Welcome to our 2022 recap of the latest updates on myeloma treatments reported at the American Society of Hematology (ASH) meeting that kicked off Saturday in New Orleans. Some of the studies presented provided updates to data previously presented at meetings earlier this year and late last year. Let’s dig into a big day of updates in myeloma treatment.
Tecvayli is the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated relapsed refractory multiple myeloma (RRMM). Dr Emma Searle and colleagues presented results from phase 1 MajesTEC-2 trial on 32 relapsed/refractory myeloma patients treated with Tecvayli-Darzalex-Revlimid, the first fully immune-based triplet treatment combination (ABSTRACT 160). The median prior lines of therapy were 2 (range of 1-3), and 31% had received a CD38 monoclonal antibody. Results showed that 93.5% of patients responded to treatment:
- 81% of patients experienced cytokine release syndrome (which is a flu–like syndrome in which a patient experiences fevers, chills, and low blood pressure after administration of a bispecific antibody)
- 75% developed neurotoxicity
- Other common side effects included fatigue, diarrhea, insomnia, cough, and upper respiratory infections
The authors conclude that Tecvayli-Darzalex-Revlimid was well tolerated, with a safety profile consistent with Tecvayli or Darzalex-Revlimid individually. Promising response rates rarely seen in this population supports the potential for this combination to have enhanced early disease control through the addition of Tecvayli. The randomized phase 3 MajesTEC-7 study will compare Tecvayli-Darzalex-Revlimid versus the combination of Darzalex-Revlimid-dexamethasone in newly diagnosed multiple myeloma patients not eligible for or not intending to pursue autologous stem cell transplant as initial treatment.
Talquetamab is a first-in-class, T-cell redirecting bispecific antibody targeting GPRC5D on myeloma cells and CD3 receptors on T cells. Last week Janssen submitted a Biologics License Application to the U.S. Food and Drug Administration for talquetamab for the treatment of patients with RRMM. Dr. Ajai Chari and researchers presented results from a phase 2 study of talquetamab as administered as an injection as opposed to an infusion which is how most other bispecifics are given at 2 different doses (0.405 mg/kg weekly and 0.8 mg/kg every other week) in relapsed/refractory patients (ABSTRACT 157). Eligible patients had RRMM or were intolerant to standard therapies. Patients had received at least 3 or more lines of prior therapy or were double refractory to a proteasome inhibitor such as Velcade and/or Kyprolis and an immunomodulatory drug such as Revlimid and/or Pomalyst. Prior treatment with a CD38 monoclonal antibody was allowed with a 90-day washout; prior BCMA-directed therapies were permitted. The results showed:
- 74% of patients responded to talquetamab 405 μg/kg once a week
- 73% of patients responded to talquetamab 800 μg/kg once every other week
- Median progression free survival (the time before disease progression) was 7.5 months and 11.9 months for talquetamab 405 μg/kg and 800 μg/kg, respectively
- Common side effects included cytokine release syndrome, dry mouth, low white cell counts, skin-related side effects, and infections
The authors conclude that talquetamab shows highly promising efficacy in a heavily pretreated RRMM patient population. An ongoing phase 3 study is comparing talquetamab with approved therapies.
Updated results were presented on the MagnetisMM-1 trial, a phase 1 trial investigating the safety and efficacy of the BCMA-targeted bispecific antibody elranatamab as a single agent. Fifty-five patients who had been exposed to a median of 6 prior treatments (91% no longer responded to three classes of standard therapies; 24% had received prior BCMA-targeted therapy) received elranatamab subcutaneously (via injection) (ABSTRACT 158). Dr Noopur Raje and investigators reported:
- 64% responded to elranatamab, with 54% of patients who had received prior BCMA-targeted therapy (such as CAR T-cell therapy) achieving a response
- Median progression-free-survival (PFS) or basically time until the disease came back was 11.8 months
- Common side effects included low white blood cell, platelet, and red blood cell counts
- 67% of patients experienced cytokine release syndrome
Dr Nizar Bahlis presented results from the MagnetisMM-3 trial (ABSTRACT 159), a phase 2 study of elranatamab in patients with RRMM (exposed to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody). One hundred and twenty-three patients with relapsed/refractory myeloma (exposed to at least 6 prior lines of therapy) were treated with Darzalex (subcutaneously) and differing doses of talquetamab. Results showed:
- 61% of patients responded to treatment
- 53% of patients experienced CRS
The researchers suggest that subcutaneous elranatamab is efficacious and has a manageable safety profile in patients with triple-class- and penta-drug refractory MM and no prior BCMA-targeted treatment. These results support continued development of elranatamab for pts with MM.
Alnuctamab is a bispecific antibody that targets BCMA on myeloma cells and CD3 receptors on T cells that is being evaluated in a phase 1 study for patients who have been exposed to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ABSTRACT 162). Results collected from 55 patients treated with alnuctamab found:
- 53% of patients responded to treatment
Cytokine release syndrome and low red and white blood counts were the most common side effects, which is consistent with other similar therapies.
Dr Carmelo Carlo-Stella reported findings from a phase 1 study of RG6234, a bispecific antibody targeting GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, and CD3 receptors on T cells (ABSTRACT 161). One hundred and five patients with relapsed/refractory myeloma (exposed to at least a proteasome inhibitor and an immunomodulatory drug) were treated with differing doses of RG6234 (subcutaneously or intravenously). Results showed:
- 71% responded to intravenous RG6234
- 64% responded to subcutaneous RG6234
- Cytokine release syndrome was the most common side effect
Antibody-based Treatment Regimens
Dr. Paul Richardson from the Dana-Farber Cancer Institute presented updated data from the ICARIA-MM phase 3 trial which compared Sarclisa-Pomalyst-dexamethasone with Pomalyst- dexamethasone in 307 patients with relapsed or refractory myeloma (Abstract 247). Sarclisa is an antibody in the same class as Darzalex. The initial results from this trial were the basis for the approval of Sarclisa in combination with Pomalyst-dexamethasone.
In the follow-up analysis presented by Dr. Richardson, the findings showed how patients fared on subsequent therapies after no longer being on Pomalyst-dexamethasone with or without Sarclisa:
- 23% of patients on Sarclisa-Pomalyst-dexamethasone went on to receive Darzalex compared with 60% of patients treated with Pomalyst- dexamethasone
- Response rates to Darzalex monotherapy in patients previously treated with Sarclisa-Pomalyst- dexamethasone was 13% compared to 37% in patients previously treated with Pomalyst- dexamethasone
- Response rates to Darzalex combination therapy in patients previously treated with Sarclisa-Pomalyst-dexamethasone was 29% compared to 45% with Pomalyst-dexamethasone
The researchers conclude that immediate use of an anti-CD38 monoclonal antibody such as Darzalex with currently available combinations appears to be less effective following treatment with Sarclisa-Pomalyst-dexamethasone. These findings will help guide the best sequencing of treatment for patients.
CAR-T Cell Therapy
Patients with MM who relapse early after frontline therapy with autologous stem cell transplant (ASCT) have a poor prognosis. In the pivotal phase 2 KarMMa study, treatment with the BCMA-directed chimeric antigen receptor (CAR) T cell therapy Abecma resulted in frequent, deep, and durable responses in patients who were triple-class exposed and refractory to last treatment. In this presentation, Dr Krina Patel presented data collected from 37 patients who were treated with Abecma after early relapse within 18 months of frontline therapy with ASCT and Revlimid maintenance (Abstract 361). The results showed:
- 84% of patients responded to treatment
- 70% of patients achieved MRD negativity after 1 year of treatment
- Median PFS was 11.4 months
- Most common side effects were low white blood cell counts (95%) and cytokine release syndrome (81%)
The researchers conclude that these results support a favorable clinical benefit-risk profile of Abecma and its potential use in earlier lines of treatment.
