By MMRF on June 7, 2022
Another American Society of Clinical Oncology (ASCO) meeting is upon us! This year brings us several updates in multiple myeloma relating to:
Let us break down for you the key findings for each one of these topics from Saturday.
| MMRF ASCO 2022 Meeting Blogs—SATURDAY, June 4 |
In the primary analysis of the phase 2 randomized GRIFFIN study, Darzalex in combination with Velcade, Revlimid, and dexamethasone (D-RVd) improved the stringent complete response (sCR) rate by end of consolidation for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). With longer follow-up, D-RVd compared to RVd improved minimal residual disease (MRD)-negativity rates in clinically relevant patient subgroups:
In this presentation, Dr. Cesar Rodriguez and colleagues presented findings from a post hoc analysis of sustained MRD negativity in the same subgroups and in patients with either a CR or a sCR (ABSTRACT 8011). The study showed:
The investigators conclude that the addition of Darzalex to RVd induction and consolidation and Revlimid maintenance may lead to durable MRD-negativity rates in patients with transplant-eligible NDMM with high-risk cytogenetics, ISS stage III, and those who achieve either a CR or sCR. The findings support the role of D-RVd as the new standard of care for this patient population. Patients should consult with their doctor for additional guidance or more information about this treatment regimen as it relates to their specific situation and care.
Dr. Andrew Yee and researchers evaluated a different quadruplet treatment regimen consisting of Darzalex, Kyprolis, Pomalyst, and dexamethasone (D-KPd) in patients with relapsed disease (ABSTRACT 8012). Preliminary results of a phase 2 study of D-KPd with a twice per week schedule of K showed an overall response rate of 86% in patients with a median of 1 prior line (including both Revlimid and a proteasome inhibitor) was reported at the American Society of Hematology meeting in 2020. Yee and colleagues reported an update of an ongoing study of Darzalex with weekly KPd (D-wKPd) to improve the accessibility of this regimen by requiring only one visit to the clinic for treatment per week. The investigators showed that D-wKPd shows some of the highest response rates (95%) reported to date in relapsed/refractory MM and conclude that this likely reflects the incorporation of 4 active drugs in 1 treatment regimen and builds on the efficacy of Darzalex-based triplet regimens.
Teclistamab
Teclistamab is a bispecific antibody that can bind to the B-cell maturation antigen (BCMA) found on myeloma cells and a cell surface protein found on T cells called CD3. Initial data from a phase 1/2 study of teclistamab as a single agent in patients with RRMM who previously received 3 or more prior lines of therapy demonstrated an overall response rate of 62.0% in patients with no prior anti-BCMA treatment. This result was significant since only 37% patients were able to achieve a response using conventional therapies such as Darzalex as a single agent. In today’s presentation, Dr. Cyrille Touzeau and colleagues report initial results from a subset of patients who had prior exposure to an anti-BCMA treatment (such as Blenrep [an antibody-drug conjugate] or Abecma or Carvykti [CAR T-cell therapy]) (ABSTRACT 8013). Of the forty patients evaluated for effectiveness, the results showed:
The investigators conclude their initial results of serial targeting of BCMA with teclistamab following Blenrep or CAR-T treatment suggest a promising overall response rate with responses occurring early and deepening over time. The results support teclistamab as a promising new, off-the-shelf, BCMA-targeting therapy for patients with RRMM who have received 3 or more prior lines of therapy.
In a separate presentation, Dr. Niels W.C.J. van de Donk and colleagues compared teclistamab with treatment used in real-world clinical practice (RWCP) in patients with RRMM who received three or more lines of therapy (ABSTRACT 8016). The researchers found that patients treated with teclistamab had improved outcomes (overall response rate, duration of response, progression-free survival, and overall survival) compared with patients who received the standard of care in RWCP. Researchers conclude that teclistamab showed significantly improved efficacy over RWCP for almost all outcomes, highlighting its potential as a highly effective treatment option for patients with RRMM who have been exposed to three or more lines of therapy.
Elranatamab
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 (ABSTRACT 8014). Dr. Andrzej Jakubowiak and colleagues reported:
Researchers concluded that single agent elranatamab induces durable clinical and molecular responses, which are consistent with clinical findings from other investigational BCMA-targeted bispecific antibodies and support the continued development of elranatamab.
Talquetamab
Talquetamab is another bispecific antibody that binds to a different surface marker on myeloma cells than BCMA—for this antibody, GPRC5D is the target on the myeloma cell. Dr. Monique C. Minnema and researchers presented updated results with additional patients and longer follow-up from MonumenTAL-1, a phase 1 trial of talquetamab in patients with RRMM (ABSTRACT 8015).
