Based on Data from Pivotal Myeloma Clinical Trials, The Amazing New “Normal” in Myeloma Is Here for Today’s Patients

By Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO 
IMF Medical Advisor 

Scope and Methodology Statement

This article was authored by IMF Medical Advisor Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, and reflects the current standard of care in multiple myeloma treatment as of Spring 2026. Content draws on pivotal clinical trial data — including AQUILA, CARTITUDE-1, and the MajesTEC-9 study supporting Tec-Dara approval — as well as FDA approval announcements and peer-reviewed publications available through March 2026. It is intended for patients, care partners, and oncology professionals seeking an accessible overview of how frontline and early-relapse myeloma treatment has evolved. 

(This article was originally published in the 2026 Spring Edition of the IMF's quarterly publication, Myeloma Today, accessible here (https://www.myeloma.org/resource-library/myeloma-today-spring-2026).)  

Key Takeaways

• The new standard of care in myeloma:
  • Most people with myeloma are now expected to live longer than 10 years after diagnosis — a milestone only recently achieved.
  • Five major developments have fundamentally reshaped how myeloma is treated at diagnosis and first relapse.
• High-risk smoldering myeloma (HR-SMM):
  • For the first time, patients with HR-SMM can choose between monitoring ("watch and wait") or early treatment.
  • The AQUILA trial showed that 3 years of daratumumab (Darzalex) can delay progression to active myeloma and improve overall survival.
• Frontline therapy:
  • Four-drug (quadruplet) regimens are now the standard for newly diagnosed myeloma.
• CAR T-cell therapy:
  • CAR-T is now FDA-approved as early as first relapse, with over 90% response rates and durable remissions lasting more than 3 years.
  • Long-term CARTITUDE-1 data show 33% of heavily pretreated patients were still in remission 5 years later — with no maintenance therapy required.
• Bispecific antibodies at first relapse:
  • As of March 2026, teclistamab + daratumumab ("Tec-Dara") is FDA-approved for second-line treatment.
  • 83% of patients on Tec-Dara remained in remission at 3 years, compared to 29% on standard triplet regimens.
• Antibody-drug conjugates (ADCs):
  • Belantamab mafodotin (Blenrep) has re-emerged as an early-relapse option in combination with other agents, with improved side effect management and a convenient dosing schedule of every 8–12 weeks.
• Looking ahead:
  • Research is accelerating toward CAR-T and bispecifics in frontline settings, trispecific antibodies, new CELMoD agents, and ultimately a cure. 

The progress in myeloma treatment for our patients has been and continues to be remarkable. In the past two decades, more than 20 new drugs have been approved by the U.S. Food & Drug Administration (FDA) for patients with myeloma. The emergence of numerous forms of immunotherapy (https://www.myeloma.org/treatment/using-immune-system-fight-multiple-myeloma) have produced unprecedented outcomes. And all the while, a greater emphasis continues to be placed on a patient’s quality of life.  

These advances are not abstract – they have truly changed the standard of care and improved patient prognosis. In fact, we now expect most people with myeloma to live longer than 10 years after diagnosis, and this is something we couldn’t say until recently. A huge part of the improvement in patient survival is related to how we treat myeloma when it is first diagnosed and then at first relapse.  

The new “norm” of myeloma frontline therapy and treatment at first relapse has radically changed with five very important developments:

1. Treatment of high-risk smoldering multiple myeloma, 
    
2. Quadruplet (4-drug) therapies for frontline treatment, 
    
3. CAR T-cell therapy at first relapse, 
    
4. Bispecific antibodies at first relapse, and 
    
5. The reintroduction of antibody-drug conjugates.

Treatment of HR-SMM

Smoldering multiple myeloma (https://www.myeloma.org/what-are-mgus-smm-mm) (SMM) is divided into two groups: standard-risk and high-risk. There are several models that define high-risk SMM (HR-SMM). The most commonly used model is “20/2/20” risk stratification criteria published by Mayo Clinic in 2018, in which patients with two or more of the following three factors are considered high-risk: 
 

1. Bone marrow plasma cell (BMPC) infiltration > 20%,  
2. Serum monoclonal protein (M-protein) > 2 g/dL, and/or  
3. Ratio of involved-to-uninvolved serum free light chain (sFLC) > 20.

In 2014, the SLiM-CRAB criteria was developed to detect active myeloma earlier, ideally before damage occurs and is felt by the patient. The SLiM-CRAB criteria includes the following features:

S – Sixty percent (60%) plasma cells present in the bone marrow, 

Li –   Light chains ratio of involved-to-uninvolved serum free light chains (sFLC) of 100 or more,  

M – MRI imaging of 2 or more focal lesions in bone marrow, 

C – Calcium elevation due to myeloma,  

R – Renal (kidney) insufficiency due to myeloma,  

A – Anemia (low red blood cell count) due to myeloma,  

B – Bone disease related to myeloma.

