Data presented at the International Myeloma Society (IMS) annual meeting held September 27–30 in Athens, Greece, focused on 3 main topics: (1) the use of newer agents, (2) optimizing outcomes, and (3) the use of minimal residual disease (MRD) measurements to predict long-term outcome for patients or to potentially stop maintenance therapy.
Patients achieving sustained MRD negativity at 3 years post-maintenance initiation may be able to discontinue lenalidomide maintenance, according to data presented at IMS. The study enrolled 151 NDMM patients who underwent ASCT, with 42 patients successfully discontinuing lenalidomide maintenance after 3 years of sustained MRD negativity. The researchers found that MRD negativity was maintained in most patients at various time points post-discontinuation. Six months after discontinuation of lenalidomide maintenance, 39 out of 41 patients were MRD negative. At 12 months, 36 out of 38 patients continued to be MRD negative. At 18 months, all evaluable patients (n=18) remained MRD negative. At 24 months, 13 out of 14 patients were MRD negative, and at 30 months all 4 evaluable patients were MRD negative. Overall, 5 patients restarted treatment with lenalidomide monotherapy after converting from MRD negative to MRD positive following the initial completion of maintenance. One patient progressed and received second-line treatment. “Sustained MRD negativity after 3 years of lenalidomide maintenance may guide the safe discontinuation of maintenance, though this has to be proven in prospective randomized clinical trials,” the researchers note.
A predictive model involving 3 measurable risk factors in MM—ISS stage, circulating tumor cell (CTC) levels, and time to first MRD negativity—may help identify TE patients with risk factors that can predict disease recurrence. A total of 267 patients out of 458 who attained MRD negativity by next-generation flow cytometry were analyzed over a median follow-up of 73 months. The patients in this analysis had been enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials. Results showed that 54% of patients maintained MRD negativity, 42% experienced MRD resurgence or progressive disease, and 4% died without progression. Prognostic factors at diagnosis, including ISS stage III and ≥0.01% CTCs, were found to predict MRD resurgence or progression, whereas patients achieving MRD negativity sooner, particularly after induction (<6 months), exhibited a lower risk of MRD resurgence or progression. A dynamic model incorporating ISS stage, CTC levels, and time to first MRD negativity assessment demonstrated predictive potential. Five-year rates of MRD resurgence or progression in patients with no, one, or ≥2 risk factors were 16%, 33%, and 57%, respectively. According to the researchers, this model could aid in both clinical trial design and routine practice decision-making.
Serial MRD testing within the first 5 years after diagnosis may help predict long-term outcomes. Data presented at IMS included 1,744 NDMM patients who underwent single or tandem ASCT. Patients were categorized into 3 groups based on their MRD test results in the initial 5 years of treatment. Group 1, which included patients with 3 serial MRD-negative tests, demonstrated an encouraging long-term outcome, with a 10-year PFS of 74%. By contrast, Group 2 included patients with both negative and positive MRD tests and exhibited a 10-year PFS of 30%. Group 3, with consistent MRD-positive tests, had a 10-year PFS of 1%. This study suggests that achieving and maintaining serial MRD negativity in the early years of myeloma treatment may predict excellent long-term outcomes, offering potential guidance for clinical practice and trials. According to the researchers, “achievement of 3 serial MRD-negative tests in the first 5 years of therapy is predictive of an excellent long-term outcome with few treatment failures.”
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Jointly provided by the MMRF and RedMedEd.
This educational activity is supported by educational grants from AbbVie Inc., Bristol Myers Squibb, and GSK, and sponsorship from Legend Biotech USA Inc.
Data presented at the International Myeloma Society (IMS) annual meeting held September 27–30 in Athens, Greece, focused on 3 main topics: (1) the use of newer agents, (2) optimizing outcomes, and (3) the use of minimal residual disease (MRD) measurements to predict long-term outcome for patients or to potentially stop maintenance therapy.
In a study evaluating 2 vs 4 years of monthly intravenous ZOL, 192 symptomatic NDMM patients were randomized after 2 years ZOL to either 2 additional years of monthly IV ZOL or observation. The 2 additional years of ZOL were significantly superior in protecting against progressive bone disease (PBD): 8 cases were reported in the ZOL arm and 18 cases in the observational arm (HR: 0.38, 95% CI [0.17-0.88], P=0.024). In addition, there was no statistically significant difference in either osteonecrosis of the jaw (ONJ) incidence or OS between the 2 groups. According to the researchers, 79% of patients had bone involvement at diagnosis and 59% experienced bone pain. ZOL may help prevent PBD but is associated with ONJ, particularly when administered over a longer duration or with greater potency.