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 and an immunomodulatory drug. Prior treatment with a CD38 monoclonal antibody was allowed, except there was a 90-day washout; prior BCMA-directed therapies were permitted. Thirty patients received talquetamab 405 μg/kg weekly, with 10.0 and 60.0 μg/kg step-up doses during the first week of therapy, and forty-four patients received talquetamab 800 μg/kg once every two weeks.
Researchers conclude that talquetamab shows highly promising efficacy in a heavily pretreated RRMM patient population, including those who received at least 3 or more lines of prior therapy or were refractory to a proteasome inhibitor and an immunomodulatory drug.
Blenrep + Revlimid
Blenrep is a BCMA-targeting antibody–drug conjugate approved for patients with RRMM as monotherapy at 2.5 mg/kg once every three weeks. Preclinical data demonstrate synergy between Blenrep and Revlimid, suggesting added benefit when combined with standard of care such as Revlimid and dexamethasone. In this presentation Dr. Hang Quach reports interim analysis of 45 patients who received 1 or more doses of Blenrep combined with Revlimid and dexamethasone at various doses and schedules (ABSTRACT 8017). Seventy-five percent of patients responded to the combination. Dr. Quach and researchers concluded that Blenrep combined with Revlimid and dexamethasone had a tolerable safety profile, with no new safety signals identified in patients with RRMM. Side effects, including eye surface disorder called keratopathy, were common but manageable with dose modifications.
Blenrep + Keytruda
The next presentation by Dr. Attaya Suvannasankha reported on the safety and clinical activity of Blenrep with Keytruda (a checkpoint inhibitor approved for many different types of solid tumors, but not approved for or commonly used in patients with MM) in RRMM (ABSTRACT 8018). In this analysis of 34 patients, the median prior lines of therapy was 5; 10 pts (29%) had high-risk cytogenetics (t[4;14], t[14;16], 17p13del, or 1q21+) and 9 (26%) had extramedullary disease (that is, myeloma outside of the bone marrow). Results of this study are shown in the table below:
| Response, n (%) | Blenrep 2.5 mg/kg + Keytruda 200 mg every 3 weeks Part 2 (N=28) | Blenrep 2.5 mg/kg + Keytruda 200 mg every 3 weeks Parts 1 and 2 (N=34) |
| ORR, n (%) | 12 (43) | 16 (47) |
| ≥VGPR, n (%) | 7 (25) | 10 (29) |
| sCR | 0 | 0 |
| CR | 2 (7) | 4 (12) |
| VGPR | 5 (18) | 6 (18) |
| PR | 5 (18) | 6 (18) |
| SD | 6 (21) | 8 (24) |
| PD | 8 (29) | 8 (24) |
| NE | 2 (7) | 2 (6) |
Most patients had one or more side effect (any grade: 97%; Grade 3 or 4: 74%) and treatment-related side effects (any grade: 97%; grade 3 or more: 65%). Most common (35% or more) side effects were:
Side effects led to dose delays in 65% of patents and dose reductions in 32% of patients; however, side effects did not lead to discontinuation of treatment. Nine patients had a serious adverse event; 4 patients had one or more serious side effect related to study treatment. Two patients had immune-related adverse events of grade 1 (gout and autoimmune hypothyroidism).
Blenrep + Nirogacestat
Preclinical data demonstrate that nirogacestat, an investigational gamma-secretase inhibitor, may increase cell-surface levels of BCMA and reduce soluble BCMA levels, which could enhance anti-BCMA agent activity in multiple myeloma. In the DREAMM-5 Phase 1/2 platform trial Blenrep was evaluated in combination with nirogacestat to determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved Blenrep schedule (single agent dose 2.5 mg/kg once every 3 weeks) in patients with RRMM (ABSTRACT 8019). Single-agent Blenrep results in a 31% overall response rate and 44.5% grade 3/4 eye surface disorder. Dr. Sagar Lonial and colleagues found encouraging clinical activity (38% of patients responded) and a manageable safety profile (12.5% of patients experiencing grade 3 or higher eye side effects) with low-dose Blenrep (0.95 mg/kg once every 3 weeks) combined with nirogacestat (100 mg twice a day continuously) in patients with RRMM. This ongoing sub-study is actively recruiting patients and will continue to evaluate Blenrep combined with nirogacestat efficacy and safety.
Carvykti is approved for the treatment of adult patients with RRMM following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The approval for Carvykti was based on findings from the phase 1b/2 CARTITUDE-1 trial, in which Carvykti elicited an objective response rate of 98% and a sCR rate of 78% in this patient population. At ASCO, Dr. Hermann Einsele and colleagues evaluated the Carvykti safety and efficacy in patents with MM who received 1–3 prior lines of therapy and were refractory to Revlimid– a particularly difficult-to-treat population with a poor prognosis (ABSTRACT 8020). The study found that a single Carvykti infusion led to deepening and durable responses in patients with RMMM who had 1–3 prior lines of therapy and were refractory to Revlimid. Follow-up is ongoing.
| MMRF ASCO 2022 Meeting Blogs—SUNDAY, June 5 |
Ninlaro plus Darzalex
Frail patients with multiple myeloma (MM) often have worse outcomes as compared to other patients, especially in the relapsed setting as they are more likely to stop treatment due to side effects. Dr. Xavier Leleu and colleagues presented their results from a phase 2 study that evaluated the efficacy and tolerability of Ninlaro plus Darzalex without dexamethasone in 55 elderly frail patients with relapsed/refractory multiple myeloma (RRMM) (ABSTRACT 8000). Patient had a median age of 82 years, with 76% of patients having a frailty score of 2 or more. Researchers used a frailty score that combines age, functional status, and comorbidities that can predict survival and side effects. A higher score is associated with poor outcomes. Most patients (65%) had 1 prior line of therapy. Forty-seven patients were evaluated for high-risk cytogenetics, with 19% having 17p deletion, 17% having t(4;14), and 1 with both. Additionally, 36% of patients were refractory to Revlimid.
The study found that Ninlaro plus Darzalex (without dexamethasone!) showed a positive efficacy profile in frail, older patients with RRMM:
In Revlimid refractory patients:
In those with high-risk cytogenetics:
Grade 3 or higher side effects included low platelet levels (16%), infection (14%), high blood pressure (5%), diarrhea (4%), Darzalex infusion-related reaction (4%), and nausea or vomiting (2%). The investigators conclude that Ninlaro plus Darzalex is a potential combination for an elderly frail population include patients who are refractory to Revlimid and those with high-risk cytogenetics.
Kyprolis, Revlimid, and Dexamethasone
Maintenance treatment following ASCT for MM remains an area of active investigation and discussion. An earlier study showed that extended post-ASCT maintenance treatment with Kyprolis, Revlimid, and dexamethasone (KRd) after KRd as first-line therapy improved the depth and duration of response. In this open-label phase 3 study, Dr. Dominik Dytfeld and colleagues compared that strategy to standard Revlimid maintenance (ABSTRACT 8001). Patients with newly diagnosed MM (NDMM) who are transplant eligible and under the age of 66 years who had received induction and an autologous stem cell transplant (ASCT) were randomized to either KRd or Revlimid maintenance. About 20% of patients in each group had high-risk features, defined as either t(4;14), t(14;16), or deletion 17p. Patients in the KRd group received treatment for 6 cycles and those who achieved minimal residual disease (MRD)-negativity at that point went on to receive only Revlimid maintenance and those who did not continued with KRd for a total of 36 cycles. Results showed:
This is the first randomized phase 3 trial demonstrating superior PFS with extended post-transplant KRd therapy compared to Revlimid maintenance. The authors conclude that an MRD-directed, risk-adapted maintenance therapy strategy for extended KRd treatment following ASCT may represent a new standard of care for patients.
Darzalex, Kyprolis, Revlimid, and Dexamethasone
According to findings from the phase 2 IFM 2018-04 trial (ABSTRACT 8002), induction therapy with the quadruplet regimen of D-KRd appears to be feasible in newly diagnosed patients with high-risk cytogenetics (defined as either t[4;14], t[14;16], or deletion 17p), who are eligible for transplant. Dr. Cyrille Touzeau and colleagues reported:
62% of patients achieved MRD negativity (defined as 10-5 by next generation sequencing).
Results showed the regimen was well tolerated. Common treatment-related side effects were gastrointestinal disorder (46%), infection (40%), and skin rash (16%), and blood clot in a vein (14%). The researchers concluded that data from the phase 2 IFM 2018-04 trial support the use of quadruplet induction regimen D-KRd in high-risk, transplant-eligible patients
CART-ddBCMA
A phase 1 trial investigated the CAR T-cell therapy called CART-ddBCMA (ABSTRACT 8003) which a patient’s T cells are specifically engineered to improve the stability of the molecule that binds to BCMA on myeloma cells. Twenty-five patients with RRMM who had received 3 or more prior lines of therapy or were triple refractory received CART-ddBCMA. Dr. Matthew Frigault and colleagues presented their results, which show CART-ddBCMA treatment led to deep and durable responses in patients with poor prognostic factors. The results showed:
FasT CAR-T GC012F
Dr. Juan Du and researchers presented their findings from a first-in-human study on GC012F, a CAR T-cell therapy that targets two different proteins on myeloma cells: BCMA and CD19 (ABSTRACT 8005). A unique feature to this CAR T-cell therapy is that it uses a simplified manufacturing process that takes as little as 24 hours, instead of one or two weeks, for approved CAR T-cell constructs. Researchers initially presented data at ASCO 2021 for the initial 19 patients, and now Dr. Juan Du and investigators reported findings with longer follow up and additional 9 patients treated in 3 different dose levels: 1 × 105/kg, 2 × 105/kg, and 3 × 105/kg. Results showed:
Researchers concluded that GC012F continues to provide deep and durable responses with a favorable safety profile in additional RRMM patients across all dose levels demonstrating a very high MRD negativity rate including in patients refractory to anti-CD38 inhibitors like Darzalex and Sarclisa, proteasome inhibitors, and immunomodulatory drugs.
