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Clinical

JAN-22-TTD0607 - /clinical/multiple-myeloma-rc

In the first article of a 2-part series, Jack Khouri, MD, discussed the challenges that come with the toxicity profile of selinexor and how physicians can manage these adverse events.  

Selinexor Toxicity Requires Careful Management in R/R Multiple Myeloma

In the second article of a 2-part series, Ajay Nooka, MD, MPH, discussed the exciting safety profile of teclistamab and how to manage major adverse events, like cytokine release syndrome, for patients with relapsed/refractory multiple myeloma. 

Teclistamab Toxicities Highly Manageable in R/R Multiple Myeloma

In an interview with Targeted Oncology, Jeffrey R. Schriber, MD, highlighted some of the most recent updates in the field of multiple myeloma, and discussed emerging therapies that show promise.

New Data and Approvals Shape Treatment Strategies in Multiple Myeloma 

On the heels of positive results from GENESIS, a phase 3 study, the FDA has approved the first stem cell mobilization therapy for multiple myeloma.

FDA Approves Aphexda to Aid in HST Mobilization in Patients With Multiple Myeloma

Selecting and sequencing treatments in relapsed/refractory multiple myeloma involves balancing various factors due to limited historical data, as explained by Ajai Chari, MD, at the 2023 SOHO Annual Meeting.






Choosing CAR T-Cell Therapy vs Bispecific Antibodies in Multiple Myeloma

Binod Dhakal, MD, MS, assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, provides background on the phase 3 CARTITUDE-4 study (NCT04181827) of ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of patients with lenalidomide-refractory multiple myeloma.

CARTITUDE-4 study is a global, randomized, controlled, phase 3 study evaluating the dual-binding, BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy, cilta-cel, compared with the standard-of-care (SOC) regimen of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) in lenalidomide-refractory patients with multiple myeloma.

A total of 419 patients were enrolled and randomized in the study, including 208 patients who were treated with cilta-cel and 211 who received SOC. Baseline characteristics were balanced between treatment arms. In the cilta-cel group, 59% of patients vs 63% in the SOC group were cytogenetic high-risk, 24% vs 22% were anti-CD38 refractory, and 33% vs 32% had 1 prior line of therapy.

The primary end point being evaluated in the study is progression-free survival (PFS) , and secondary end points include complete response (CR) or stringent CR rate, overall minimal residual disease (MRD) negativity rate, sustained MRD negativity rate, overall survival, overall response rate, time to worsening of symptoms, PFS on next-line therapy, incidence and severity of adverse events, systemic cytokine concentrations, levels of CAR-T cell activation markers, levels of JNJ-68284528 T-cell expansion and persistence, number of patients with anti-JNJ-68284528 antibodies, and change from baseline in health-related quality of life.

CARTITUDE-4 is a phase 3 randomized study evaluating cilta-cel, which is a BCMA-directed CAR T-cell therapy vs standard-of-care regimens in patients with lenalidomide-refractory multiple myeloma after 1,2, or 3 prior lines of therapy.

 Cilta-cel is a dual binding BCMA-directed CAR T-cell therapy. It is an autologous CAR T product that means the patient's provide T cells which are manufactured to become CAR T cells. Cilta-cel has been studied in patients with 3 or more prior lines of therapy and [other] data has shown that cilta-cel is highly effective and the median PFS is almost 3 years in patients with a heavily refractory disease. CARTITUDE-4 is for patients with 1,2, or 3 prior lines of therapy and a little bit less heavily treated, but it's the first randomized study to include patients after the first relapse.

Videos

Binod Dhakal, MD, MS, provides background on the phase 3 CARTITUDE-4 study of ciltacabtagene autoleucel for the treatment of patients with lenalidomide-refractory multiple myeloma.

News

Background on the CARTITUDE-4 Trial of Cilta-Cel in Multiple Myeloma 

Prerna Mewawalla, MD, a hematologist at Allegheny Health Network, explains how the treatment landscape for multiple myeloma is growing.

