Our final day at ASH provided a glimpse of a number of different topics from the use of the Bcl-2 inhibitor Venclexta (venetoclax) for patients with the t(11;14) chromosomal translocation, minimal residual disease (MRD) detection, more promising results from bispecific antibody clinical trial, and the first data on a new class of therapy—immunocytokines. We’ve tried to capture all the information for you!
Venclexta Combination for Relapsed/Refractory Myeloma
We learned about the final results from the phase 3 BELLINI trial on Saturday regarding the use of Venclexta in patients with relapsed/refractory myeloma. In the BELLINI trial it was confirmed that patients with the t(11;14) translocation benefited the most when Venclexta was combined with Velcade-dex. In a phase 2 study by Dr. Jonathan Kaufman from Emory University, 41 relapsed/refractory myeloma patients were treated with either Venclexta-Darzalex-dex or Darzalex-Velcade-dex (ABSTRACT 817). Preliminary analysis showed that more patients responded to the Venclexta combination than the Darzalex-Velcade combination (86% to 87% at various Venclexta doses tested vs 63%). Also, more patients achieved minimal residual disease (MRD) negativity. No treatment-related deaths occurred with Venclexta treatment. These data provides more evidence that Venclexta is an appropriate option for relapsed/refractory patients with t(11;14).
Mass Spectrometry Testing
Clinicians in the United Kingdom presented their research on the use of mass spectrometry (MS) to detect free light chains (FLCs) in the blood as a potentially more sensitive test to detect MRD in patients after therapy (ABSTRACT 820). As a reminder, MRD is currently measured using a bone marrow sample and myeloma cells that may remain are detected using one of two methodologies: (1) flow cytometry, or (2) next-generation sequencing (a test called ClonoSeq).
In their study, 293 newly diagnosed patients were treated with Kyprolis-Revlimid-Cytoxan-dex followed by an autologous stem cell transplant (ASCT) and then randomized to maintenance therapy with either Revlimid or observation only. MS measurements were performed after induction therapy, 100 days after ASCT, and then after patients were randomized to either maintenance group. The results showed:
- MS positivity (that is, being able to detect FLCs in blood using this methodology) was associated with patients having a shorter time until disease progression compared to being MS negative
- In patients who achieved a complete response (CR) or stringent CR, 16% to 34% were MS positive following induction, ASCT, or prior to maintenance and these patients also had a shorter time until disease progression compared to being MS negative and in CR/sCR
- Some patients who were MRD negative (by flow cytometry at a sensitivity of 4 × 10-5) and also MS positive also had a shorter time until disease progression compared to being MRD negative and MS negative
Ultimately, MS may provide a useful alternative to bone marrow testing to detect MRD in patients and may even help to identify patients at increased of early relapse if they are MRD negative but MS positive during maintenance therapy.
To learn about bispecific antibodies discussed during Day 1 of ASH, please check out our blog here.
In a small retrospective analysis, Dr. Tarek Mouhieddine at the Icahn School of Medicine at Mount Sinai evaluated the clinical outcome of 61 relapsed/refractory myeloma patients after relapsing from bispecific antibody treatment targeting BCMA or GPRC5D (ABSTRACT 821). The majority of the patients evaluated in this analysis had previously received at least six prior lines of therapy and a prior ASCT; some patients had even had prior bispecific antibodies, CAR T-cell therapy, or antibody-drug conjugate treatment (Blenrep).
- With respect to the treatments these patients received following their relapse from bispecific antibody treatment, 33% received a second bispecific antibody or CAR T-cell therapy, 33% received triplet therapy, and 19% received an intensive chemotherapy regimen.
- 58% of patients responded to their treatment, but patients who received another bispecific antibody or CAR T-cell therapy fared the best.
These results suggest that patients who relapse from bispecific antibodies may still have a good outcome especially if receiving another T-cell-directed therapy like bispecific antibodies or CAR T cells and it will be important to research in the future the appropriate sequence of these treatments once bispecifics are an approved therapy for patients.
