Dr Hashmi on Real-World Teclistamab Use in Relapsed/Refractory Multiple Myeloma

Hamza Hashmi, MD, hematologist-oncologist, Medical University of South Carolina Hollings Cancer Center, discusses findings from a real-world study of the efficacy and safety of teclistamab-cqyv (Tecvayli) in patients with relapsed/refractory multiple myeloma.

A study spotlighting the efficacy and safety of the BCMA-directed bispecific T-cell engager teclistamab in a real-world population of patients with relapsed/refractory disease was presented at the 

, Hashami says. This retrospective, multicenter analysis included 106 real-world patients who received at least 1 full dose of teclistamab for relapsed/refractory disease as of July 15, 2023. Many of these patients were elderly and frail with high-risk disease biology, Hashmi notes. Furthermore, several patients had high-risk cytogenetics and/or extramedullary disease, both of which are markers of aggressive disease biology in multiple myeloma, Hashmi explains. Because of these characteristics, 83% of the patients included in this real-world analysis would have been ineligible for enrollment in the phase 2 MajesTEC-1 trial (NCT04557098). Findings from the MajesTEC-1 trial supported the 2022 

 for patients with relapsed/refractory multiple myeloma who have received 4 or more prior lines of therapy.

The safety profile of teclistamab in this real-world population was similar to that of the agent in MajesTEC-1, Hashmi notes. However, the agent’s efficacy was slightly inferior in this analysis vs in the pivotal trial, Hashmi emphasizes. The decreased efficacy of this agent in a real-world setting was largely influenced by patient characteristics and disease features. Many real-world patients were heavily pretreated, had high-risk disease features, and were refractory to prior BCMA-targeted agents, according to Hashmi.

Overall, this study demonstrated that teclistamab is a safe treatment option for patients with relapsed/refractory multiple myeloma who have received prior CAR T-cell therapy, even if they do not meet the MajesTEC-1 enrollment criteria, Hashmi says. However, the inferior efficacy of teclistamab in this real-world population emphasizes the need for more effective treatment options for patients who have received prior BCMA-directed therapy, Hashmi concludes.

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Hamza Hashmi, MD, discusses a real-world study of the efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma.

In this fifth episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, of the Medical University of South Carolina, reviews the implications of up-front vs delayed transplant on survival, quality of life, and risk of secondary malignancies in newly diagnosed, multiple myeloma.

Finally, I will talk about the DETERMINATION trial [NCT01208662], which was presented at the 2022 ASCO Annual Meeting by Paul Richardson, MD, of Dana-Farber Cancer Institute, and later published in the 

. DETERMINATION is a phase 3, randomized, controlled trial comparing up-front vs delayed transplant in patients with newly diagnosed, transplant-eligible multiple myeloma. ‘Up front’ was defined as high-dose chemotherapy [and] autologous transplant after 3 cycles of induction [treatment with] lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [RVd]. ‘Delayed transplant’ was defined as transplant that was performed post relapse.

A total of 700 patients were randomized into 2 arms. Arm A received RVd induction followed by high-dose chemotherapy and transplant, followed by 2 cycles of consolidation, followed by lenalidomide maintenance until disease progression or intolerable toxicity. Arm B, the delayed transplant arm, received RVd induction for 3 cycles, followed by stem cell mobilization and collection, followed by 5 more cycles of RVd consolidation, followed by lenalidomide maintenance until disease progression or intolerable toxicity.

At 6 years of follow-up, we learned that patients who underwent up-front transplant after completion of their induction [treatment] had a superior progression-free survival [PFS] of around 66 months vs 48 months for patients who underwent delayed transplant. This trial also looked at patients based on their cytogenetic risk profile, and we learned that the patients who have standard-risk [disease], which is typically 70% to 80% of all myelomas, had a median PFS of close to 84 months or 7 years compared with around 55 months for patients who underwent delayed transplant. Looking at high-risk cytogenetic abnormalities, defined as patients having deletion 17p, translocation 4:14, and translocation 14:16, we learned that up-front transplant associated with significantly superior PFS of close to 55 months vs only 18 months with delayed transplant. Having noticed this improvement in PFS, there is still no difference in overall survival [OS], and perhaps that's related to the follow-up of only 6 years at this time. Maybe with longer follow-up we will see a difference in OS, as well.