CAR T cell therapies targeting B‑cell maturation antigen (BCMA) have resulted in unprecedented responses in RRMM; however, relapses are frequent, and the development of new approaches is needed. Dr Susan Bal and colleagues presented interim results from a phase 1 dose-finding study of BMS-986393, a GPRC5D-targeted CAR T cell therapy, in patients with RRMM (Abstract 364). Patients enrolled in the trial had at least 3 prior lines of therapy containing a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and, unless ineligible, a stem cell transplant. The results showed:
- Most common side effects were cytokine release syndrome, and low white blood cell and platelet counts
- 12 of 19 patients (89.5%) responded to therapy
- o 78% of patients who received prior BCMA-targeted therapy responded
These results appear promising, especially for patients who relapse following BCMA-targeted treatment. The dose-finding trial is ongoing and additional updates will be presented at future meetings.
GC012F is a new, dual-targeting CAR-T cell therapy that binds to BCMA and CD19 on myeloma cells and is manufactured within 24 hours of removal of plasma from a patient. Dr Juan Du and colleagues reported their findings from a phase 1 trial of GC012F in high-risk, transplant-eligible patients with NDMM (Abstract 366). Patients were considered high-risk if they had one or more of the following features: R-ISS-2 or-3; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease; IgD or IgE subtype; LDH > the upper limit of normal; or any of the high-risk definition of mSMART3.0. The results showed:
- All 13 patients achieved a response and MRD negativity (the deepest response that is measurable) following 5 months of treatment
- Cytokine release syndrome occurred only in three pts (23%) with 15% grade 1 (n=2) and 8% grade 2 (n=1), respectively
The authors conclude that these promising preliminary results require further assessment of GC012F for transplant-eligible NDMM with more patients and longer follow-up.
Racial disparities exist in incidence and survival from myeloma and other blood cancers, and these differences are driven by multiple factors the most influential likely being access to clinical trials. Black patients only make up 5-7% of participants in cancer clinical trials, despite accounting for 14% of the population in the United States and more than 20% of multiple myeloma patients. Dr Shakira Grant presented two abstracts (Abstract 360 and Abstract 363) in Patient Representation and Equity in Hematologic Malignancies. Dr Grant and researchers conducted focus groups with Black patients with MM and interviewed hematologists to identify factors that influence Black participant enrollment in hematology-focused clinical trials).
Dr Grant and colleagues reported that the relationship between the patient and their hematologist is one of the most influential drivers of whether Black patients are given an opportunity to participate in clinical trials. Additional factors include 1) race and socioeconomic status-based bias and stereotyping on the part of hematologists, 2) the legacy of medical mistrust among Black persons, 3) geographic barriers, and 4) the use of stigmatizing languages such as the word “trial.”
Researchers reported that addressing disparities in clinical trial enrollment among Black participants requires numerous interventions such as
- Building better patient-clinician relationships
- Improving clinical trial availability and partners in the community
- Providing support to overcome logistical barriers
- Acknowledging and finding strategies to address physician biases
Increasing equitable access to clinical trials and ensuring our own research efforts are representative of the broader multiple myeloma population in the US are priorities for the MMRF, reflected in our most recent strategic plan.
MyDRUG Platform Trial
Dr Shaji Kumar presented findings from the MMRF’s MyDRUG platform trial (Abstract 1931). Unlike traditional clinical trials, which test one drug or a single combination of drugs, the MyDRUG platform trial is a phase 1/2 study of patients with RRMM, who have received at least one prior but no more than 3 prior therapies and were exposed to both a proteasome inhibitor and an immunomodulatory drug and had early relapse after initial treatment or were primary refractory to initial treatment. Through different subprotocols, patients received targeted agents, immunotherapy, or novel agents in combination with a backbone regimen of Ninlaro/Pomalyst/dexamethasone, also known as IPD.
In this abstract, Dr Kumar and colleagues reported data collected from thirty-eight patients who were treated with Darzalex plus IPD. Results showed:
- 92% of patients responded to Darzalex plus IPD, with half achieving a very good partial response
- 97% experienced a side effect, 92% of which were related to Darzalex
Stay tuned for more updates from ASH 2022!