Dr Raza on Unmet Needs in R/R Myeloma With Extramedullary Disease

"This highlights one of the unmet needs: to explore therapeutic options and determine what type of therapies would be ideal. This study is trying to answer the question of whether we can improve survival for these patients with [the combination]."

Shahzad Raza, MD, a hematologist/oncologist at the Cleveland Clinic, discussed challenges associated with the management of relapsed/refractory multiple myeloma with extramedullary disease (EMD), and how this provided the rationale for the phase 1b/2 RedirecTT-1 study (NCT04586426).

Raza began by emphasizing the unique nature of RedirecTT-1, noting that while myeloma studies typically classify patients by refractory status, lines of therapy, and measurable disease, no prior quality studies have specifically focused on EMD, where myeloma is present outside the bone marrow niche in areas like the liver or kidney, he expanded. This study is pioneering in addressing this critical gap, Raza asserted. Furthermore, RedirecTT-1 introduces unique criteria for defining EMD, clearly distinguishing it from paraskeletal diseases, he added. A significant inclusion criterion for this study is the enrollment of patients with unmeasurable, oligosecretory, or nonsecretory disease, a population often excluded from previous clinical trials, Raza noted.

The prognosis for patients with EMD generally remains poor, underscoring the urgent need to identify more effective therapeutic strategies, Raza continued. RedirecTT-1 aims to explore potential therapeutic options and determine the ideal types of therapies to improve survival for these patients. He explained that the study seeks to answer whether the combination of talquetamab (Talvey) and teclistamab (Tecvayli) can enhance survival outcomes in this challenging patient population. This study represents a dedicated effort to address a historically overlooked and difficult-to-treat aspect of multiple myeloma, Raza concluded.

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Shahzad Raza, MD, highlights the challenges associated with managing relapsed/refractory multiple myeloma with extramedullary disease.

Dr Raza on Talquetamab Plus Teclistamab in Patients With R/R Myeloma and Extramedullary Disease

“This is a [subset] of patients [that is] difficult to treat; they are relapsing quickly without many good [treatment] options available. From an efficacy point of view, [these data] are quite exciting for myeloma investigators.”

Shahzad Raza, MD, a hematologist/oncologist at the Cleveland Clinic, discussed efficacy data from the phase 2 RedirecTT-1 study (NCT04586426) of talquetamab (Talvey) in combination with teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma with extramedullary disease.

Findings from RedirecTT-1 presented during the 

 revealed that the median progression-free survival (PFS) after 13 months of follow-up was 15.4 months (95% CI, 10.8-not evaluable) among patients with relapsed/refractory multiple myeloma and true extramedullary disease who received the combination (n = 90), Raza began. The 12-month PFS rate was 61.0% (95% CI, 49.6%-70.6%). Raza noted that this finding was significant because standard-of-care therapy for the treatment of this patient population usually confers a median PFS of approximately 3 months.

At a median follow-up of 12.6 months (range, 0.5-19.5), patients treated with talquetamab plus teclistamab achieved an overall response rate (ORR) of 78.9% (95% CI, 69.0%-86.8%), Raza said. The complete response or better rate was 54.4% and the very good partial response rate was 70.0%. Most patients experienced durable responses and were still responding after 1 year, Raza added.

The ORR among patients who received a prior anti-BCMA CAR-T cell therapy (n = 18) was 83.3% (95% CI, 58.6%-96.4%). Those treated with prior belantamab mafodotin (Blenrep; n = 11) or a prior anti-FcRH5 bispecific antibody (n = 8) experienced ORRs of 90.9% (95% CI, 34.9%-96.8%) and 75.0% (95% CI, 34.9%-96.8%), respectively.

Such data have not been previously reported in this patient population, Raza explained. He noted that patients with relapsed/refractory multiple myeloma with extramedullary disease have been historically difficult to treat because they are experiencing disease relapse quickly and do not have many good treatment options. These data are exciting for patients and investigators, he concluded.

