Multiple Myeloma Coverage from Every Angle

(NEW) Teclistamab-cqyv

Posted: Thursday, December 21, 2023

First Off-the-Shelf BCMA-Targeted Therapy for Relapsed or Refractory Multiple Myeloma

Teclistamab-cqyv (Tecvayli) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager. It is a first-in-class FDA (U.S. Food and Drug Administration)-approved therapy for patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy (including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody).1 The approval of teclistamab-cqyv was based on safety and efficacy data from the MajesTEC-1 trial, which enrolled patients who had received a median of five or six previous lines of therapy.2,3

The real-life clinical benefit of teclistamab was demonstrated when it was indirectly compared with conventional care in patients with triple-class–exposed relapsed or refractory multiple myeloma4,5 and even in patients who would have been ineligible for the MajesTEC-1 trial.6-10 Based on these results in patients with heavily pretreated relapsed or refractory multiple myeloma, teclistamab is now being evaluated in a number of clinical trials in earlier-stage disease (eg, MajesTEC-2, MajesTEC-3, MajesTEC-4, MajesTEC-7, MajesTEC-9, MASTER-2, Immuno-PRISM),11,12 with limited administration,13 and in outpatient settings.14

Adverse Effects of Teclistamab: Prevention, Monitoring, and Management

The most common adverse effects in the MajesTEC-1 trial were hematologic (eg, neutropenia, 70.9%; anemia, 52.1%; and thrombocytopenia, 40%).3 Infections (76.4%; 44.8% of those were grade 3 or 4) and hypogammaglobulinemia (74.5%) were also quite prevalent. Cytokine-release syndrome (CRS) was the most common nonhematologic adverse effect (72.1%), with most of the episodes being grade 1 or 2 and occurring after step-up and cycle 1 doses. Neurotoxic effects, including immune effector cell–associated neurotoxicity syndrome (ICANS), were reported in 14.5% of patients and were mostly grade 1 or 2.

Cytokine-Release Syndrome

All cases of CRS in the MajesTEC-1 trial (50.3% grade 1, 21.2% grade 2) resolved, and none led to treatment discontinuation.3 Most CRS episodes occurred after step‐up dose 1 (43.6%), followed by step‐up dose 2 (35.2%), and after the first treatment dose on cycle 1, day 1 (24.2%). Additionally, 46% of patients experienced more than one CRS episode.

Clinicians need to be vigilant with regard to CRS during initiation of teclistamab, especially because of a lack of any clearly predictive baseline characteristics.

Therefore, clinicians need to be vigilant with regard to CRS during initiation of teclistamab, especially because of a lack of any clearly predictive baseline characteristics. Management of CRS in the MajesTEC-1 trial consisted mostly of tocilizumab and steroids, but it also included low‐flow oxygen by nasal cannula, a single vasopressor, intravenous fluids, and use of acetaminophen. Of note, data suggest that tocilizumab may decrease the likelihood of subsequent CRS episodes without compromising the efficacy of teclistamab and may even be considered for prophylactic use.15,16

Infections, Hypogammaglobulinemia, and Neutropenia

Patients with multiple myeloma face increased risk of infection, and the risk is particularly high in heavily pretreated patients with relapsed or refractory disease.17 BCMA-targeted therapy such as teclistamab may further increase the risk of infection through on‐target, off‐tumor toxicity, causing neutropenia and hypogammaglobulinemia.

Thus, before starting teclistamab, patients should be free of any active infections (and screened for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus); they also should be vaccinated against COVID‐19, influenza, varicella zoster, and pneumococcal disease.18 Based on the MajesTEC-1 trial, prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex virus or varicella zoster is recommended for all patients. Also, immunoglobulin G (IgG) levels should be monitored every 4 to 6 weeks, and IgG replacement should be administered every 3 to 6 weeks to maintain IgG levels of at least 400 mg/dL. Of note, as IgG replacement does not mitigate IgA depletion, there is a remaining risk of infection with pathogens causing gastrointestinal disorders. As for the management of neutropenia (grade 3 or 4), use of granulocyte colony-stimulating factors should be considered.

Insights on Use of Teclistamab: From Real-World Clinical Practice

“In our practice today,” Amrita Krishnan, MD, told JNCCN 360, “triple-class–exposed patients, with relapsed disease after four or more lines of therapy, will be offered CAR [chimeric antigen receptor] T-cell therapy, bispecific antibodies such as teclistamab, with which we have the most experience, or a clinical trial.19 That said, CAR T-cell therapy hinges upon slot availability, and clinical trial options depend on patient eligibility, among other things.”

The ‘ideal’ teclistamab patient would be someone with a good performance status, no history of infections, and little extramedullary disease.