We look forward to more updates on these new CAR T-cell constructs with information on how long responses may last!
Elranatamab
Dr. Alexander Lesokhin and colleagues reported initial safety results from the MagnetisMM-3 trial, a phase 2 trial investigating the safety and efficacy of the BCMA-targeted bispecific antibody elranatamab (ABSTRACT 8006). The patients included in this study were divided into two groups based on whether they had received prior BCMA-directed treatment or not. Patients received subcutaneous elranatamab 76 mg every week on a 28-day cycle with 2-step-up doses of 12 mg and 32 mg subcutaneous on days 1 and 4, respectively, in the first week.
Participants of this study represent a particularly difficult-to-treat MM patient population, as 96% of patients had triple-class refractory disease (at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody). In this interim analysis, safety and efficacy data were available only from the 94 patients who were in the group that had not received prior BCMA-directed treatment were given at least one dose of elranatamab.
Results showed the most common treatment related side effects were cytokine release syndrome (61%) and low red blood cell counts (44%). Initial efficacy results showed that 60.6% of patients had a response to elranatamab. The trial is still ongoing to the primary endpoint analysis with results expected later this year.
Teclistamab
Dr. Ajay Nooka and researchers presented updated efficacy and safety results from the teclistamab (another BCMA-targeted bispecific antibody) phase 1/2 MajesTEC-1 study (ABSTRACT 8007). Among the 165 patients who received teclistamab, 78% of the patients were triple-class refractory, and 30% were penta-drug refractory. Results showed:
Researchers conclude that updated data from the phase 1/2 MajesTEC-1 study reaffirm the deep and durable responses that have been observed with teclistamab in patients with highly refractory MM, with no new safety signals.
Of all bispecific antibodies under investigation, teclistamab is the furthest along in development and we hope to see it approved by the FDA later this year!
Patients with MM have compromised immune systems due to multiple factors that may increase the risk of severe COVID-19. Dr. Amit Mitra and colleagues analyzed risk factors associated with COVID-19 severity and death in patients with MM using a national database of COVID-19 cases (ABSTRACT 8008). The results showed that Black patients as well as those with a history of lung or kidney disease were more likely to become very sick from COVID-19. Treatment with immunomodulatory drugs was also associated with an increase in the risk of COVID-19 severity. A protective association was observed between COVID-19 severity and a stem cell transplant, Darzalex therapy, and COVID-19 vaccination. Overall, the survival probability was 91% across the course of the study.
Researchers identified previously unpublished potential risk factors for COVID-19 severity and death in MM as well as confirmed some published ones. The authors add that this is the largest nationwide study on MM patients with COVID-19.
One of the most important studies to investigate the optimal timing of ASCT in newly diagnosed myeloma patients is the large, phase 3 international study call the DETERMINATION trial. This study was conducted in Europe by the IFM group (called the IFM 2009 trial) and in the US led by Dr. Paul Richardson at the Dana-Farber Cancer Institute in Boston. Both the European and American trials compared early versus late ASCT for newly diagnosed myeloma patients. Patients were divided in 2 groups:
The results from the European trial, previously reported, has already shown that patients in the early ASCT group have a longer time until disease progression than patients treated in the late ASCT group, but overall survival was similar between the groups.
In a late-breaking abstract (ABSTRACT LBA4), Dr. Paul Richardson and colleagues presented the highly anticipated first findings from the US trial in which 722 patients with NDMM between the ages of 18 and 65 were randomly assigned to the two arms. Of note, the study enrolled 19% Black myeloma patients. Results showed
The data confirmed high-dose chemotherapy followed by stem cell transplant as part of initial therapy as an important treatment option for many patients that is proven to extend remission. That said, researchers also concluded that early transplant is not critical for every patient and that treatment can be adapted for each patient in consultation with their physician. Dr. Paul Richardson and colleagues also noted the use of continuous maintenance therapy with Revlimid until progression in both groups offered substantial clinical benefit.