In this trial, we saw a clear decline in the patient quality of life [QOL] as they went through transplant, which is related to the adverse effects of high-dose melphalan causing mucositis and myelosuppression, but that transient decline in the QOL improved over a period of time as patients recovered from the transplant. We also learned that patients who undergo high-dose chemotherapy with melphalan followed by transplant and lenalidomide maintenance have a slightly higher incidence of secondary hematologic malignancies, including myelodysplastic syndrome and acute myeloid leukemia. When compared with the IFM 2009 trial [NCT01191060], the sister trial of the DETERMINATION trial, which was done in Europe, we had a very similar trial design and patient population. The major difference was [IFM 2009 explored] maintenance chemotherapy with lenalidomide for only 1 year after transplant. We very clearly saw [in DETERMINATION] that by continuing lenalidomide maintenance until disease progression or intolerability, instead of for only 1 year, after transplant, [there is] an improvement in PFS of close to 2 years.

This clinical trial very clearly established the PFS benefit for newly diagnosed multiple myeloma. It's important to highlight some of the important features of this trial when applying its results to everyday clinical practice. Patients who are above the age of 65 years were not included in the trial, so we haven't seen patients who are in their late 60s or early 70s. We have to bear in mind that patients only grow older and frailer with time, and hence, perhaps the best time to do transplant for them is early on, in the up-front setting. Secondly, it can be sometimes challenging to collect and store stem cells if there is no intent to do transplant within 1 year of the collection of the stem cells. Thirdly, patients with high-risk cytogenetic abnormalities very clearly had a significantly superior benefit with up-front transplant compared with patients who had high-risk disease and underwent delayed transplant. Twenty percent of the patients [in the delayed transplant arm] were not able to undergo transplant [at the time of relapse]. The reasons behind that remain unclear; whether this was due to the patient's comorbidities, age, frailty, or perhaps physician preference, remains unknown. However, it is also an important point to bear in mind when seeing patients who come for transplant consultation.

In my opinion, up-front high-dose chemotherapy and autologous stem cell transplant after adequate duration of induction chemotherapy is the standard of care; it leads to a clear difference in PFS, at the cost of transient decline of QOL and slightly increased risk of secondary malignancies. Again, although there are no OS data, it's important to bear in mind that we have not reached the median follow-up on this trial. As such, perhaps we will even see an OS benefit emerge with longer follow-up on this trial.

In this fifth episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, reviews the implications of up-front vs delayed transplant on survival, quality of life, and risk of secondary malignancies in newly diagnosed, multiple myeloma.

Unpacking Data From Pivotal Trials in Multiple Myeloma: Exploring Key Takeaways from the DETERMINATION Trial

In this fourth episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, of the Medical University of South Carolina, explains the optimal use of CAR T-cell therapy and common symptoms of adverse effects, including cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome in relapsed/refractory multiple myeloma.

The next trial that I will talk about is CARTITUDE-1 [NCT03548207], which is a phase 1/2 study evaluating ciltacabtagene autoleucel [Carvykti; cilta-cel] for patients with relapsed or refractory multiple myeloma. In this trial, patients who have had at least 3 prior lines of therapy were enrolled and given a single one-time infusion of cilta-cel, [which] is a BCMA-targeting CAR T-cell therapy, with a special feature of having 2 BCMA-binding domains on its antigen-binding site. Patients on this trial, on average, have had at least 6 prior lines of therapy. A vast majority [of patients] were refractory to an anti-CD38 monoclonal antibody, a proteasome inhibitor [PI], and an immunomodulatory drug [IMiD]. Moreover, the vast majority [also had] received a prior transplant. About 25% to 30% of the patients had extramedullary disease and high-risk cytogenetic abnormalities. 

Once cilta-cel was given as a single one-time infusion, it led to some groundbreaking efficacy, with an overall response rate of 98%. The stringent complete remission [rate achieved with the therapy was] around 80%, and around 90% [of patients had] minimal residual disease negativity at 105. This depth of response very clearly translated to a very durable remission, as well. The median duration of response in this heavily pretreated patient population was around 24 months. Median progression-free survival, as well as overall survival, at the 2-year follow-up was not yet reached.