Dr. Krishnan shared her thoughts on patients who might be eligible for treatment with teclistamab. “The ‘ideal’ teclistamab patient would be someone with a good performance status, no history of infections, and little extramedullary disease. Of those patient characteristics, history of infections is the most important. A patient with a history of infections would not be a good candidate for teclistamab.”20

Dr. Krishnan also pointed out that tumor burden is not much of an issue with the use of teclistamab. “As a matter of fact,” she continued, “patients with a high tumor burden would be more likely to get teclistamab than CAR T-cell therapy, as they usually are in need of immediate intervention. For those patients who are in between,” she explained, “who have a choice among treatment modalities, it comes down to slot availability for CAR T-cell therapy and their preferences.” Dr. Krishnan is Director of the Judy and Bernard Briskin Multiple Myeloma Center at the City of Hope Orange County Lennar Foundation Cancer Center in Irvine, California.

“The safety and efficacy of teclistamab in our practice compare quite well with what we have seen in the MajesTEC-1 trial. Over time, though, we have gotten much better at using supportive care and are now managing opportunistic infections prophylactically (eg, by using intravenous immunoglobulin much more aggressively),” she commented.

Dr. Krishnan continued: “When it comes to triggers for withholding or dose-reducing teclistamab, those would be low blood cell counts and infections. As for multifocal leukoencephalopathy, unfortunately, we don’t know the associated risk factors. It is very rare, and we have not seen it in our practice.” She observed that another potential scenario in which teclistamab may be stopped or switched to biweekly dosing would be in patients with deep and sustained responses (ie, prolonged measurable residual disease [MRD]-negative status). “The potential benefits of that strategy would be reducing T-cell exhaustion and the risk for infections, as well as the emergence of anti-BCMA–refractory disease,” she added. “But, again, we need to learn more before we consider doing it in select patients.”

“As for future uses of teclistamab, researchers are looking to define its role in earlier lines of therapy, finding optimal combination therapies, as well as fixed-duration therapies. Ongoing and future clinical trials will, hopefully, answer some of those questions,” Dr. Krishnan told JNCCN 360.

The advent of novel bispecific antibodies such as teclistamab has been a huge step forward in terms of our ability to treat patients with very advanced disease.

“Overall,” she added, “the advent of novel bispecific antibodies such as teclistamab has been a huge step forward in terms of our ability to treat patients with very advanced disease. Outstanding questions center on how best to manage patients with extramedullary disease, renal failure, and CNS disease, which remain important clinical challenges.”

Donna Catamero, ANP-BC, OCN, CCRC, Associate Director, Myeloma Research, Mount Sinai Health System, New York, shared her experience with teclistamab with JNCCN 360: “At our institution, we typically use teclistamab in patients who cannot wait for CAR T-cell therapy (eg, those with rapidly progressing disease). Our experience with it, in terms of its safety and efficacy, is pretty much similar to what was reported in MajesTEC-1 trial. And, we have also seen a good safety profile and efficacy in patients who would not have been eligible to enroll into MajesTEC-1 trial because of their relatively poor performance status and compromised renal function. We saw the same response rates and CRS, mostly grade 1 during the step-up dose, which was easily manageable, she noted.

“We now have a fair amount of experience in managing treatment-related adverse events,” Ms. Catamero continued, “and feel quite comfortable to go pretty aggressively. With regard to CRS, for example, at the first sign of fever, we give tocilizumab and acetaminophen. On the other hand, managing infections can be a little bit more problematic, and that is my biggest concern.” For that reason, the team at Mount Sinai initiates intravenous immunoglobulin in all patients receiving teclistamab and maintains it for the duration of therapy. “Prophylactic sulfamethoxazole and trimethoprim, either daily or three times a week, is also administered for Pneumocystis jirovecii pneumonia, as are antivirals. To maintain an absolute neutrophil count above 1,000 cells/mm3, growth factor support is used. Furthermore, patients should be up to date with all vaccinations,” Ms. Catamero explained. “Recently, that includes vaccination for respiratory syncytial virus [RSV]. We go aggressively with all of this to keep patients out of trouble and to prevent hospitalizations and dosing interruptions.”

According to Ms. Catamero, ICANS is rare, occurring in roughly 3% of patients. “I have not seen a patient with multifocal leukoencephalopathy in this clinical setting,” she observed.

Overall, Ms. Catamero reiterated Dr. Krishnan’s concerns about infections when using teclistamab. “Unlike with CAR T-cell therapy,” she told JNCCN 360, “that one-and-done approach, teclistamab is a weekly therapy, and the patient’s immune system gets pounded. In patients who are responding really well (ie, those who achieve a complete response or MRD-negative status), we switch from weekly dosing to every-other-week dosing. That way, we feel we are also able to reduce the risk of infections.”