The final OS analysis of the OPTIMISMM trial comparing PVd vs Vd alone in patients with lenalidomide-refractory RRMM was reported. This randomized open-label phase 3 trial showed a nonsignificant trend towards improved OS with PVd (35.6 vs 31.6 months, respectively). During the study, 71% vs 70% died in the PVd and Vd groups, respectively. However, PFS was significantly improved with PVd versus Vd (22.1 vs 16.9 months; HR [95% CI], 0.77 [0.64–0.94]; P=.008). Time to treatment failure was also longer with PVd versus Vd (8.8 vs 4.6 months). The most common TEAEs with PVd were neutropenia (54%), peripheral sensory neuropathy (48%), and thrombocytopenia (40%); with Vd, the most common TEAEs were thrombocytopenia (39%), peripheral sensory neuropathy (38%), and diarrhea (31%). Peripheral neuropathy was the most common TEAE that resulted in discontinuation (PVd, 11%; Vd, 8%). According to the researchers, these data support the use of PVd as an effective treatment option in patients with RRMM.
The GMMG-CONCEPT trial evaluated the quadruplet isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in both transplant-eligible (TE) and ineligible (TNE) patients with newly diagnosed high-risk MM (HRMM), defined International Staging System (ISS) stage 2 or 3 and HRCA such as del17p, t(4;14), t(14;16), or >3 copies 1q21 (amp1q21). Results presented at IMS indicated substantial MRD negativity after consolidation, with rates of 67.7% for TE patients and 54.2% for TNE patients. The current analysis includes 127 TE and 26 TNE patients with sustained MRD negativity and PFS. After a median follow-up of 40 months for TE patients and 33 months for TNE patients, the median PFS had not yet been reached in either study arm. Exploratory analyses revealed promising 1-year and 2-year PFS rates for both groups. Additional subgroup analyses showed that patients with elevated lactate dehydrogenase (LDH) or ≥2 HRCAs or del17p were least likely to reach MRD negativity and had shortened PFS. The researchers reported that Isa-KRd induces high rates of sustained MRD negativity in newly diagnosed HRMM, translating to a median PFS that was not yet reached. The results of this study are now published and can be found here.
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Jointly provided by the MMRF and RedMedEd.
This educational activity is supported by educational grants from AbbVie Inc., Bristol Myers Squibb, and GSK, and sponsorship from Legend Biotech USA Inc.
Data presented at the International Myeloma Society (IMS) annual meeting held September 27–30 in Athens, Greece, focused on 3 main topics: (1) the use of newer agents, (2) optimizing outcomes, and (3) the use of minimal residual disease (MRD) measurements to predict long-term outcome for patients or to potentially stop maintenance therapy.
CC-220-MM-001 is an ongoing phase 1/2 trial of iberdomide, used alone and in various combinations, in patients with both relapsed/refractory (RRMM) and newly diagnosed (NDMM) multiple myeloma. Iberdomide-dexamethasone in RRMM, as published here, showed clinical activity in heavily pretreated patients, including those with immunomodulatory-refractory disease.
The initial results of iberdomide, bortezomib, and dexamethasone (IberVd) in 18 transplant-ineligible NDMM patients demonstrated an 88.9% (95% CI, 65.3-98.6) overall response rate (ORR) in the intent-to-treat population, with 4 stringent complete responses (sCRs), 5 CRs, 5 very good partial responses (VGPR), and 2 partial responses; 2 patients were not evaluable. Overall, 9 (50.0%) patients achieved at least a CR and 14 (77.8%) patients achieved a VGPR or better. Grade 3/4 treatment-emergent adverse events (TEAEs) were noted in 70.6% of patients. Neutropenia and pneumonia were the most common AEs (17% each). No patients discontinued due to AEs, however. The researchers reported that the combination showed “high efficacy with deep, ongoing responses in this cohort of mostly older patients… supporting further assessment of iberdomide combinations in the frontline setting.” Iberdomide is currently being studied (versus lenalidomide) as maintenance therapy following autologous stem cell transplant (ASCT) in a phase 3 trial.
