab may be added to Lenalidomide with or without Dexamethasone.

Transplant-Eligible MM: Measurement of Response
2.5.1. Depth of response should be assessed with each cycle using IMWG criteria as a guideline. Frequency of assessment may be less frequent but at minimum every 3 months, once best response is attained or while receiving maintenance therapy.
MRD status may be valuable in assessing depth of response but should not be relied on as the sole measure.
Whole-body low-dose CT scan, FDG PET/CT and/or diffusion-weighted MRI are the recommended methods for assessing bone lesions at baseline and during surveillance.


Transplant-Ineligible MM: Therapy
3.1.1. A CD38-targeted monoclonal antibody (Daratumumab OR Isatuximab) in combination with Bortezomib, Lenalidomide, and Dexamethasone should be offered to transplant-ineligible patients who are not frail and can tolerate therapy.

3.1.2. Daratumumab, Lenalidomide, and Dexamethasone OR Bortezomib, Lenalidomide, and Dexamethasone are reasonable alternatives in transplant-ineligible patients who are not suitable candidates for quadruplet therapy

Transplant-Ineligible MM: Goals of Therapy and Measurement of Response
3.2.1. The goal of initial therapy for transplant-ineligible patients should be achievement of the best quality and depth of response. Depth of response for all patients should be assessed per Recommendation 2.5.1 regardless of transplant eligibility.

3.2.2. Upon initiation of therapy, one should define patient-specific goals of therapy. Quality of life (including symptom management and tolerability of treatment) should be assessed at each visit to determine if the goals of therapy are being maintained/met, and this should influence the intensity and duration of treatment. The goals should be redefined periodically, based on response, symptoms, and quality of life.

3.2.3. Patients should be monitored closely with consideration of dose modifications based on levels of toxicity, neutropenia, fever/infection, tolerability of adverse effects, performance status, liver and kidney function, and in keeping with the goals of treatment.

 

Relapsed/Refractory MM: Therapy
4.1. Treatment of biochemically relapsed myeloma should be individualized. Factors to consider include patient’s tolerance of prior treatment, rate of rise of myeloma markers, cytogenetic risk, presence of comorbid conditions (ie, renal insufficiency), frailty, and patient preference.

4.2. All relapsed patients with disease-related symptoms due to myeloma should be treated immediately.

4.3. Triplet therapy or T-cell redirecting therapies should be offered to eligible patients with relapsed/refractory multiple myeloma based on the following principles:
a) Whenever possible, patients should be offered treatment regimens that include agents that are different than those in their prior therapies.
b) Triplets should be offered to eligible patients.
c) CAR T-cell therapy should be offered to eligible patients. A thorough patient-centered discussion regarding the risks, benefits, and timing of CAR T-cell therapy is advised.
d) Patient preferences with respect to toxicity tolerance, dose and schedule convenience, and means of administration should be factored in with shared decision making when deciding between triplet or CAR T-cell therapy.
e) CAR T-cell therapy may not be appropriate for patients with rapidly progressive relapsed myeloma given the time required for CAR T-cell manufacturing. In this setting, an agent that is immediately available may be favored over CAR T-cell therapy.
f) If the patient is unable to receive triplet or CAR T-cell therapy (based on tolerability, frailty, access, etc), doublet therapy is reasonable.
g) Bispecific antibodies should be offered to eligible patients (including older and frail patients).
h) The optimal sequencing of therapy is an evolving consideration. In the context of a limited evidence base, sequencing decisions should be made based on patient factors, disease characteristics, mechanism of action, and prior treatment responses.
i) Patients for whom existing options have been exhausted or for whom the risks are likely to outweigh the benefits should be offered best supportive care and hospice referral.

4.4.1. ASCT, if not previously received, may be offered to transplant-eligible patients with relapsed multiple myeloma.

4.4.2. Repeat ASCT should not be offered in relapsed multiple myeloma unless the patient experienced a long remission (typically considered >4-5 years) from first transplant.

