Bispecific Antibodies Excite the Multiple Myeloma Field

Prerna Mewawalla, MD

The multiple myeloma space is exploding with treatment options for patients with relapsed or refractory disease. According to Prerna Mewawalla, MD, the recent introduction of bispecific antibodies has been most exciting.

Teclistamab-cqyv (Tecvayli) was approved in 2022 as the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager to be indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Results from studies in the MajesTEC-1 program (NCT03145181; NCT04557098) supported the approval.¹

Treatment with teclisatamab achieved an overall response rate of 61.8% (95% CI, 52.1-70.9). The estimated duration of response rate associated with teclisatamab was 90.6% (95% CI, 80.3%-95.7%) at the 6-month mark, and 66.5% (95% CI, 38.8%-83.9%) at the 9-month timepoint.

In terms of safety, the most common adverse events were pyrexia, cytokine release syndrome, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. Common grade 3 and 4 laboratory abnormalities observed in patients receiving teclisatamab include decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

According to Mewawalla, hematologist at Allegheny Health Network, having an agent with a response rate above 60% is amazing. The use of bispecific antibodies has also been a helpful alternative when chimeric antigen receptor (CAR) T-cell therapy is not an option for patients.

In an interview with Targeted Oncology™, Mewawalla discussed the role of bispecific antibodies in multiple myeloma treatment and options to consider before patients reach the relapsed/refractory setting.

TARGETED ONCOLOGY: Can you talk about the explosion of agents in the multiple myeloma space and how they’ve impacted care?

Mewawalla: 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 [Darzalex] plus lenalidomide [Revlimib], bortezomib [Velcade], and dexamethasone, or dara-RVD, in the upfront setting in more and more patients to get deeper responses.

How are you optimizing each type of therapy in your clinic?

For the newly diagnosed patients who are transplant eligible, I have started using the quadruple treatments like dara-RVD in the high-risk population, as well as in my younger patients who we want to achieve a deeper response and have a higher progression-free survival.

I'm also transplanting these patients after 4 to 6 cycles based on the DETERMINATION trial [NCT01208662] and having the PFS of 18 months by doing the transplant. For my newly diagnosed transplant-ineligible patients, I now use DRD upfront in the stations, per the MAIA study [NCT02252172]. My patients are doing well on it, and they tolerate it extremely well. With time, it becomes once a month, so patients like getting it as well.

I am looking forward to data from the SWOG S0777 study [NCT00644228], which is going to compare DRD to RVD-light and see if that would be another option for these transplant-ineligible patients upfront.

Which therapies are showing the most toxicity and how are you managing this?

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 lend-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 is, I base it on if they have any unique genetic mutations such as translocation 1114, in which cases I can use venetoclax [Venclexta]. It's a unique population where one can use 1 other plaque, 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 antibody or CAR T, I have been using the teclisatamab earlier on, and so far, have had positive results with that.

What is the most exciting new clinical trial data in the multiple myeloma space?

I think a unique toxicity that we have encountered is with the bispecifics. We encounter more infections than we previously saw with other agents. It occurs in around 70%, which is very high. There are different things we are doing to sort of help with that. I started using prophylactic IVIG in all my patients who get teclisatamab, and I’m also using growth factors if they become neutropenic while they're on teclisatamab. We've recently started also using EJP prophylaxis in our patients with teclisatamab, which we didn't do prior. I think these are the 3 big things we've done.

Can you discuss the new targets of interest in multiple myeloma?

BCMA has been a target of interest for some time now. All our current CAR Ts and even teclisatamab are all targets for BCMA. The other newer targets are GPRC5D, and FCRH5.

What are the needs for the future of multiple myeloma treatment?

I think the biggest unmet need in my practice is the ultra-high-risk population, because I have a lot of these patients. They progress on every treatment. If we put them on frontline, they go through their first-, second, third-, and fourth-line treatment, and they either don't respond to them at all, or they respond briefly and relapse right away. I still don't think we have any good options for these ultra-high-risk patients. I wish there was something we could do.

The second thing which I think needs to be addressed is the availability of CAR T. A lot of the accredited centers still don't have CAR T. Even though recently the slots of CAR T went up, a lot of these centers don't have it. Patients either have to travel, or they have to wait long times to be able to get CAR T. I think that is something which needs to change sooner rather than later.

Last but not the least, the thing we all want and hope for is truly a cure for myeloma. Not multiple lines of treatment where to keep the disease in remission, but truly a cure where you've given something like in lymphoma. For example, you've given a treatment of our child and we can truly tell our patient you are cured. That would be the biggest achievement for myeloma.

_REFERENCES:

_{FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed May 4, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma}