Each year, myeloma sessions at the American Society of Hematology (ASH) Summit have different patterns of interest and importance. This year, bispecific antibodies became the area of great excitement, with results from many trials reported.
Focus on Talquetamab
Talquetamab is “an investigational, off-the-shelf (ready to use), bispecific T-cell engager antibody. Talquetamab targets both GPRC5D, a novel target on multiple myeloma cells, and CD3 on T cells, activating the body’s immune system to fight this blood cancer,” according to Johnson & Johnson’s press release.
Abstract #157: Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1 garnered the most interest, with participants of the oral session spilling over five extra rooms.
G protein-coupled receptor, class C, group 5, member D (GPRC5D) is highly expressed in myeloma cells and is targeted by talquetamab—a novel, first in class, off-the-shelf antibody. This has been studied in the MonumenTAL-1 trial and updated results were reported at ASH. The report included patients previously treated with CAR T cells and other bispecific antibodies.
Overall response rates (ORR) were very similar, at 73-74 percent for each of the 0.4 and 0.8mg/kg QW or Q2W SC cohorts with 57-59 percent at the >= Very Good Partial Response (VGPR) levels. For those with prior T cell-directed therapies, the ORR was 63 percent. Overall, there was a very low rate of discontinuation due to adverse events. Remarkably, the median duration of response (DOR) was >= 9 months.
The relatively high ORR allowed flexibility for dose reductions as needed to prevent toxicities and to allow continuation of treatment. It seems likely that combination therapies will be feasible and studies with teclistamab, daratumumab, immunomodulatory drugs (iMiDs), and other agents are either being planned or are ongoing.
The overall results in the heavily pretreated patient population clearly impressed the meeting participants.
Other Bispecific Antibody Results Presented
Results from five other bispecific trials were also presented:
The first four against B-cell maturation antigen (BCMA) as a target had very good ORR rates in the 50 to as high as the 83 percent range. The ABBV-383 antibody was notable in that step and up dosing was not required.
Additional datasets of interest included a follow-up on the recently FDA-approved teclistamab (Correlative analyses in Abstract #97: Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Correlative Analyses from MajesTEC‑1), in combination with Abstract #160: Teclistamab in Combination with Subcutaneous Daratumumab and Lenalidomide in Patients with Multiple Myeloma: Results from One Cohort of MajesTEC-2, a Phase1b, Multicohort Study Clinically Relevant Abstract plus RG 6234 [Abstract #161: RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study] and an NK cell trifunctional antibody: BCMA/16/NKp46 (Abstract #4486: The Novel Trifunctional Anti-BCMA NK Cell Engager SAR’514 Has Potent in-Vitro and in-Vivo Anti-Myeloma Effect through Dual NK Cell Engagement).
New Dual Target CAR T Therapy in Frontline
Although CAR T-cell therapy reports were not as dominant in recent years, a new CAR T approach in the frontline setting from Shanghai, China became notable—Abstract #366: Phase I Open-Label Single-Arm Study of BCMA/CD19 Dual-Targeting FasTCAR-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma.
Abstract # 366 evaluated a BCMA/CD19 dual-targeted FasT CAR T (GC012F) as a first line therapy. The manufacturing time for this new product was 22-36 hours—definitely much faster than the standard approaches—while producing a good quality T cell product.
Seventeen patients with newly diagnosed high-risk myeloma (mSMART 3.0 / R-ISS stage II/III) were treated. All patients responded (17/17: 100%), with all becoming minimal residual disease (MRD) negative. The lead into CAR T therapy was two cycles of Velcade, Revlimid, and dexamethasone (VRd), the Standard of Care (SOC) therapy induction, pre CAR T.
Only 29% (5/17) experienced cytokine release syndrome (CRS) which was at a grade 1-2 level. Thus, very fast deep responses were safely achieved with this strategy and now results of follow-up (since results are still early) and further studies are eagerly awaited.
Another topic of major interest was the iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) Study with a total of ten abstracts (four oral and six posters) being reported from its countrywide screening program.
The four oral abstracts from iStopMM include:
The six poster abstracts from iStopMM are as follows:
iStopMM: Icelandic Screening Datasets
There was tremendous interest in these unique datasets from a screened cohort of 75,422 persons >=40 years living in Iceland where 3,358 monoclonal gammopathy of undetermined significance (MGUS) cases were identified.
Avoiding bone marrow sampling in screened patients
Greatest attention was given to Abstract #107 which evaluates the need for upfront bone marrow sampling for MGUS patients. The goal was to predict the probability of having >=10% plasma cells in the bone marrow which would indicate more advanced disease than MGUS.
The predictors selected were:
- Type [isotype] of monoclonal protein: IgG / IgA / Biclonal
- Monoclonal protein level [ Gms /dl ]
- Freelite chain ratio (abnormal over normal)
- Total IgG , IgA and IgM levels
Using this risk model, a very high level of correlation was achieved. Because of this technique (set to give 97.3% predictability) it became possible to avoid bone marrow sampling in 366 patients (36.1 percent).
This is a remarkable step forward in potential future clinical practice— leading to a new standard of care if externally validated using other datasets of screened individuals and/or clinical MGUS patients.
A calculator app has already been developed and can be accessed at istopmm.com/riskmodel/
With this calculator, patients’ laboratory results can be entered to obtain an output of the predicted percent of plasma cells in the bone marrow. Patients and treating MDs can use these results to decide the best approach for each individual patient while considering factors such as age, cost, and preference.
If the likelihood of finding > 10 percent plasma cells is low, bone marrow sampling can be deferred if the patient and treating physician discuss and agree. If the likelihood is high, it will usually be important to go ahead with bone marrow sampling to confirm and assess disease status which may be smoldering or even active myeloma.
It is recommended that all abstracts from iStopMM be reviewed. However, there was a special comment about Abstract # 4507 which indicates that for screened individuals (with NO known illness prior to testing), there is NO correlation with underlying autoimmune disease. This calls into question prior linkage of monoclonal proteins as possible causes of autoimmune problems.
In Abstract #967, the important notion that the development of a new monoclonal protein can be temporary or transient was assessed as particularly related to very low-level proteins being detected using mass spectrometry.
Transient monoclonal proteins can come and go and may be related to an episode of infection. This leads to the classification as MGUS but only if a protein is persistent for a period of time such as 6 months.
It also leads to detailed immunological studies of both transient and stable monoclonal proteins (called MGUS).
Collectively, the iStopMM abstracts point to many new paradigms in the evaluation and management of monoclonal protein disorders.
This is the beginning of a new era in the study of early disease entities which can be precursors to myeloma and/or other lymphoproliferative disorders. Stay tuned for more new observations!
Results of the so-called CURE trials were also reported in Abstract #757: 57 Fixed Duration Therapy with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone for High-Risk Smoldering Multiple Myeloma-Results of the ASCENT Trial and Abstract #118: Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Post-Hoc Analysis of Sustained Undetectable Measurable Residual Disease (MRD).
Linked to these studies were reports made related to MRD assessment, including Abstract #865: Ultra-Sensitive Assessment of Measurable Residual Disease (MRD) in Peripheral Blood (PB) of Multiple Myeloma (MM) Patients Using Bloodflow and Abstract #866: Clinical Impact of Next Generation Flow in Bone Marrow Vs Qip-Mass Spectrometry in Peripheral Blood to Assess Minimal Residual Disease in Newly Diagnosed Multiple Myeloma Patients Receiving Maintenance As Part of the GEM2014MAIN Trial (comparing mass spectrometry and Next-Generation Flow/NGF)
Among several clinical reports, Abstract # 569: A Dexamethasone Sparing-Regimen with Daratumumab and Lenalidomide in Frail Patients with Newly-Diagnosed Multiple Myeloma: Efficacy and Safety Analysis of the Phase 3 IFM2017-03 Trial became a point of interest because of a dexamethasone sparing regimen of lenalidomide + daratumumab for elderly/frail patients.
Potential Curative Approaches
Abstract #757: The ASCENT Trial
In Abstract #757, the results of the ASCENT trial were presented. This fixed duration aggressive induction for patients with high-risk smoldering multiple myeloma (HR SMM) utilized the combination of daratumumab, carfilzomib, lenalidomide, and dexamethasone for two years of therapy. This is an initiative of the International Myeloma Foundation’s (IMF) Black Swan Research Initiative® (BSRI).
Eighty-seven patients were enrolled in the study, with 31 percent still receiving active treatment at this time. Best overall response rate thus far is 97 percent with 84 percent of patients achieving bone marrow MRD negativity.
The median time for MRD negativity was 6.6 months with 53 cases occurring at the end of induction, 16 at the end of consolidation, and 4 at the end of maintenance. This means that more MRD negativity will be achieved as patients complete the planned therapy.
Overall results have been very good, with only 3 patients progressing—resulting in ~90% of patients being in remission in 3 years. The therapy has been well-tolerated with no unexpected toxicity signals. There is great optimism about the potential for long-term MRD negativity, with the possibility of “cure” for a fraction of the patients.
Abstract #118: The CESAR Trial
This is the longer-term follow-up from the companion trial utilizing Kyprolis (carfilzomib), Revlimid (lenalidomide) and dexamethasone (KRd) + autologous stem cell transplant (ASCT) rather than daratumumab.
The results were very similar—with 63 percent of patients achieving MRD negativity after maintenance (a little less as compared to the ASCENT trial). With almost 6 years of follow-up (70.1 months), 5 patients have progressed with 94 percent of patients still in remission. Thus far, only 7 patients have died—giving a 6-year survival rate that’s also in the 90 percent range.
Longer follow-up is required for both trials, but it is reasonable to anticipate excellent long-term benefits.
Abstracts #865 and #866: MRD Testing Approaches
In Abstracts #865 and #866, MRD testing approaches were evaluated. Abstract #865 discusses an ultrasensitive method used to enhance the NGF method to enable sensitivity to a level of 10-7 or 10-8 using blood samples. This is called the bloodflow method and shows great promise to reduce the need for bone marrow sampling.
The second study evaluated mass spectrometry testing and showed that bone marrow NGF testing, and blood mass spectrometry testing gave similar predictive information. It seems that newer blood testing approaches have the potential to substantially reduce the reliance and need for bone marrow sampling—a very promising trend for both patients and the efficiency of clinical trials.
Abstract #569: Dexamethasone Sparing Approach
There was considerable interest in a non-aggressive approach to the treatment for frail patients. In this study, lenalidomide/dexamethasone was compared to daratumumab /lenalidomide (the MAIA regimen without dexamethasone).
The non-dexamethasone regimen had excellent results and was well-tolerated. Therefore, this has become an option for elderly/frail patients although more deep responses occurred with the full MAIA regimen incorporating dexamethasone.
The Bottom Line
Overall, it was a very exciting ASH 2022 with numerous new observations and great hope for the immediate future!