Mezigdomide was combined with either bortezomib and dexamethasone (MeziVd) or carfilzomib and dexamethasone (MeziKd) in RRMM patients who had received 2 to 4 prior regimens or MeziVd-1.0 mg in RRMM patients who had received 1 to 3 prior regimens in the phase 1/2 CC-92480-MM-002 trial. The most common grade 3/4 TEAEs were hematologic and included neutropenia and thrombocytopenia with MeziVd and neutropenia and infections with MeziKd or MeziVd-1.0 mg. Dose reductions of mezigdomide due to TEAEs were required in 25% to 40% of patients, depending on the dose and combination. The ORR was 75.0% with MeziVd (21/28); 84.2% with MeziVd-1.0 mg (32/38); and 85.2% with MeziKd (23/27). Median time to response (range) was 1.38 (0.7-3.3), 0.89 (0.7-2.4), and 0.95 (0.9-5.1) months in the MeziVd, MeziVd-1.0 mg, and MeziKd cohorts, respectively. Median duration of response was 10.4 and 11.9 months in the MeziVd and MeziKd cohorts and was not reached in the MeziVd-1.0 mg group. These data support further exploration of mezigdomide in phase 3 studies. Mezigdomide is currently being studied in the SUCCESSOR-1 and -2 phase 3 trials.
Venetoclax, a potent oral BCL-2 inhibitor, has the potential to be the first biomarker-directed therapy for patients with RRMM positive for the t(11;14) translocation, who tend to exhibit higher BCL-2 levels.
In an ongoing phase 2 study, venetoclax, carfilzomib, and dexamethasone (VenKd) was used to treat patients with t(11;14)-positive RRMM. Patients were randomized 5:3:5 to receive K (70 mg/m2 weekly) and d (40 mg) in combination with daily venetoclax (400 mg or 800 mg) or Kd alone. The current analysis included 56 patients. The most common TEAEs, occurring in at least half of patients, were diarrhea, nausea, fatigue, and vomiting and were more common in venetoclax-treated patients than in those treated with Kd alone. Grade ≥3 TEAEs occurring in at least 20% in any group were lymphopenia, neutropenia, and hypertension. Grade ≥3 infection rates were higher in the VenKd groups vs Kd alone (29% vs 20% vs 11%). After a median follow-up of approximately 1–2 years, ORRs (95% CI) were 94% (71-100), 95% (75-100), and 58% (34-80) in the venetoclax 400 mg, 800 mg, and Kd-alone groups, respectively. CR/sCR rates were 29, 50, and 11%, respectively. Median time to response was 1.0, 1.0, and 2.4 months, and 12-month progression-free survival (PFS) estimates were 67, 85, and 79%, with median PFS of 42.4 months. Overall survival (OS) data are not yet mature. Study enrollment is ongoing. According to the researchers, treatment with VenKd was well tolerated and produced favorable responses in at least 90% of patients.
The CANOVA study compared once-daily oral venetoclax and dexamethasone (Vd) versus pomalidomide and dexamethasone (Pd) in 263 patients 18 years and older who had t(11;14)-positive RRMM and had received ≥2 prior lines of therapy. Vd did not significantly improve PFS relative to Pd, the primary end point of the trial. Patients receiving Vd showed a median PFS of 9.9 months compared with 5.8 months with Pd (HR = 0.823, 95% CI: [0.596, 1.136]; P=0.237). The safety profile of Vd was generally consistent with the known safety profiles when used as single agents, and no new safety signals emerged. The most common AEs in the Vd group were infection (61%), diarrhea (41%), lymphopenia (24%), and nausea (22%). The most common AEs in the Pd group were neutropenia (63%), infection (57%), thrombocytopenia (39%) and anemia (35%).
Bispecific antibodies (bsAbs) that target B-cell maturation antigen (BCMA) may contribute to increased infection risk in RRMM patients and warrant preventive measures against infection.
To devise recommendations for clinical practice, researchers analyzed data from the phase 1/2 MajesTEC‑1 study of teclistamab, a BCMA×CD3 bsAb, involving 165 RRMM patients. After a median follow-up of 21.7 months, approximately 78% of patients (n=129) developed infections, with over half of the overall study participants developing grade 3/4 infections. Twenty patients (12.1%) died due to infections (17 had COVID-19). Median time to first onset of any grade infection was 1.7 months. Overall, 70.9% of patients had at least 1 IgG value <400 mg/dL and 45.5% received intravenous immunoglobulin (IVIG). Grade 3/4 neutropenia occurred in 65.5% of patients at a median of 2.3 months, and 53.3% of patients received granulocyte colony-stimulating factor (G-CSF).