Cilta-cel does come at a cost of some treatment-related adverse effects, most notably cytokine release syndrome [CRS], which was seen in a vast majority of patients. One of the differences to highlight here between cilta-cel and idecabtagene vicleucel [Abecma; ide-cel] is that although CRS is common, the onset of CRS is around 7 days with cilta-cel vs around 1 day with ide-cel. Most patients [who received] cilta-cel experienced CRS after 4 days. [This toxicity] is managed in a very similar manner with tocilizumab [Actemra]. Having an onset of CRS after 72 hours of infusion does allow us to give this CAR T-cell product in the outpatient setting which sometimes translates into better financial reimbursement for this product.

Immune cell effector–associated neurotoxicity syndrome [ICANS] was seen in about 20% of the patients and about 10% of the patients experienced non-ICANS neurotoxicity, which mimicked Parkinson-like disease, with patients having cognitive impairment, shuffling gait, movement disorders, and tremors. In some of these patients, this neurotoxicity was not reversible.

In more recent trials with this construct, the recommendation has been to use bridging chemotherapy, early steroids, and more careful handwriting monitoring to be able to identify and mitigate this non-ICANS neurotoxicity. Cytopenias were common and prolonged, as [what has been seen with] ide-cel, and were managed with supportive care, as well as hypogammaglobulinemia.

Cilta-cel is another great option for patients with heavily pretreated, relapsed or refractory multiple myeloma and it is commercially approved for patients who have at least 4 prior lines of therapy, with prior exposure to an anti-CD38 monoclonal antibody, PI, and an IMiD. [Cilta-cel] is given as a single agent. One of the challenges that we have encountered is that the product is not currently available at all cancer centers [throughout] the country, so access is limited and perhaps will improve with time.

Check back next Wednesday for the final episode in this series.

In this fourth episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, explains the optimal use of CAR T-cell therapy and common symptoms of adverse effects, including cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome in relapsed/refractory multiple myeloma.

Unpacking Data From Pivotal Trials in Multiple Myeloma: Taking a Closer Look at Cilta-cel and CARTITUDE-1 Data

In this third episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, of the Medical University of South Carolina, highlights the efficacy and safety profile of teclistamab, a BCMA-directed bispecific T-cell engager, in heavily pretreated multiple myeloma.

The next trial that I would like to discuss is the MajesTEC-1 trial [NCT04557098]. The phase [2], single-arm study looked at teclistamab-cqyv [Tecvayli], which is BCMA-targeting bispecific T-cell engager, in patients with heavily pretreated relapsed or refractory multiple myeloma.

The trial enrolled patients who have had at least 3 prior lines of therapy, and have had exposure to daratumumab [Darzalex], a proteasome inhibitor, and an immunomodulatory agent. [Patients received a] medium of 6 prior lines of therapy. Patients had teclistamab given subcutaneously in a step-up manner on day 1, 4, and 7. After that, teclistamab was continued every week until disease progression or intolerable toxicity.

The trial had its results [shared at a] recent meeting; [data were] also published [in] a major journal. [We saw] that 66% of the patients achieved a response; at least half of these responses were very good partial remissions. Time to initial response was around 1 month, time to best response was around 4 months, and median duration of response was around 18 months. [Moreover, the] median progression-free survival on this trial was around 11 months. The median overall survival was around 18 months although the data remain immature at this time and [we need] longer follow-up.

Teclistamab [resulted in] very deep, and perhaps durable, responses in a heavily pretreated patient population [but it] was associated with some treatment-related adverse effects [AEs], notably cytokine release syndrome [CRS], which was seen in about 70% of the patients. The majority [of CRS cases were] grade 1 and 2, and only less than 1% were grade 3. One-third of these patients required tocilizumab [Actemra] for the management of CRS. Onset was early with the step-up doses and the duration was only around [2 days]. Immune cell effector–associated neurotoxicity syndrome, or ICANS, was seen in about 10% of the patients and less than 1% required management with dexamethasone. No grade 3 effects were seen.

A very common [AE] that was reported was cytopenias, [and this was experienced by] about two-thirds of the patients; this included neutropenia, anemia, and thrombocytopenia. These cytopenias were transient, usually [occurring] in the first couple of months and cycles and were manageable with supportive care and resolved spontaneously over time. Another very important, and perhaps the most relevant, clinical AE that was noticed was hypogammaglobulinemia; it was seen in about 70% of the patients, and at least one-third of these patients required intravenous immune globulin [IVIg] administration. Significant hypogammaglobulinemia translated into severe infections—especially COVID-19 infection, [which was] the leading cause of mortality [in the trial].

Teclistamab has been recently approved by the FDA for patients with relapsed or refractory multiple myeloma, who have had at least 4 prior lines of therapy and who have had exposure to an anti-CD38 monoclonal antibody, proteasome inhibitor, and an immunomodulatory agent, and who had progressive disease on their last line of therapy. [The agent] is approved with the REMS [Risk Evaluation and Mitigation Strategy] program, with the step-up dosing requiring in-patient stay for at least 1 week and availability of tocilizumab for management of CRS. [Because teclistamab is an] available off-the-shelf option for patients with relapsed or refractory multiple myeloma, it is a very desirable option. These patients may not have many other options available. Compared with CAR T-cell therapy, being available off the shelf and not requiring any leukapheresis, chemotherapy, or lymphodepletion, makes it perhaps a more desirable option for patients who have aggressive disease and cannot wait 6 to 7 weeks before they have CAR T cells infused. Having said that, it is a continuous treatment that is given every week for as long as patients are responding; that does entail some inconvenience and some financial toxicity.

AEs are manageable, including CRS and ICANS. Patients who are receiving teclistamab should receive IVIg for management of hypogammaglobulinemia and subsequent infections. Very importantly, [they] should receive Evusheld for COVID-19 in case they are planning to continue with teclistamab.

Check back next Wednesday for the next episode of this series.

In this third episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, highlights the efficacy and safety profile of teclistamab, a BCMA-directed bispecific T-cell engager, in heavily pretreated multiple myeloma.

Unpacking Data From Pivotal Trials in Multiple Myeloma: Lessons Learned From the MajesTEC-1 Trial of Teclistamab 

In this second episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, of the Medical University of South Carolina, discusses the depth of response reported with daratumumab, carfilzomib, lenalidomide, and dexamethasone in transplant-eligible multiple myeloma.

The second clinical trial that I would like to discuss was presented at the [2022] ASCO [Annual] Meeting was the MASTER study [NCT03224507]. Here, investigators looked at a very potent quadruplet induction regimen of daratumumab [Darzalex], carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone [D-KRd] for patients with transplant-eligible, newly diagnosed multiple myeloma.

In this phase 2, single-arm trial, patients received 4 cycles of induction [treatment] with D-KRd followed by high-dose melphalan and stem cell rescue, followed by 4 to 8 cycles of consolidation [treatment] with D-KRd.

Minimal residual disease [MRD] assessments were done before transplant, after 4 and 8 cycles of consolidation, and any time patients achieved sustained MRD negativity, which was defined as [having] MRD (determined by clonoSEQ) at 10-5 and sustained for least 4 to 8 full cycles. Patients entered into an MRD surveillance phase, where they just underwent observation without any consolidation or maintenance [treatment]. 

The trial showed us that D-KRd was associated with very deep responses, with MRD negativity 105 seen in about 80% of the patients and MRD negativity 106 seen in about 66% of the patients. Sustained MRD negativity 105 sustained at least 4 cycles or 4 months apart, was seen in about 70% of the patients. Seventy percent of the patients entered the MRD surveillance phase and had follow-up [data] presented after 2 years. [Here,] we learned that patients who had standard-risk multiple myeloma and zero or only one high-risk cytogenetic abnormality did not have any significant progression despite not being on maintenance [treatment]. Having said that, patients who had two or more high-risk cytogenetic abnormalities experienced progression very early after entering this observation or surveillance phase [of the research]. We learned from this clinical trial that D-KRd is a very strong, potent induction regimen—especially for [patients with] high-risk multiple myeloma, so those who have lesion 17p, translocation 4:14, translocation 14:16, and gain or amplification 1q. It leads to deep remissions in these patients.

