Multiple Myeloma Treatment: Past, Present and Future
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- čas přidán 25. 07. 2024
- Multiple myeloma treatment was started as early as 200 years ago, and has been evolved until now. Emerging therapy with newly developed powerful drugs will revolutionize the treatment again.
Also, I am mentioning 8 Nobel Prize laureates for their multiple myeloma related research.
Thank you for the clear overview.
thanks for the wonderful overview
You’re welcome
Recent trend of treatment for relapsed myeloma:
1. One challenge in managing relapsed MM is the high likelihood of the disease being refractory to 1 or more agents used during prior therapy. Resistance to lenalidomide is common after the maintenance interval of initial therapy.
2. When choosing a combination regimen in relapsed MM, an anti-CD38 antibody should be the backbone for patients who are not resistant. Daratumumab and isatuximab have each shown improved efficacy vs doublet regimens in combination with pomalidomide or carfilzomib in phase 3 trials.
3. In the relapse setting, daratumumab in combination with pomalidomide or carfilzomib is FDA-indicated in second or later lines. Isatuximab with carfilzomib is indicated in second or later lines, or with pomalidomide in third or later lines.
4. A single-center experience at Emory University has demonstrated that second line anti-CD38/pomalidomide regimens have the greatest efficacy among patients that experience longer first remissions (> 30 months post-diagnosis). Earlier first relapse can be considered functionally high risk and may benefit from an alternative second-line regimen.
5. Other agents indicated in the early relapse setting include selinexor combinations, which have shown to be most tolerable with weekly dosing, and venetoclax with dexamethasone which has shown substantial efficacy when limited to a precision approach for patients with translocation (11;14).
“Teclistamab (BCMA x CD3 bispecific antibody) resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma”
N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478
Abstract:
- 165 patients had relapsed/refractory MM after at least three lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.
- The overall response rate was 63% at a median follow up of 14.1 months, with 39.4% of patients having a complete response or better.
- There were 44 patients (26.7%) who had no minimal residual disease (MRD). The MRD-negativity rate was 46% in patients with a complete response or better.
- The median duration of response was 18.4 months (95% CI, 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1).
- Infections were reported in 76.4% of patients, cytokine release syndrome in 72.1% of patients, neutropenia (70.9%), anemia (52.1%), thrombocytopenia (40%), neurotoxic events (14.5%), including immune effector cell-associated neurotoxicity syndrome in 3% of patients.
On October 25, 2022, the Food and Drug Administration granted accelerated approval to teclistamab-cqyv (Tecvayli, Janssen Biotech, Inc.), the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, for adult 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.
Teclistamab-cqyv was evaluated in MajesTEC-1 (NCT03145181; NCT04557098), a single-arm, multi-cohort, open-label, multi-center study. The efficacy population consisted of 110 patients who had previously received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and had not received prior BCMA-targeted therapy.
The main efficacy outcome measure was overall response rate (ORR) as determined by the Independent Review Committee assessment using International Myeloma Working Group 2016 criteria. ORR was 61.8% (95% CI: 52.1, 70.9). With a median follow-up of 7.4 months among responders, the estimated duration of response (DOR) rate was 90.6% (95% CI: 80.3%, 95.7%) at 6 months and 66.5% (95% CI: 38.8%, 83.9%) at 9 months.
The prescribing information for teclistamab-cqyv has a Boxed Warning for life threatening or fatal cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity (ICANS). Among patients who received teclistamab-cqyv at the recommended dose, CRS occurred in 72% of patients, neurologic toxicity in 57%, and ICANS in 6%. Grade 3 CRS occurred in 0.6% of patients and Grade 3 or 4 neurologic toxicity occurred in 2.4%.
Because of the risks of CRS and neurologic toxicity, including ICANS, teclistamab-cqyv is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS.
The most common adverse reactions (≥20%) occurring in the 165 patients in the safety population, were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.
The recommended teclistamab-cqyv dose is 0.06 mg/kg via subcutaneous injection on Day 1, 0.3 mg/kg on Day 4, and 1.5 mg/kg on Day 7, followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity.
The phase III DREAMM-3 trial, which compared belantamab mafodotin with pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma, did not meet its primary endpoint.
The primary endpoint of the open-label, randomized, head-to-head superiority trial was progression-free survival (PFS), with the PFS in DREAMM-3 demonstrating a hazard ratio of 1.03 (95% CI, 0.72-1.47), GSK plc, the manufacture of the drug, said in the announcement.
Belantamab mafodotin is an antibody-drug conjugate comprising a humanized B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent auristatin F by a non-cleavable linker. The U.S. Food and Drug Administration (FDA) granted the drug accelerated approval as a monotherapy for adult patients with relapsed or refractory multiple myeloma who received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
According to a recent study published in The Lancet Oncology, carfilzomib, daratumumab, and dexamethasone (KdD) showed a clear progression-free survival benefit over carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma.
There remains a large unmet need for new treatment options for patients with relapsed or refractory multiple myeloma. With each consecutive regimen, patients face shorter durations of response and poorer survival outcomes. Immunomodulatory drugs like lenalidomide often lead to resistance or relapse.
Carfilzomib is a second-generation proteasome inhibitor that is part of the KdD regimen in combination with daratumumab and dexamethasone that was recently approved by the FDA. The National Comprehensive Cancer Network refers to KdD as the preferred regimen for previously treated multiple myeloma.
The randomized, multi-center, open-label, phase 3 CANDOR study looked at patients with relapsed or refractory multiple myeloma who had at least a partial response to previous therapies. The primary endpoint was progression-free survival.
The following study procedure was followed:
“All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old).”
A total of 466 patients were enrolled in the CANDOR study; 312 received KdD and 154 received Kd. Median progression-free survival was 28.6 months in the KdD group (95% CI, 22.7-NE) and 15.2 months in the Kd group (95% CI, 11.1-19.9).
Grade 3 or higher treatment-emergent adverse events occurred in 87% of patients in the KdD group and 76% in the Kd group. The most common adverse events were thrombocytopenia, hypertension, pneumonia, and anemia.
Despite the high rates of adverse events observed during the study, the substantial progression-free survival benefit of KdD over Kd makes KdD the new standard of care for patients with relapsed or refractory multiple myeloma.
In August 2023,
The US Food and Drug Administration (FDA) has granted accelerated approval to the off-the-shelf biologic agent elranatamab (Elrexfio) for the treatment of relapsed or refractory multiple myeloma.
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma, according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a bi-weekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity and embryo-fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
Now, a new treatment for relapsed myeloma was presented in ESMO 2022:
Instead of daratumumab, another CD38 inhibitor, isatuximab was used in combination with carfilzomib and dexamethasone:
The addition of isatuximab to combination therapy with carfilzomib and dexamethasone significantly extended median progression-free survival in patients with relapsed multiple myeloma receiving proteasome inhibitor therapy, according to updated results from the phase 3 IKEMA clinical trial.
According to a press release issued by the manufacturer, the triplet demonstrated a median PFS of 35.7 months (HR = 0.58; 95% CI, 25.8-44), compared with 19.2 months (95% CI, 15.8-25.1) in patients assigned to carfilzomib and dexamethasone alone.
“To observe PFS of more than 3 years in patients with relapsed multiple myeloma when [isatuximab] was added to a proteasome inhibitor backbone of therapy is unprecedented and reinforces our confidence in [isatuximab] as a potential best in class anti-CD38 antibody,” said Peter C. Adamson, MD, global head of oncology clinical development and pediatric innovation at Sanofi, in the press release.
In addition, a PFS analysis based on censoring rules recommended by the FDA to align with US prescribing information showed a significantly extended median PFS with the isatuximab-based triplet, compared with carfilzomib and dexamethasone alone (41.7 months vs. 20.8 months; HR = 0.59; 95% CI, 27.1-not estimable). These data represent the longest median PFS seen in the studies of second-line therapy with a proteasome inhibitor backbone for patients with relapsed myeloma.
The median time to next treatment was also significantly longer among patients assigned isatuximab (44.9 months vs 25 months), and no new safety signals for isatuximab were observed. The most common treatment-emergent adverse events of any grade were infusion-related reaction (isatuximab vs control, 45.8% vs 3.3%), diarrhea (39.5% vs 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), fatigue (31.6% vs 20.5%), dyspnea (30.5% vs 22.1%), pneumonia (27.1% vs 21.3%), back pain (25.4% vs 21.3%), insomnia (25.4% vs 24.6%) and bronchitis (24.3% vs 12.3%).
Patients assigned to isatuximab experienced an increased rate of grade 3 or higher adverse events (83.6% vs 73%) and serious adverse events (70.1% vs 59.8%). However, differences did not persist after adjustment for exposure.
Data from this analysis were presented at the European Society for Medical Oncology Virtual Plenary on May 19, 2022.
“The increase in PFS, observed consistently across all subgroups, when adding [isatuximab] to carfilzomib and dexamethasone is remarkable in patients with relapsed multiple myeloma in a proteasome inhibitor combination,” said Philippe Moreau, MD, head of hematology at University Hospital of Nantes (France). “Relapse is common in multiple myeloma, creating the need for differentiated second-line treatments that provide patients a longer period of time without disease progression. This updated analysis reinforces the potential for [isatuximab] to become a new standard of care for patients with relapsed multiple myeloma.”
Belantamab mafodotin (Blenrep): a monoclonal antibody conjugate against BCMA will be withdrawn from marketing as of 11/22/2022 at the request of the U.S. FDA. This request was based on the outcome of the DREAMM-3 phase III confirmatory trial, which did not meet the requirements of the U.S. FDA Accelerated Approval regulations.
The drug was given speedy approval by the FDA in 2020 and approved for patients with relapsed or refractory multiple myeloma who received at least four previous therapies.
Standard Tx for New patients: ASCO 2022
RVd x8 (Group A) vs.
RVd x3 + ASCT + RVd x 2 (G. B)
Both Revlimid maintenance x3-4 yrs.
- PFS: 4 yrs vs 5 2/3 yrs.
- 4-yr OS: 84% vs 85%
Patients treated with lenalidomide, bortezomib, and dexamethasone (RVd) with or without autologous stem cell transplantation (ASCT) and followed by lenalidomide maintenance significantly extended progression-free survival among those with newly diagnosed multiple myeloma, according to data from a phase-3 trial recently presented at the ASCO2022 Annual Meeting.
“Optimal use of triplet/quadruplet induction, ASCT, and [lenalidomide]-based maintenance in patients with newly diagnosed multiple myeloma who are eligible for transplant continues to evolve,” Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Boston, and colleagues wrote. “The IFM 2009 trial, which used [lenalidomide] maintenance for 1 year, showed progression-free survival…but no overall survival benefit…with RVd + ASCT vs RVd alone in the setting of multiple elective options at relapse, including ASCT at first relapse in 77% of patients.”
The researchers enrolled a total of 722 newly diagnosed multiple myeloma patients aged 18-65 years who were randomly assigned to receive three RVd cycles, stem cell mobilization, and then five more RVd cycles (Arm A) or IV melphalan 200 mg/m + ASCT and two RVd cycles (Arm B) in the US DETERMINATION trial, which used lenalidomide maintenance until progression.
Each 21-RVd cycle comprised 25 mg twice daily lenalidomide (days 1-14), IV/SC bortezomib 1.3 mg/m (days 1, 4, 8, 11), and dexamethasone 20 mg twice daily in cycles 1-3 (days 1, 2, 4, 5, 8, 9, 11, 12) and 10 mg twice daily for each subsequent cycle (days 1, 2, 4, 5, 8, 9, 11, 12) and both cohorts received lenalidomide 10-15 mg/day of maintenance until progression or intolerance. The study had a primary endpoint of PFS, and the data cutoff was December 10, 2021.
Arms A and B were comprised of 357 and 365 patients, respectively. The median age of patients included in the study was 57 and 55 years, 14% and 13% had ISS stage III multiple myeloma, and 18% of patients in each group had high-risk cytogenetics. A total of 291 and 290 patients in the respective groups received lenalidomide maintenance for a median duration of 36 and 41 months. A median follow-up of 76 months and 328 events showed a median PFS of 46.2 vs 67.6 months in Arm A vs Arm B (HR = 1.53; 95% CI, 1.23-1.91; P < .0001).
Researchers reported 52% of patients in Arm A and 62% of patients in Arm B achieved complete response; 79% vs 83%, respectively, achieved at least very good partial response; and 94% vs 95%, respectively, achieved partial response.
Among 251 evaluable patients, MRD negativity (10-5) was achieved among 37.3% of patients in Arm A compared with 52.1% in Arm B (P = .021) within 1 year of maintenance.
About half of patients in each arm went on to receive subsequent treatment (63% vs 53%). In Arm A, 22% had ASCT as the first non-protocol therapy. With 90 vs 88 patients having died in Arm A vs B, 4-year OS was 84% (95% CI, 80-88%) vs 85% (95% CI, 81-88%) (HR = 1.10 ; 95% CI, 0.81-1.47; P = .274).
Treatment related grade ≥ 3 adverse events were less common among patients in Arm A vs B (78 vs 94%; hematologic: 61 vs 90%; P < .0001); 10 vs 11% had secondary malignancies (ALL, 7 vs 3 patients, P = .22; AML/MDS, 0 vs 10 patients, P = .002).
In assessing quality of life, researchers noted a difference in mean change from baseline in EORTC QLQ-C30 global health status score of less than 10 points throughout treatment, except at RVd cycle 5 vs post-ASCT (compliance rate, 75% vs 55%; mean change +3.0 vs -11.1; P < .0001).
Whole-genome sequencing, additional quality of life, and correlative analyses are ongoing. “RVd± ASCT and [lenalidomide] maintenance to progression resulted in the longest median PFS reported for each approach, and a highly significant 21.4-mo gain in median PFS benefit using RVd + ASCT,” Richardson and colleagues wrote in the abstract. “No OS advantage has been observed to date.”
Myeloma CAR T-Cell Therapy Produces Deep and Durable Responses
Ciltacabtagene autoleucel (Cilta-cel) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy
It was FDA-approved in February 2022 for R/R MM with more than four lines of therapy based on the phase Ib/II CARTITUDE-1 study. Ciltacabtagene autoleucel has, to date, the best response rates, PFS, and DoR of the CAR-T products that are-or have been-in various clinical trials.
- Ninety-seven advanced myeloma patients had an ORR of 98% and sCR rate of 82.5% with high rates of MRD negativity after a single ‘one and done’ infusion of cilta-cel. This forms the basis of studies being done now in earlier lines of therapy including in high-risk and newly diagnosed myeloma patients.
- Follow up study confirmed the efficacy of Cilta-cel therapy.
meetings.asco.org/abstracts-presentations/207899
Teclistamab
On 10/25/2022, the FDA approved teclistamab-cqyv for the treatment of patients with relapsed or refractory multiple myeloma, making it the first bispecific T-cell engager antibody approved for this indication.
MajesTEC-1
The FDA based its approval on results from the clinical trial, a pivotal phase 2 study of heavily pretreated patients with relapsed or refractory multiple myeloma.
Treatment with teclistamab produced an overall response rate of 61.8% (95% CI, 52.1-70.9), with 28.2% of patients achieving a complete response or better. The estimated duration of response at 6 months was 90.6% (95% CI, 80.3-95.7) with a 9-month estimated duration of response of 66.5% (95% CI, 38.8-83.9).
In the study, teclistamab was well tolerated. Commonly observed adverse events included pyrexia, cytokine release syndrome, musculoskeletal pain, injection site reactions, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. Grade 3-4 abnormalities affecting more than 20% of patients included decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.
Based on these results, the FDA granted accelerated approval to teclistamab. Continued approval may depend upon further verification.
NCCN guidelines update for multiple myeloma treatment
NCCN recommends the following primary therapies for transplant candidates8:
* Bortezomib + lenalidomide + dexamethasone (preferred, Category 1)
* Carfilzomib + lenalidomide + dexamethasone (preferred, Category 2A)
* Daratumumab + lenalidomide + bortezomib + dexamethasone (other recommended)
NCCN also provides multiple alternative primary therapy regimens that are useful in certain circumstances. Following primary therapy, NCCN recommends maintenance therapy with lenalidomide (preferred, Category 1), bortezomib (other recommended, Category 2A), daratumumab (other recommended, Category 2A), or ixazomib (other recommended, category 2B).
Patients With Newly Diagnosed MM Ineligible for HDT and ASCT
For patients who are not candidates for transplantation, the NCCN recommends the following primary therapies:
* Bortezomib + lenalidomide + dexamethasone (preferred, Category 1)
* Daratumumab + lenalidomide + dexamethasone (preferred, Category 1)
* Daratumumab + bortezomib + melphalan + prednisone (other recommended, Category 1)
* Carfilzomib + lenalidomide + dexamethasone (other recommended)
* Ixazomib + lenalidomide + dexamethasone (other recommended)
* Daratumumab + cyclophosphamide + bortezomib + dexamethasone (other recommended)
Following primary therapy, NCCN recommends maintenance therapy with lenalidomide (preferred, Category 1), ixazomib (other recommended, category 2B), bortezomib (other recommended, category 2A), or bortezomib + lenalidomide (useful in certain circumstances, Category 2A).
Refractory/Relapsed Disease
The NCCN guidelines provide multiple treatment options for patients with RRMM, with treatment recommendations divided into early relapse (1 to 3 prior therapies) and late relapse (> 3 prior therapies). Of note, patients who did not receive ASCT or who had a prolonged response to ASCT should be considered for ASCT.
Early Relapse (1 to 3 prior therapies)
If a patient was treated with an induction regimen and then relapsed after > 6 months, that same regimen may be repeated. Patients with lenalidomide-refractory disease should be considered for a lenalidomide-free triplet regimen. NCCN Guidelines provide a comprehensive list of preferred, recommended, and useful regimens for early relapses.
Preferred regimens for early relapse include ixazomib + lenalidomide + dexamethasone (Category 1) and bortezomib + lenalidomide + dexamethasone (Category 2A). NCCN notes, however, that for patients who are still sensitive to bortezomib and/or lenalidomide, any of these regimens may be appropriate. The remaining preferred regimens are divided into the bortezomib-refractory category and the lenalidomide-refractory category. NCCN also provides recommendations based on how many therapies a patient has received and which type; clinicians should consult the latest NCCN guidelines for detailed instructions.
Bortezomib-refractory regimens8:
* Daratumumab + lenalidomide + dexamethasone (Category 1)
* Daratumumab + carfilzomib + dexamethasone (Category 1)
* Carfilzomib + lenalidomide + dexamethasone (Category 1)
* Isatuximab-irfc + carfilzomib + dexamethasone (Category 1)
* Carfilzomib + pomalidomide + dexamethasone
Lenalidomide-refractory regimens:
* Daratumumab + carfilzomib + dexamethasone (Category 1)
* Daratumumab + bortezomib + dexamethasone (Category 1)
* Isatuximab-irfc + carfilzomib + dexamethasone (Category 1)
* Carfilzomib + pomalidomide + dexamethasone
Late Relapse (> 3 prior therapies)
For patients who have been treated with > 3 therapies, NCCN recommends bendamustine, bendamustine + bortezomib + dexamethasone, bendamustine + carfilzomib + dexamethasone, bendamustine + lenalidomide + dexamethasone, or high-dose or fractionated cyclophosphamide (all Category 2A recommendations).8
Patients with late relapses who have received at least 4 prior therapies (including an anti-CD38 monoclonal antibody, a PI, and an immunomodulatory agent) may be treated with any of the following:
* Belantamab mafodotin-blmf (an ADC that targets BCMA)
* Idecabtagene vicleucel (a cell-based gene therapy)
* Ciltacabtagene autoleucel (a cell-based gene therapy)
* Teclistamab-cqyv (ahuman bispecific monoclonal antibody)
For patients who have received at least 4 prior therapies and whose disease is refractory to a least 2 PIs, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody, NCCN recommends selinexor + dexamethasone.