Recommendations
At IMS, the findings of a systematic review of 9 studies evaluating whether bsAbs are effective in managing extramedullary disease (EMD) and high-risk cytogenetic abnormalities (HRCAs) in RRMM—including ORRs of the entire cohort (N=660)—were reported. The ORRs for EMD and HRCAs were reported in 3 (n=78) and 4 (n=100) studies, respectively. From the studies that reported ORR for EMD, talquetamab (GPRC5D×CD3) was shown to have the highest ORR (0.45 [0.17; 0.77]), followed by elranatamab (BCMA×CD3; 0.38 [0.23; 0.55]) and teclistamab (0.36 [0.19; 0.56]). There was no significant difference in ORR among the agents with respect to EMD status. In studies that reported ORR for HRCAs, talquetamab had an ORR of 0.67 (0.17; 0.77) followed by teclistamab (0.61 [0.43; 0.76]), and elranatamab 0.55 (0.36; 0.73). Similarly, there was no significant difference in the ORR among these agents with respect to HRCA status. According to the researchers, EMD responses are significantly lower than the full cohort ORR; however, it is encouraging that responses to high-risk MM closely approximate ORR of these agents. The authors note that the reporting of EMD responses “needs to be improved, and clinical trials should report EMD responses distinctly, as it directly informs clinical decisions.”
Teclistamab, a bsAb recently approved for RRMM patients who have undergone ≥4 lines of therapy, has shown promise in clinical settings. Researchers from the Dana-Farber Cancer Institute/Brigham and Women’s Hospital reported their experience with teclistamab in 34 patients (median age 65; median 6 prior lines of therapy). Notably, 62% of patients had HRCAs, and 38% had EMD. Observed hematologic toxicities included anemia, neutropenia, and thrombocytopenia, and cytokine release syndrome (CRS), primarily grade 1 or 2, occurred in 56% of patients. Neurological toxicity was minimal, affecting 3% of patients. Infectious complications were noted in 32% of cases, with 9% classified as grade 3 or higher and no treatment-related deaths recorded. At a median follow-up of 6 weeks, ORR was 44%, with 9% achieving CR and 29% reaching VGPR or better. Teclistamab also demonstrated efficacy in patients with renal dysfunction, EMD, and/or HRCAs. According to the researchers, “teclistamab treatment in a commercial setting generated comparable responses to the previously reported clinical trials without any new toxicity signals.”
Forimtamig, a GPRC5D×CD3 T cell–engaging bsAb, has demonstrated significant clinical efficacy across various high-risk subgroups of RRMM patients, according to findings from a phase 1a dose-escalation study. In this first-in-human study, which included patients who were heavily pretreated and refractory to both proteasome inhibitors and immunomodulatory drugs, forimtamig exhibited an ORR of 66.7%, with 54.2% of patients achieving a VGPR or better. Importantly, the median duration of response was 12.2 months, with a majority of responders maintaining their responses at the time of data cutoff. Researchers also saw promising results in specific high-risk subgroups, including patients aged ≥65, those with >4 prior lines of therapy, and individuals with HRCAs. Of note, patients with 1q21 gain, known to be a HRCA, exhibited an ORR of 86.7%. Forimtamig also demonstrated effectiveness in patients previously treated with BCMA-targeted therapies, including antibody-drug conjugates, bsAbs, and CAR T-cell therapy, suggesting its potential as a salvage therapy. The study’s authors emphasized the need for further optimization of forimtamig dosing and scheduling and ongoing evaluation of its long-term treatment benefits, particularly in patients with high-risk disease characteristics.
The CARTITUDE-4 trial is a global, open-label, randomized controlled trial comparing ciltacabtagene autoleucel (cilta-cel) with physician’s choice of standard of care (SOC): either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) in lenalidomide-refractory MM patients. As of November 1, 2022, median follow-up was 15.9 months (range, 0.1–27), and 208 patients were randomized to cilta-cel (of whom 176 received cilta-cel) and 211 to SOC. Cilta-cel significantly improved PFS compared to SOC (median not reached vs 11.8 months), with a hazard ratio (HR) of 0.26 (P< 0.0001). In prespecified subgroup analyses, cilta-cel consistently demonstrated improved PFS across various patient subgroups. This includes patients <65 and 65–75 years of age and those who have any of the following: HRCAs, ≥1 HRCAs, ISS stage III, soft tissue plasmacytomas, high bone marrow plasma cell counts, or triple-class–refractory disease. Cilta-cel also showed efficacy when compared to both PVd and DPd. According to the researchers, the benefit shown was “similar to that seen in the overall ITT population, confirming efficacy of a single cilta-cel infusion in a range of clinically relevant MM subgroups.”