Closing Thoughts

Dr. Krishnan shared these closing thoughts with JNCCN 360: “Ultimately, the long-term therapeutic success of teclistamab will depend upon our ability to maximize its efficacy—including our understanding of its optimal sequencing and mechanisms of resistance—while being able to successfully manage associated adverse events and preserve patients’ quality of life.”

“I want to stress how impressive it is that now we can get these great responses in the late-stage setting with single-agent teclistamab,” Ms. Catamero concluded. “I hope we’ll see it soon being used in earlier lines of therapy.”

 

Disclosures

Amrita Krishnan, MD, has served as a speaker for BMS; has served as a consultant for Sanofi, Pfizer, GlaxoSmithKline, Regeneron, Janssen Pharmaceuticals, Bristol Myers Squibb, and AstraZeneca; and owns stock in Bristol Myers Squibb.

Donna Catamero, ANP-BC, OCN, CCRC, has served as a consultant and speaker for Janssen Pharmaceuticals.

 

References

  1. Teclistamab (Tecvayli) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761291s004lbl.pdf. Accessed December 12, 2023.
  2. Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet 2021;398:665–674.
  3. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 2022;387:495–505.
  4. Krishnan A, Nooka AK, Chari A, et al. Teclistamab versus real-world physician’s choice of therapy in triple-class exposed relapsed/refractory multiple myeloma. J Comp Eff Res 2023;12:e220186.
  5. Moreau P, van de Donk NWCJ, Delforge M, et al. Comparative efficacy of teclistamab versus current treatments in real-world clinical practice in the prospective LocoMMotion study in patients with triple-class-exposed relapsed and/or refractory multiple myeloma. Adv Ther 2023;40:2412–2425.
  6. Dieterle MP, Mostufi-Zadeh-Haghighi G, Kus JW, et al. Safe and successful teclistamab treatment in very elderly multiple myeloma patients: a case report and experience from a total of three octogenarians. Ann Hematol 2023;102:3639–3641.
  7. Dima D, Sannareddy A, Ahmed N, et al. Toxicity and efficacy outcomes of teclistamab in patients with relapsed-refractory multiple myeloma above the age of 70 years: a multicenter study. 2023 ASH Annual Meeting & Exposition. Abstract 3330.
  8. Joiner L, Bal S, Godby KN, et al. Teclistamab in patients with multiple myeloma and impaired renal function. Am J Hematol 2023;98:E322–E324.
  9. Lachenal F, Lebreton P, Bouillie S, et al. Teclistamab in relapsed refractory multiple myeloma patients on dialysis: a French experience. 2023 ASH Annual Meeting & Exposition. Abstract 4739.
  10. Dima D, Davis JA, Ahmed N, et al. Real-world safety and efficacy of teclistamab for patients with heavily pretreated relapsed-refractory multiple myeloma. 2023 ASH Annual Meeting & Exposition. Abstract 91.
  11. Kang C. Teclistamab: first approval. Drugs 2022;82:1613–1619.
  12. Martino EA, Bruzzese A, Labanca C, et al. Teclistamab-cqyv in multiple myeloma. Eur J Haematol. October 17, 2023 [online ahead of print].
  13. Razzo B, Grady C, Susanibar-Adaniya S, et al. A phase 2, single-arm, non-inferiority study of limited-duration teclistamab for relapsed and refractory multiple myeloma (LimiTec). 2023 ASH Annual Meeting & Exposition. Abstract 3394.
  14. Rifkin RM, Sharman JP, Fowler J, et al. Optec: a phase 2 study to evaluate outpatient administration of teclistamab, a BCMA-targeting bispecific antibody, in patients with multiple myeloma. 2023 ASH Annual Meeting & Exposition. Abstract 3374.
  15. Martin TG, Mateos MV, Nooka A, et al. Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma. Cancer 2023;129:2035–2046.
  16. Kowalski A, Lorayne Lykon J, Diamond B, et al. Tocilizumab prophylaxis for patients treated with teclistamab: a single-center experience. 2023 ASH Annual Meeting & Exposition. Abstract 4709.
  17. Raje NS, Anaissie E, Kumar SK, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol 2022;9:e143–e161.
  18. Nooka AK, Rodriguez C, Mateos MV, et al. Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study. November 14, 2023 [online ahead of print].
  19. Kumar SK, Callander NS, Adekola K, et al. NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. Version 2.2024. Accessed December 12, 2023. To view the most recent version, visit NCCN.org.
  20. Mazahreh F, Mazahreh L, Schinke C, et al. Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis. Blood Adv 2023;7:3069–3074.



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