Second Revision of the International Staging System (R2-ISS) published by European Myeloma Network (EMN) in October 2022 incorporated del(17p), f(4:14) and 1q+ as the adverse prognostic chromosomal abnormalities and delete t(14;16).
However the authors forgot to describe the scoring system: Which adverse prognostic factors get how many points?
ascopubs.org/doi/full/10.1200/JCO.21.02614
R2-ISS, it helps predict both progression-free survival (PFS) and overall survival (OS) in patients with MM. According to data on 7072 patients at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. The R2-ISS stratifies patients into 4 risk groups according to the total additive score: low (0 points), low-intermediate (0.5-1 points), intermediate-high (1.5-2.5 points), high (3-5 points).
Median OS and PFS:
Low risk: not reached; 68 months
Low-intermediate: 109.2 months; 45.5
Intermediate-High: 68.5; 30.2
High risk: 37.9 months; 19.9 months
www.nejm.org/doi/full/10.1056/NEJMoa2203478?query=TOC
Teclistamab is a bispecofic targeted treatment directed at CD3 expressed on T cells and B-cell maturation antigen (BCMA) expressed on myeloma cells. In a phase 1 study, 40 patients with relapsed or refractory myeloma were treated with intravenously administered teclistamab (1.5 mg/kg every week), with 65% achieving a partial response or better.
The phase 2 portion of the study enrolled 165 patients with relapsed or refractory disease after at least three previous therapy lines. In total, 77.8% of the cohort had triple-class refractory disease after prior treatment with an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody.
The median age of patients in phase 2 was 64 years (range, 33-83), with 15.2% of the cohort (n = 19) aged ≥ 75 years. Men comprised 56% (n = 70) of the study population. The median time since diagnosis was 6.2 years (range, 0.9-22.7).
Weekly subcutaneous administration of teclistamab at 1.5 mg/kg was selected as the recommended phase 2 study dose. Overall response rate served as the primary endpoint.
Median follow-up was 14.1 months (range, 0.3-24.4). The ORR was 63% (n = 104; 95% CI, 55.2-70.4), with 58.8% (n = 97) achieving a very good partial response or better and 39.4% (n = 65) achieving a complete response or better. The researchers observed a median time to first response of 1.2 months (range, 0.2-5.5) and a median time to best response of 3.8 months (range, 1.1-16.8).
In addition, minimal residual disease negativity occurred in 44 patients (26.7%; 95% CI, 20.1-34.1), and 46% (n = 30) of patients with a complete response or better had no minimal residual disease.
Responses were durable, with a median duration of response of 18.4 months (95% CI, 14.9-not estimable). The researchers estimated a 68.5% (95% CI, 57.7-77.1) maintenance of response at 12 months. The median progression-free survival of 11.3 months (95% CI, 8.8-17.1).
Adverse events were reported for all patients in the phase 1 and phase 2 portions of the study. A total of 119 patients (72.1%) developed cytokine release syndrome, the majority of which were grade 1 or grade 2. Other frequent adverse events included neutropenia (70.9%; grade 3-4, 64.2%), anemia (52.1%; grade 3-4, 37%) and thrombocytopenia (40%; grade 3-4, 21.2%).
In total, 76.4% of patients developed infections, of which 44.8% were grade 3 or grade 4. Twenty-four patients developed neurotoxic events, including five cases of immune effector cell-associated neurotoxicity.
At the time of reporting, 68 patients had died, mostly due to progressive disease (n = 41). The researchers determined that five patient deaths were related to teclistamab, including COVID-19 (n = 2), streptococcal pneumonia (n = 1), hepatic failure (n = 1), and treatment discontinuation due to progressive multifocal leukoencephalopathy (n = 1).