Autologous GPRC5D CAR T-cell therapy shows promising results in RRMM patients who have previously undergone anti-BCMA CAR T-cell therapy, according to the latest findings from a phase 2 trial. In this single-arm study conducted in China, 11 patients with RRMM who had previously received anti-BCMA CAR T-cell therapy were enrolled and treated. At a median follow-up of 14.8 months, all 11 patients achieved a response, with 45% achieving a CR or better. Of note, 73% of patients were MRD negative in bone marrow. The median PFS was 6.4 months, and 45% of patients remained progression-free at the time of analysis. The safety profile of GPRC5D-targeted–CAR T-cell therapy was manageable, with grade 3 or higher hematological toxicities being the most common AEs. CRS occurred in 91% of patients, but all cases were grade 1 or 2, and CRS was effectively managed with tocilizumab and dexamethasone. No neurological toxic effects were reported. According to the researchers, “GPRC5D-targeted CAR T-cell therapy is clinically active with a favorable safety profile in patients who do not respond to or relapse after anti-BCMA CAR T-cell therapy.”
PHE885, a fully human CAR T-cell agent manufactured using the T-Charge platform, has demonstrated durably persistent CAR T expansion in a phase 1 study conducted at the Dana-Farber Cancer Institute. Though CAR T-cell therapy targeting BCMA has shown benefit in the RRMM setting, challenges such as lengthy manufacturing times and limited in vivo persistence still need to be resolved. PHE885 had previously demonstrated a 98% ORR across all dose levels, with a 100% ORR at doses exceeding 5×106 CAR T cells. The latest analysis of serial samples from 32 patients suggested that the manufacturing process successfully preserved stem-like memory T cells in the final product, resulting in a diverse and proliferative CAR T expansion following infusion. CAR T cells also maintained a diverse T-cell receptor repertoire, particularly in patients with long-term persistence. The researchers concluded that “T-Charge… successfully preserved stem-like memory T cell clones in the final product, leading to a highly heterogeneous and proliferative CAR T expansion with durable persistence.”
A fourth-generation BCMA CAR T-cell therapy, InstanCART, has exhibited promising results in the treatment of RRMM during a phase 1 clinical trial. Typically, CAR T-cell therapy has prolonged production times and high costs. The traditional production process, which the China-based researchers have called TraditionCART, takes 9–14 days, leading to extended vein-to-vein times and disease progression during production. By contrast, InstanCART, manufactured using the Instant Manufacturing Platform, offers a streamlined production process, optimizing T cell function. The latest phase 1 clinical trial compared the safety and efficacy of TraditionCART and InstanCART in RRMM patients. Both approaches demonstrated favorable safety profiles, with no grade 3 or greater neurotoxicity or CRS observed. However, InstanCART showed lower rates of grade 3 AEs than did TraditionCART. Notably, InstanCART achieved an ORR of 100%. There was no statistically significant difference in PFS and OS between InstanCART and TraditionCART. However, the expansion and duration of InstanCART cells was significantly higher than TraditionCART cells, highlighting its potential for enhanced therapeutic benefit. According to the researchers, InstanCART was well tolerated and showed noninferior efficacy and more encouraging pharmacokinetic profile than TraditionCART for RRMM therapy. The study is ongoing, and long-term follow-up will assess durable efficacies.
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Jointly provided by the MMRF and RedMedEd.
This educational activity is supported by educational grants from AbbVie Inc., Bristol Myers Squibb, and GSK, and sponsorship from Legend Biotech USA Inc.
Welcome to our final day of coverage from the latest advances presented at the 20th International Myeloma Society (IMS) Annual Meeting. Highlights from today include recent findings on standard and emerging treatments including bispecific antibodies, and CAR T-cell therapy in patients with relapsed/refractory multiple myeloma (RRMM). Here’s a quick recap!