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% were triple-class refractory, 22% had received prior BCMA-targeted therapy) received elranatamab subcutaneously (that is, under the skin as an injection as opposed to an infusion) (ABSTRACT 895). Investigators from Canada and the US reported:
- Common side effects included low white blood cell, platelet, and red blood cell counts
- 87% of patients experienced cytokine release syndrome
- 69% responded at the highest dose which is the recommended phase 2 dose—that is, the dose deemed safe and effective to be studied in larger trials; including 70% of patients with prior BCMA-directed therapy
- All patients with a CR or better achieved MRD negativity (measured by next-generation sequencing at a sensitivity of 1 × 10-5)
International investigators presented updated results from the MajesTEC-1 trial on 165 relapsed/refractory myeloma patients treated at the recommended phase 2 dose of BCMA-targeted teclistimab (ABSTRACT 896). Patients with a median of 5 prior lines of therapy received teclistamab as a subcutaneous injection. Results showed:
- 72% of patients experienced cytokine release syndrome; 2.5% developed neurotoxicity
- Other common side effects included injection site reaction, fatigue, and low white blood cell, platelet, and red blood cell counts
- 62% of patients responded to treatment
TNB-383B (also known as ABBV-383)
Dr. Shaji Kumar at the Mayo Clinic investigated the clinical efficacy of another BCMA-targeted bispecific antibody called TNB-383B in patients with relapsed/refractory myeloma (ABSTRACT 900). Dr. Kumar and his colleagues treated 118 patients—61% were triple-class refractory and had a median of 5 prior lines of therapy —with TNB-383B at different doses. The results showed:
- 81% of patients responded to treatment at doses 40 mg or more
- 54% of patients experienced cytokine release syndrome
Clinical development of all these bispecific antibodies continues. We look forward to hearing more about these agents at future meetings!
Blenrep (belantamab mafodotin)
Antibody–drug conjugates (ADCs) are antibodies that are combined with a cancer-fighting substance—either a drug or a toxin. The antibody part binds to a myeloma cell and the cancer drug kills the myeloma cell. The first ADC, which targets BCMA on myeloma cells—Blenrep (belantamab mafodotin)—was approved as a single agent in 2020 for treatment of relapsed or refractory myeloma patients. At this meeting, results from the DREAMM-5 study—evaluating the combination of Blenrep with feladilimab (a molecule that helps activate cancer-fighting T cells) in relapsed/refractory myeloma patients—were presented by international investigators (ABSTRACT 897).
- 25 patients who had received a median of 5 prior lines of therapy were treated with Blenrep-feladilimab at different doses.
- Overall, 52% of patients responded—which is an improvement on the ~30% response rate seen in the DREAMM-2 study that led to Blenrep’s approval (please note that the DREAMM-5 study was not a comparative trial).
- Also, approximately 70% of patients experienced ocular (eye) side effects.
This study is ongoing.
A New Class of Drug: Immunocytokines
Data on an agent from a new class of drug called the immunocytokines was presented by Dr. Dan Vogl at the University of Pennsylvania. Immunocytokines are engineered to deliver cytokines (a protein produced by immune cells) that can prevent myeloma cells from dividing and to help boost myeloma-fighting immune cells. In a phase 1 study, an immunocytokine drug called modakafusp alfa was evaluated (ABSTRACT 898). Modakafusp alfa is an antibody that can bind to CD38 on myeloma cells (similar to the two anti-CD38 antibodies Darzalex and Sarclisa) that is fused to the cytokine interferon (IFN) alpha. However, modakafusp alfa binds to a different site on CD38 than Darzalex and Sarclisa. Modakafusp alfa was administered to 29 patients who had a median of 7 prior lines of therapy (97% of patients had previously received an anti-CD8 antibody) at a dose of 1.5 mg/kg and the results showed:
- Common side effects included low white blood cell, platelet, and red blood cell counts, fatigue, and infusion reactions
- 38% of patients responded to treatment
- 38% of patients responded who were refractory to anti-CD38 antibody treatment
- 75% of patients responded who received an anti-CD38 antibody in their most recent line of therapy prior to enrollment on this trial
- 20% of patients responded who received BCMA-targeted therapies
Possibly an effective option for patients who have relapsed from Darzalex or Sarclisa? We look forward to further updates on this agent.
As always, thanks for following along with us! We’ll be back at it again next year before you know it. Until then, stay safe, and Happy Holidays to all!