Recently, the introduction of bispecific antibodies has excited hematologists, due to the significant efficacy and tolerability shown with these agents in the clinical trial setting. Teclisatamab-cqyv (Tecvayl), a bispecific B-cell maturation antigen CD3 T-cell engager was granted approval in 2022 for the 

treatment of adults with relapsed or refractory multiple myeloma

 who were previously treated with at least 4 prior lines of therapy, including proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Moreover, bispecifics can be an alternative to chimeric antigen receptor (CAR) T-cell therapy, says Mewawalla. Another key regimen for multiple myeloma is the use of 4-drug combination in the frontline setting. For example, daratumumab (Darzalex) plus lenalidomide (Revlimib), bortezomib (Velcade), and dexamethasone 

dara-RVD) appears to be a promising treatment option for patients with multiple myeloma

 We have so many new agents that have been approved for myeloma or are in the process of it. The ones that I am most excited about are our bispecifics. The first one, which was recently approved, was teclisatamab, with response rates of over 60% and with the progression-free survival [PFS] of over a year. Prior to the teclisatamab, all the other single agents, which were approved in this space, generally had a response rate of around 30%. For a single agent to have a response rate of over 60% in a patient population that is so heavily pretreated is just amazing.

The other advantage of having teclisatamab is that we also have a CAR T shortage, and a lot of our patients were not able to get to CAR T. Having teclisatamab has also helped these patients who will normally have no other option to received something else. That is something I'm excited about.

 Another drug, which is not technically new, but it has been practice-changing, is using quadruplets upfront. We’re using daratumumab plus lenalidomide [bortezomib, and dexamethasone, or dara-RVD, in the upfront setting in more and more patients to get deeper responses.

Prerna Mewawalla, MD, discusses how the treatment landscape for multiple myeloma is growing. 

An Explosion of Agents for Myeloma Treatment

Binod Dhakal, MD, MS, assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, discusses results from the phase 3 CARTITUDE-4 study (NCT04181827) of ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with lenalidomide-refractory multiple myeloma.

Cilta-cel achieved a 74% reduction in the risk of disease progression or death compared with standard of care treatment in CARTITUDE-4, according to a presentation given by Dhakal at the 2023 American Society of Clinical Oncology Annual Meeting.

Dhakal says the results show that cilta-cel is highly effective for treating lenalidomide-refractory multiple myeloma. In addition to the progression-free survival advantage, the response rate, and minimal disease negativity rate shown with cilta-cel were also positive.

The primary end point of the study was progression-free survival, and we saw cilta-cel significantly reduced the risk of disease progression or death vs standard-of-care by 74%. The hazard ratio was 0.26. The median PFS at 16 months follow-up was not reached in the cilta-cel arm compared with 11.8 months in the standard-of-care arm, and the 12-month PFS rates were 76% in the cilta-cel arm compared with 49% in the standard-of-care arm. We also observed that cilta-cel consistently prolonged the progression-free survival in all subgroups, including the key subgroups of patients with high-risk disease, soft tissue plasmacytoma, and triple-class refractory disease.

| Cilta-cel led to significantly higher rates of response and default response compared with standard-of-care. The overall response rates are 85% and better in patients with cilta-cel vs 67% with the standard-of-care. When looking at the MRD negativity and the complete response rates, the complete response rates were 72% in the cilta-cel arm vs 22% in the standard-of-care arm, and MRD negativity rates for all patients were 61% in the cilta-cel arm vs 16% in the standard-of-care arm. These results suggest cilta-cel is highly effective and provides superior efficacy responses compared with standard-of-care in the study.

A phase 3 study of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma is discussed by Binod Dhakal, MD, MS.


Dhakal Recaps Findings From the CARTITUDE-4 Study

Prerna Mewawalla, MD, a hematologist at Allegheny Health Network, discusses how she approaches the choice of therapy for relapsed/refractory multiple myeloma now that many different options are available for patients.

Mewawalla says she bases her choice of therapy on 3 factors. The first is what therapies they have previously received and are refractory to, which could influence the option to use another drug in a class such as a proteasome inhibitor (PI) or anti-CD38 antibody.

She also considers what comorbidities patients have and the level of toxicity that they can tolerate. Some agents are significantly toxic and patients have already undergone combination therapy in earlier lines. Finally, she will look for particular genetic alterations, such as translocation (11;14), which was associated with antimyeloma response with venetoclax (Venclexta).