Whether we can stop all chemotherapy after achieving sustained MRD negativity for 4 months or 4 cycles apart for a [patient with] standard[-risk] multiple myeloma needs to be determined with longer follow-up. The trial very clearly showed us that for patients who have high-risk [disease], with 2 or more high-risk cytogenetic abnormalities, taking them off chemotherapy—whether consolidation or maintenance—is perhaps not the right strategy, as these patients relapse very quickly after stopping chemotherapy.

Check back next Wednesday for the next episode in this series.

In this second episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, discusses the depth of response reported with daratumumab, carfilzomib, lenalidomide, and dexamethasone in transplant-eligible multiple myeloma.

Unpacking Data From Pivotal Trials in Multiple Myeloma: Shining a Light on the MASTER Trial Evaluating D-KRd 

In this first episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, of the Medical University of South Carolina, provides perspective on the use of daratumumab-based quadruplets as induction therapy in multiple myeloma.

I'm Hamza Hashmi, MD. I am one of the physicians here, at Medical University of South Carolina. I specialize in plasma cell disorders...[and] I'm interested in clinical trials in CAR T-cell therapy and cellular immunotherapy for [these] disorders.

Today, I will be talking about some of the more recent data that have come out of [the 2022] ASCO and ASH Annual Meetings. [I will] discuss some relevant topics and practice-changing studies that have been presented at [those] meetings [and their significance with regard to clinical practice].

First of all, [there was the] GRIFFIN trial [NCT02874742]; 3-year follow-up data [from the maintenance phase of the trial were] recently presented at the [2022] International Myeloma Society meeting. GRIFFIN is a phase 2, randomized trial that looked at patients with transplant-eligible, newly diagnosed multiple myeloma [and compared] the quadruplet regimen of daratumumab [Darzalex], lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [D-RVd] vs the triplet of RVd alone.

Patients received induction [treatment for] 4 cycles followed by high-dose melphalan [with] autologous stem cell rescue, followed by 2 cycles of consolidation, followed by 2 years of maintenance [treatment]. We had 3-year follow-up on the maintenance phase that showed that the quadruplet regimen was associated with a better depth and duration of remission, with sustained minimal residual disease [MRD] negativity seen in about 50% of the patients [on the quadruplet arm] vs only 15% of the patients on the triplet arm. That translated into a difference in progression-free survival [PFS], with 90% of the patients in the [investigative arm] progression free at the 3-year follow-up vs about 66% [of those in the control arm] progression free. So, very clearly, [we saw] MRD negativity 10

 sustained at least 12 months apart, [and this] translated into a difference in PFS outcomes.

D-RVd has now emerged as a new standard-of-care induction [regimen]. Many centers in United States are already [using this combination] for induction [before] transplant [and the quadruplet] is leading to better outcomes. Whether daratumumab needs to be continued for maintenance purposes for a 2-year duration remains to be determined.

There is a phase 3 randomized controlled trial, the CASSIOPEIA trial [NCT02541383], that looked at a combination of daratumumab, bortezomib, thalidomide [Thalomid], and dexamethasone [D-VTd] and compared it with [VTd] alone. [Data showed] that the daratumumab arm, as maintenance, does not lead to any significant benefit in PFS as long as it has been given as induction. I think this is the reason why D-RVd has been incorporated as an induction regimen. Further data [are needed, as the [role of these agents as] maintenance [treatment] remains to be determined.

In this first episode of OncChats: Unpacking Data From Pivotal Trials in Multiple Myeloma, Hamza Hashmi, MD, provides perspective on the use of daratumumab-based quadruplets as induction therapy in multiple myeloma.

Hamza Hashmi, MD

Articles

Dr Hashmi on Real-World Teclistamab Use in Relapsed/Refractory Multiple Myeloma

Unpacking Data From Pivotal Trials in Multiple Myeloma: Exploring Key Takeaways from the DETERMINATION Trial

Unpacking Data From Pivotal Trials in Multiple Myeloma: Taking a Closer Look at Cilta-cel and CARTITUDE-1 Data

Unpacking Data From Pivotal Trials in Multiple Myeloma: Lessons Learned From the MajesTEC-1 Trial of Teclistamab

Unpacking Data From Pivotal Trials in Multiple Myeloma: Shining a Light on the MASTER Trial Evaluating D-KRd

Unpacking Data From Pivotal Trials in Multiple Myeloma: Examining Findings From the GRIFFIN Trial of D-RVd