Treatment of Multiple Myeloma: ASCO–Ontario Health (Cancer Care Ontario) Living Guideline. Hicks LK,  Messersmith HJ, Hadidi SA, et al. J Clin Oncol. 2026;44:914-941.

 

Teclistamab Plus Daratumumab Sets a New Standard of Care in Early Relapsed or Refractory 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, 36,000 new cases will be diagnosed in 2026, and 10,850 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 2026;394:739-752.

Expert Perspectives on MRD Testing in Multiple Myeloma

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Learn how leading oncologists use MRD to inform treatment strategy and predict relapse risk

Written by: Dr. Gary Simmons & Dr. Kashif Ali
This educational opportunity is sponsored by Adaptive Biotechnologies

Measurable residual disease (MRD) testing has become a valuable tool across the multiple myeloma disease continuum, offering unprecedented insight into disease burden, treatment response, and relapse risk.  NCCN guidelines define MRD negativity as the absence of clonal plasma cells by next generation flow cytometry or next generation sequencing (NGS), at a sensitivity of at least 1 in 10-5 cells, and recommend assessing MRD status after induction, post-transplant, post-consolidation and during maintenance therapy.1  MRD results are shaping key decisions ranging from the role and timing of autologous stem cell transplant to strategies for monitoring and treatment adjustment.  Notably, MRD may be measured from bone marrow or peripheral blood, with data indicating that blood-based testing complements – but does not replace – bone marrow-based testing.2  In this dual-perspective Thought Leader Article, Dr. Gary Simmons (Virginia Oncology Associates) explores how MRD guides transplant decision-making, and Dr. Kashif Ali (Maryland Oncology Hematology) examines the value of blood-based MRD in monitoring response and predicting relapse in multiple myeloma.

The Role of MRD in Informing Autologous Stem Cell Transplant Decision-Making

Despite remarkable advances in multiple myeloma therapy, autologous stem cell transplant still plays a role in the treatment of many patients.  Traditionally, clinical decision-making around transplant was limited to weighing patient-specific factors such as age, comorbidities, and the limited methods that existed to gauge response to induction therapy.  MRD testing provides unprecedented, personalized insight into the induction response achieved by each patient, which directly influences the decision of whether to follow up with transplant.  MRD does not diminish the value of transplant but is rather a stratification tool to identify patients who would derive additional benefit from transplant, from those for which monitoring would suffice.  Several clinical trials including Determination, Perseus and GMMG-HD7 have demonstrated that transplant increases achievement and duration of MRD negativity.3,4,5 Thus, there is a bi-directional relationship in which MRD negativity supports the therapeutic value of transplant, and MRD results help to ensure that patients receive the minimal level of treatment required to achieve optimal outcomes.

In my practice, I evaluate MRD status alongside several variables including patient age, comorbidities, and standard- vs high-risk cytogenetics per the International Myeloma Working Group, when deciding on upfront vs deferred vs no transplant following induction therapy.  In many cases, patient-specific factors significantly influence the weight of MRD results in guiding transplant decision-making.  Notable among these is patient age.  I tend to recommend transplant in young patients, even those who are MRD negative, given data showing a substantially increased disease-free survival6 and improved clinical outcomes in younger fit patients.7  Conversely, there are populations in which MRD negativity would lead me to defer upfront transplant, especially in patients demanding a conservative approach, such as those greater than 75-years-old and/or those with significant comorbidities.  In these patients, MRD negativity often leads me to delay transplant, with the understanding that if/when the patient relapses, there are alternative treatment options to pursue, such as CAR T-cell therapy.  In general, I encourage most standard-risk myeloma patients that if they are MRD negative over the next 5 years, the disease-free is similar with or without transplant; that is encouraging to patients.

As myeloma testing and treatment options rapidly evolve, it’s increasingly important to stay abreast of the gold standard MRD testing options and latest clinical guidelines, to ensure optimal patient outcomes.  We’re always reviewing the options and the depth of MRD testing in our myeloma patients.  At this point, I tend to exclusively use the clonoSEQ assay, as it has a depth of 1×10-6 cells.  We know that depth of MRD and duration of MRD are related to improved clinical outcomes.  Therefore, despite the clinical trials using a MRD cutoff of 1×10-5 cells, we prefer the increased sensitivity offered by clonoSEQ of 1×10-6, for optimal assurance that negativity accurately identifies patients who are truly “MRD negative”.  While this piece is focused on the value of MRD in guiding transplant decisions, it’s worth nothing that assay depth and sensitivity also come to be very important post-stem cell transplant – as MRD negativity after a few years of maintenance can be used to determine if patients can stop maintenance therapy.  In the MASTER trial, MRD status and cytogenetics could predict risk of relapse in two years, highlighting the utility of MRD to help guide continuing maintenance or identify patients who may be able to stop.8 Altogether, these insights underscore how MRD drives personalized care from transplant decision-making to maintenance, ensuring optimal outcomes for patients with multiple myeloma.

The Role of Peripheral Blood-Based MRD Assessment in Monitoring Disease Response

While bone marrow evaluation remains the standard method for MRD assessment, peripheral blood-based MRD testing is an increasingly valuable approach for guiding treatment decisions and monitoring response in multiple myeloma.  MRD negativity by both peripheral blood and bone marrow is associated with an improved progression-free survival (PFS) compared to one modality alone, underscoring their complementary nature.2 Notably, peripheral blood MRD positivity has a 100% positive predictive value of bone marrow MRD positivity.10  Understandably, the negative predictive value of peripheral blood MRD is lower, demonstrating that peripheral blood MRD negativity does not exclude bone marrow disease.11 Therefore, in my practice, blood-based MRD positivity does not prompt confirmatory bone marrow testing, whereas blood-based MRD negativity should be confirmed by bone marrow biopsy, if the goal is to alter treatment.

Confidence in blood-based MRD results is influenced by several factors, including myeloma disease biology and timing.  Patients who present with circulating plasma cells at diagnosis have more aggressive disease and worse outcomes.12,13,14 In the post-transplant setting, studies have shown that patients negative for circulating DNA at three months post-transplant had significantly better PFS (84 vs 31 months) with a positive predictive value of 93.3%.15,16 Those who achieve a complete response will have no detectable plasma cells, as opposed to those who have a relapse, and blood-based MRD testing opens the door to uncover previously undetectable levels of circulating plasma cells.  There are also situations, such as patients with patchy bone marrow involvement or extramedullary disease17, in which MRD assessment of blood is more informative and bone marrow testing alone would be insufficient.18

Timing is another important consideration.  The concordance between bone marrow and blood-based MRD is lowest early after transplant and increases with time, suggesting enhanced reliability of peripheral blood MRD during maintenance.19 Peripheral blood MRD is well suited for longitudinal monitoring post-induction, post-transplant, and especially during maintenance in situations where repeated bone marrow biopsies would not be feasible.10,20 I routinely incorporate peripheral blood MRD testing at these timepoints and find it to be a less invasive alternative that enables more frequent assessment of patients who are reluctant to undergo repeat bone marrow biopsies.20,21 When the goal is to continue maintenance treatment, I utilize serial peripheral blood MRD testing and myeloma-related lab tests.  In these scenarios, I would only check a bone marrow biopsy if the goal were to discontinue or de-escalate treatment.  In the case of a blood-based MRD positivity, given the high concordance between peripheral blood and bone marrow, I would not mandate that an unwilling patient also undergo bone marrow-based MRD.  In my practice and outside of a clinical trial, most patients with blood-based MRD positivity, after hearing about data on concordance, decide not to undergo bone marrow confirmation although I do offer it to them.  Together, the expanding clinical utility of MRD assessment by blood and bone marrow underscores its value for guiding treatment decisions, monitoring response and prognosticating outcomes in multiple myeloma.

References:

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