In patients who are relapsed/refractory after multiple lines of therapy, they are eligible for chimeric antigen receptor (CAR) T-cell therapy or bispecific agents such as teclistamab (Tecvayli), which Mewawalla says has led to positive results for her heavily pretreated patients.

 In the relapsed/refractory setting, I generally choose my treatments based on 3 different things. First, what have they already been on—so what are the refractory to? Are they [lenalidomide (Revlimid)]-refractory? Are they PI-refractory or are they anti-CD38-refractory? Then, I decide what treatment to use. I also base it on what their comorbidities are and what they can tolerate. The third thing I base it on is if they have any unique genetic mutations such as translocation (11;14), in which cases I can use venetoclax [Venclexta]. It's a unique population where you can use venetoclax, and that's how I decide what to do in my relapsed/refractory population early on. After they've been through a lot of these agents and they come to a point where they either can get a bispecific [antibodies] or CAR T-[cell therapy]. Because of access to CAR T, I have been using the teclistamab earlier on, and so far, have had positive results with that.

Prerna Mewawalla, MD, discusses how she approaches the choice of therapy for relapsed/refractory multiple myeloma now that many different options are available for patients.

Key Factors for Therapy Choice in Relapsed/Refractory Multiple Myeloma

Yi Lin MD, PhD, a hematologist/oncologist, consultant, Division of Hematology, Department of Internal Medicine, enterprise leader, Cancer Regenerative Medicine, Biotherapeutics, and Biomanufacturing, Mayo Clinic Comprehensive Cancer Center, associate medical director, Center for Regenerative Biotherapeutics, and consultant, Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, discusses the CARTITUDE-1 study (NCT03548207), which supports the use of ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of relapsed or refractory multiple myeloma.

Lin explains that the BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy, cilta-cel demonstrated deep and durable responses in 

, which consisted of a heavily pretreated group of patients with relapsed/refractory multiple myeloma. The overall response rate, as published in 

, was 97% (95% CI, 91.2%-99.4%), which included stringent complete response in 67% of patients. Moreover, the was a short time to first response of 1 month.

 Cilta-cel, also known as now Carvykti as a regulatory approved CAR T is an autologous CAR T that are made from patient's own white blood cells, a subgroup of white blood cells called T cells. B cells are genetically changed to be able to target cells that has BCAM or B-cell maturation antigen markers. And plasma cells, particularly myeloma cells can have a relatively higher expression of these markers on them. So, CARTITUDE-1 is the first registration study that led to the FDA approval where they're used in United States. In this particular trial, patients with multiple myeloma who has had at least 3 prior lines of treatment, and the main backbone of myeloma treatment, which includes a proteasome inhibitor, an image or immunomodulatory drug and a CD38 targeting monoclonal antibody.

 Based on those initial primary results, which [are] already published and peer reviewed, [the] FDA had approved its use now in United States. The approval is for patients who's had 4 prior lines of therapy, including exposure to those drugs that I had talked about.

Yi Lin MD, PhD explains how results from CARTITUDE-1 impact the treatment landscape for relapsed or refractory multiple myeloma.

Lin Reviews Data on Cilta-Cel in Multiple Myeloma

George Nahas, DO, attending physician, and hematology and oncology specialist at Miami Cancer Institute, discusses ongoing research that may shape the future treatment landscape of multiple myeloma.

In recent years, chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers have become available for the treatment of patients with multiple myeloma. However, they are utilized in later lines of therapies. Since they are newer developments, questions remain regarding how to use them, when to use them, and more.

As the field continues to evolve and more options become available for patients with multiple myeloma, Nahas notes that CAR T-cell therapies and bispecifics will likely be moved up into the earlier lines of therapy, even as early as in the second-line setting.

The reason why I think it is important to mention bispecific trials is because not only do we have the MajesTEC trials demonstrating a similar patient population of patients who are relapsed or refractory with later lines of therapy, these are patients who are refractory to the most recent therapy as well, these patients also had a great overall response rate of 60 plus percent, with CR rates as high as 40% or so percent. We have a BCMA bispecific, but are there other bispecifics that we can combine too?

Recent data at ASCO also demonstrated that combining 2 biospecifics did have an overwhelmingly amazing overall response rate of up to 90 plus percent. That is going to be something moving forward. Can we combine bispecific T-cell engagers?

The other question is, when we have to use bispecifics for CAR T, how early can we use them? These are important research points that are certainly being studied now and they'll give us a lot of information in the future on how to treat our patients.

George Nahas, DO, discusses ongoing research that may shape the future treatment landscape of multiple myeloma.


Growing Use of Bispecifics for the Treatment of  Multiple Myeloma 

Ben Derman, MD, assistant professor of medicine at the University of Chicago Medical Center, discusses next steps for using minimal residual disease (MRD)-guided discontinuation of maintenance therapy in patients with multiple myeloma.

The prospective MRD2STOP trial (NCT04108624) permitted patients receiving lenalidomide (Revlimid) maintenance therapy for multiple myeloma to stop based on MRD negativity at the 10

 threshold. After 15 months, only 5 out of 38 patients regained MRD positivity and 2 had biochemical progression.

According to Derman, longer-term follow-up for this study is crucial to see if patients can stay off therapy and remain MRD-negative at 24 or 36 months. This could show that multiple myeloma will not relapse in this subset of patients, and they are potentially cured. Another aspect that is promising is reducing the cost of therapy, as lenalidomide can cost $18,000 a month. Derman calculated that in the 507 months of observation among these 38 patients, $9 million were saved, not counting the costs of the trial and patients who needed to reinitiate therapy.

In addition to longer follow-up, Derman says that investigators are collecting quality-of-life surveys and creating a formal cost-saving analysis. They are also trying to use peripheral blood tests to reduce the need for bone marrow biopsies for MRD testing.

 What's going to be important is to see what happens beyond a year, what happens at 24 months, what's going to happen at 36 months, and try to see, is 10

 negativity going to be able to tell us who can come off of therapy safely without worrying about their disease coming back? That may help us define patients who may be cured of their myeloma, which is a controversial concept. I think what's encouraging is the fact that when you think about $18,000 a month for lenalidomide right now in the United States and you multiply that by 507 months of observation that we had just in this short follow-up on the study, we actually saved about $9 million US dollars from stopping lenalidomide alone. Now, you have to factor in the cost of testing and reinitiating treatment in patients who relapse, but that's still going to lead to significant cost savings on the order of millions of dollars.

 What we're looking for is longer follow-up right now. We are actually collecting quality-of-life surveys that we hope to be able to share soon, do a formal cost savings analysis, and then also try to incorporate some peripheral blood tests that might be able to help circumvent the need for bone marrow biopsies in the future.

Ben Derman, MD, discusses next steps for using minimal residual disease-guided discontinuation of maintenance therapy in patients with multiple myeloma.

Next Steps for Using MRD to Guide Maintenance Therapy for Multiple Myeloma

George Nahas, DO, attending physician, and hematology and oncology specialist at Miami Cancer Institute, discusses recent and ongoing research that has impacted the current treatment landscape for patients with multiple myeloma.

According to Nahas, the use of immunotherapy has proven to be beneficial in this space. Specifically, treatment with chimeric antigen receptor (CAR) T-cell therapy and bispecifics have shown promise for patients with multiple myeloma.

, has shown promise with the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti). In the trial, treatment with cilta-cel led to a significant improvement in progression-free survival vs standard-of-care (SOC) pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) in patients with lenalidomide-refractory multiple myeloma who received 1 to 3 prior lines of therapy.

In the interview with Targeted OncologyTM, Nahas highlights these updated findings that show promising efficacy with the use of CAR T-cell therapy for this patient population.

 The most relevant topic in the current landscape is probably the use of immunotherapy, specifically CAR T cells and bispecific T-cell engagers in later lines and even earlier lines of therapy, and when to use them. These are new therapies. They are available for later lines of therapy. For example, I mentioned CAR T cells first because they are the most talked about and have the greatest efficacy so far.

 We have the updates to the CARTITUDE-4 trial for our patients with relapsed/refractory myeloma. This is a phase 1/2 trial. These are patients who are triple-class refractory with 4 lines or later treatment. Originally, results demonstrated 95% plus, 98% overall response rate with high complete response rates as well. This is a later line treatment for patients who are difficult to find good responses like this for.

George Nahas, DO, discusses recent and ongoing research that has impacted the current treatment landscape for patients with multiple myeloma. 


MULTIPLE MYELOMA

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