Shahzad Raza, MD, discusses talquetamab in plus teclistamab in relapsed/refractory multiple myeloma with extramedullary disease.

Dr Raza on Talquetamab Plus Teclistamab in R/R Myeloma and Extramedullary Disease

Dr Raza on Early Safety and Efficacy Data With NXC-201 in AL Amyloidosis  

"What's unique about this drug is that we have not seen any neurological toxicity. We typically see toxicities like CRS quite early [with CAR T-cell therapy]… and there were no severe CRS [events]. It's quite exciting that this is so tolerable."

Shahzad Raza, MD, a hematologist/oncologist at the Cleveland Clinic, discussed safety and efficacy data from the phase 1b/2 NEXICART-2 (NCT06097832) evaluating the autologous BCMA-targeted CAR T-cell therapy NXC-201 in relapsed/refractory light chain (AL) amyloidosis.

NEXICART-2 is the first United States clinical trial of any CAR T-cell therapy in this disease state. Preliminary findings from the phase 1 portion of the study were presented during the 

 and showed that administration of NXC-201 was safe, had a manageable toxicity profile, and resulted in rapid, deep hematologic responses in all 7 patients treated.

No neurotoxicity was observed with NXC-201, and only mild, manageable cytokine release syndrome (CRS) was reported, Raza stated, adding that this is a common complication associated with CAR T-cell therapies. All patients received infusion within 14 days of leukapheresis, and no delays in manufacturing were observed.

Among the 7 patients treated in the phase 1 portion, all experienced rapid and deep hematologic responses. The median time to first response was 7 days, and the median time to best response was 26 days. Of the 9 patients evaluable for minimal residual disease (MRD), 8 were MRD negative by day 25. The primary end point of hematologic complete response (CR) was achieved in 70% of patients, with additional patients achieving very good partial responses (VGPR). Raza noted that responses appeared durable at this early follow-up and are expected to deepen with time.

Organ responses were also observed, with 4 out of 5 evaluable patients demonstrating organ improvement. Importantly, no disease relapses or progressions had occurred at the time of reporting. Raza highlighted the unexpected tolerability of NXC-201, especially given that BCMA-directed CAR T-cell therapies used in multiple myeloma are often associated with higher rates of CRS and neurotoxicity. The absence of significant neurotoxicity and severe CRS in this cohort was a notable distinction.

Raza emphasized the potential impact of these findings, stating that the early data support further evaluation of NXC-201 as a promising therapeutic option in this historically difficult-to-treat population. He concluded that achieving rapid MRD negativity and hematologic CR with minimal toxicity represents a significant step forward in the treatment of relapsed/refractory AL amyloidosis.

Shahzad Raza, MD, shares preliminary data from the NEXICART-2 trial of NXC-201 in relapsed/refractory light chain amyloidosis.

Dr Raza on Early Safety and Efficacy Data With NXC-201 in AL Amyloidosis

Newer treatment for patients with cancer such as monoclonal antibodies, immunotherapies, antibody–drug conjugates, growth factor receptors, checkpoint inhibitors, and targeted therapies have been shown to improve prognosis. Yet in the real-world setting, cases of 

ocular adverse effects have emerged with greater frequency both in new and established therapies than has been previously observed in many clinical trials.

Investigators at Cleveland Clinic Taussig Cancer Center recently published a clinical review that compiles ocular toxicities of several anticancer drugs in an attempt to predict who will be impacted by these AEs and what treatments and interventions can mitigate these risks. The researchers analyzed patient cases as well as prior medical literature to
better understand ocular complications that have occurred in patients taking antineoplastic agents.

“As clinicians, we need to look at not just the efficacy of a treatment but what toxicities are occurring to vital organs like the eyes and the impact this has on that patient’s quality of life,” Shahzad Raza, MD, a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic Taussig Cancer Center in Ohio, and senior author of the study, said in an article.