But we have now gone much further by intervening before the onset of active myeloma with limited therapy for HR-SMM. The AQUILA clinical trial (https://www.myeloma.org/videos/daratumumab-vs-active-monitoring-high-risk-smoldering-multiple-myeloma-aquila-study-results) demonstrated that 3 years of Darzalex® (daratumumab) therapy in people with HR-SMM can delay the diagnosis of active myeloma and even improve the overall survival (OS). Indeed, people with HR-SMM now have a choice: they can consider monitoring the disease (“wait and watch”) or they can elect to be treated.  

In an era where we seek to intercept all cancers earlier, this is a fundamental shift. I think it signals that in the future we will be able to prevent so much of the damage caused by myeloma when we treat it earlier.

CAR-T (https://www.myeloma.org/emerging-therapies/car-t-cell-therapy)has truly revolutionized the way we treat myeloma. For most patients, no other therapy delivers response rates of over 90% or lasts more than 3 years, the way CAR-T can. The long-term follow-up of the CARTITUDE-1 clinical trial (https://www.myeloma.org/videos/cartitude-4-exceptional-long-term-outcomes-cilta-cel-standard-risk-relapsed-myeloma)shows that 33% of patients were still in remission with no active disease or treatment 5 years later. Keep in mind that this group of patients was very heavily pretreated, with 6 prior lines of therapy on average.  

We know that patient outcomes can improve when treatment is given earlier. Indeed, this is what’s happening with CAR-T, which is now approved by the FDA for use in myeloma as early as first relapse. As we continue to make this modality of treatment safer and more conveniently delivered, even more patients with myeloma will be able to receive CAR-T earlier in their therapy. Furthermore, after a single infusion of CAR-T, myeloma patients typically do NOT require maintenance therapy, and they truly can be off treatment. Personally, I love giving “nada” therapy!

Bispecific antibodies at first relapse

Bispecific antibodies (https://www.myeloma.org/emerging-therapies/bispecific-therapies) bind to two (“bi”) targeted cells, the myeloma cell and the T cell, and activating the T cells to release cytotoxic granules to kill the myeloma cells. Much like CAR T-cell therapy, we have been using bispecific antibodies in late relapse, only after myeloma patients have been treated with 4 prior lines of therapy.  

As of March 2026, the new “norm” is the ability to give bispecific antibodies to patients as soon as their first relapse. Bispecific antibodies are remarkable, allowing us to engage a patient’s T cells without the need of collecting their cells and later re-infusing them. Bispecific antibodies are “off the shelf” drugs that can be delivered to patients without delay.

The FDA granted approval for the use of Tecvayli® (teclistamab-cqyv) in combination with Darzalex Faspro® (https://www.myeloma.org/news-events/multiple-myeloma-news/fda-approves-tec-dara-for-treatment-of-rrmm) (daratumumab + hyaluronidase-fihj), called “Tec-Dara” for short, as a second-line treatment for patients with relapsed or refractory multiple myeloma (RRMM). Second-line treatment refers to the next treat-ment used after patients receive their initial frontline therapy.  

Incredibly, 83% of patients enrolled in the clinical trial who received treatment with Tec-Dara were still in remission at 3 years This is even more remarkable when you consider the comparator: the study patients in the group who received the typical triplet regimens had only 29% of patients in remission at 3 years. It is evident that immunotherapies are now becoming the new standard of care.  

Antibody-drug conjugates

Blenrep® (belantamab mafodotin-blmf) (https://www.myeloma.org/blenrep-belantamab-mafodotin-blmf) is an antibody-drug conjugate (ADC). Blenrep was previously FDA-approved as a mono therapy in late relapse, before re-emerging as an option for earlier-line therapy in combination with either Velcade (https://www.myeloma.org/velcade-bortezomib) or Pomalyst® (https://www.myeloma.org/pomalyst-pomalidomide) (pomalidomide). This unique treatment hooks on to the myeloma cell as an antibody but also delivers a toxin to enhance the destruction of myeloma cells. Blenrep is a very simple therapy to deliver, with most infusions given every  8–12 weeks. Side effects are controlled much better now than before. Blenrep offers yet another way to treat early relapse with a novel immunotherapy drug, giving patients even more choice.

Stay Tuned for News in SMM, CAR T-cell Therapy and Bispecifics at Frontline, as well as New Agents

It is genuinely hard to believe that these five significant developments have occurred so rapidly and that they have now become the new “norm.” I am so thankful for the many choices we can currently provide for our patients, and I am so enthusiastic about the newer approaches that are on their way. Stay tuned for news in smoldering myeloma, frontline therapy with CAR-T and bispecific antibodies, newer CAR-T agents and new bispecific antibodies – and even TRI-specifics, a new drug class of CELMoD agents, and much, much more. The pace of research continues to accelerate; I am excited to see what the next new norm will be soon as we move closer and closer to a cure.