“Patients struggle because they don’t know how to navigate the situation, and physicians are often unsure what steps to take to alleviate ocular toxicities. Ophthalmologists should be involved much earlier [on] in treatment decision-making and the potential risks to the eyes.”

Many unknowns remain about how to manage these issues, including when to pause treatment and when to reintroduce
it. The study authors combined in-depth clinical data regarding how ocular toxicities occur with data from published literature to develop a reference tool for providers to help guide them on what steps to take to mitigate these toxicities.

Commonly used chemotherapy agents such as alkylating agents, antimetabolites, microtubule inhibitors, and new targeted therapies can cause eye complications. These include corneal ulcers, keratoconjunctivitis, inflammation of eyelids, uveitis, macular edema, and loss of vision.

In the phase 1 DREAMM-1 trial (NCT02064387), patients treated with belantamab mafodotin-blmf (Blenrep; n = 35) experienced keratopathy at a rate of 53%.

In another study, patients treated with high-dose carmustine (n = 110) experienced retinal hemorrhaging at a rate of 24%.

Several eye toxicities require frequent communication
between oncologists and ophthalmologists. Similarly, it is important to have open communication between oncologists and patients, especially in cases of very advanced cancers with limited prognosis where such treatments may not add much to the quantity or quality of life.

Although eye toxicities are not the norm, they do occur more frequently than is typically observed in clinical trials, and in some cases rapidly. Depending on the therapy, a temporary cessation of treatment or lowering of dose can help reverse more severe toxicities. Based on these findings, the study authors recommend the following if a patient is
receiving a therapy with which there is a risk of ocular AEs:

Administer a baseline ophthalmic exam prior to initiating cancer treatment and perform periodic exams throughout treatment to detect ocular toxicities earlier on.

Discuss the risks of ocular toxicities with patients so that if they experience early symptoms they can notify their care team immediately.

Ensure the patient already has an ophthalmologist so that if a problem arises, they can get an appointment quickly.

“In some cases, eye issues occur gradually but in some instances such as retinal detachment, they can happen right away and become an emergency,” Raza said. “If a patient is just starting to reach out to an ophthalmologist when these toxicities occur, often the damage has already been done, and by the time their oncologist is holding the drug, the cancer [has] progress[ed]. The moment an issue emerges,
there should be a lifeline to an ophthalmologist.”

Raza and a team of computational mathematicians are using data mining to evaluate overall toxicity trends of oncology agents. By mining national patient databases of thousands of patients, they hope to discover what role factors such as race, ethnicity, drug dosing, and gene modification play in drug toxicities. “What we don’t yet understand is why one patient
has an AE and another does not,” Raza explained. “What factors are involved? [It] may be inherent genetics but we feel there are particular pharmacokinetic and pharmacogenomic signals involved that may amplify certain toxicities.”

Ultimately, the goal is to bring pharmacovigilance and genomics together to better predict when toxicities will occur so that clinicians can tailor treatment accordingly. 

Eye toxicities more prevalent side effect of cancer treatment than previously understood. Cleveland Clinic. September 7, 2023. Accessed October 10, 2023. https:// consultqd.clevelandclinic.org/eye-toxicities-more-prevalent-side-effect-of-cancer-treatment-than-previously-understood/

Bader A, Begemann M, Al-Obaidi A, Habib MH, Anwer F, Raza S. Ocular complications of antineoplastic therapies. Future Sci OA. 2023;9(7):FSO871. doi:10.2144/fsoa-2022-0081

Articles

In the real-world setting, cases of ocular adverse effects have emerged with greater frequency both in new and established therapies than has been previously observed in many clinical trials.

Shahzad Raza, MD

Articles

Dr Raza on Unmet Needs in R/R Myeloma With Extramedullary Disease

Dr Raza on Talquetamab Plus Teclistamab in R/R Myeloma and Extramedullary Disease

Dr Raza on Early Safety and Efficacy Data With NXC-201 in AL Amyloidosis

Prevalence of Eye Toxicities in Patients With Cancer Is Much Higher Than Previously Known