Sarclisa (isatuximab) is an anti-CD38 monoclonal antibody approved in combination with Kyprolis (carfilzomib) and dexamethasone (Isa-Kd) for patients with relapsed/refractory multiple myeloma (RRMM) after one or more prior therapy. The IKEMA trial, which compared the combination of Sarclisa, Kyprolis, dexamethasone (Isa-Kd) with Kyprolis and dexamethasone, showed that patients with RRMM (who had received 1-3 prior lines of therapy) benefit from the use of Isa-Kd, with a longer time before their disease returns (progression-free survival [PFS]) of 36 months compared to 19 months with Kd. In this final analysis of the IKEMA trial, French researchers reported a meaningful benefit in overall survival with Isa-Kd compared to Kd. Side effects associated with Isa-Kd, such as infusion reactions, diarrhea, and high blood pressure, were consistent with previous analyses, supporting it as a standard-of-care therapy for RRMM.
Yesterday we learned about the activity of venetoclax when combined with Kyprolis and dexamethasone in patients with a translocation of chromosomes 11 and 14 (t[11;14]). Today, researchers from Spain shared their findings from the Phase 3 CANOVA study that evaluated venetoclax and dexamethasone (VenDex) against pomalidomide and dexamethasone (PomDex) in patients with t(11;14)-positive RRMM who have received two or more prior treatments.
Their findings revealed that patients receiving VenDex showed a small improvement in progression free survival (the time before their disease came back) compared to PomDex (10 months vs 6 months) as well as an 8-month improvement in overall survival (32 months for VenDex compared to 24 months with PomDex. The most common side effects experienced by patients treated with VenDex included any infection, diarrhea, low white blood cell counts, and nausea (22%).
Forimtamig, a GPRC5DxCD3 T-cell-engaging bispecific antibody (BsAb), is currently being evaluated in patients with RRMM who have received one or more prior line(s) of therapy, and were refractory to a proteasome inhibitor (such as Velcade, Kyprolis or Ninlaro) and an immunomodulatory drug (such as Revlimid or Pomalyst). Forimtamig is in the same class as Talvey (talquetamab), which received FDA approval several weeks ago. Findings from an early phase study showed forimtamig induced deep and durable responses in heavily pre-treated pts and had a safety profile consistent with other investigational GPRC5D-directed therapies. (Carlo-Stella et al. ASH 2022).
In this abstract, researchers from the United Kingdom presented their analysis of clinical responses in high-risk patients. For this study, high-risk patients were defined as: age ≥65 years, >4 prior LOT, triple-class and penta-drug refractory disease, prior BCMA-targeted therapy (such as CAR-T or a bispecific antibody like Tecvayli aka teclistimab), high-risk cytogenetics (del(17p), t(4;14), t(14;16)), 1q21 gain (irrespective of other high-risk aberrations), International Staging System Stage III at baseline, and presence of soft tissue plasmacytoma (bone-based and extramedullary).
ORR across all dose levels of forimtamig was 67% and high ORRs were observed across all risk groups. Future studies will seek to identify the best dose and schedule of forimtamig for patients with RRMM.
Tecvayli (Teclistamab) was the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated RRMM (patients who have received 4 or more lines of therapy). In this abstract, Dr Shonali Midha and colleagues from the Dana-Farber Cancer Institute in Boston shared their preliminary experience with the real-world use of Tecvayli. Their findings revealed that treatment with Tecvayli in a real-world setting showed similar responses to the previously reported clinical trials without any new side effects. The authors conclude that additional real-world follow up on the use Tecvayli in the real-world is needed to confirm these findings.
Carvykti (ciltacabtagene autoleucel) is approved for RRMM patients after at least four previous treatments. Given the success of CAR T-cell therapy in patients with RRMM who have failed many different treatments there is an interest in testing CAR T-cell therapy for patients who have received fewer prior therapies. Findings from the CARTITUDE-4 trial showed Carvykti significantly improved PFS compared to the standard of care (that is physician’s choice of either Pomalyst, Velcade and dexamethasone or Darzalex, Pomalyst, and dexamethasone. In this abstract, researchers from France reported findings from a prespecified subgroup of patients, including those aged < 65 yrs, patients who received 1 prior line of therapy (that is first relapse), ISS stage III, triple-class refractory, etc.
The results showed that Carvykti improved progression free survival in all subgroups, including by age, in those with high-risk features, and after first relapse. The authors conclude that these findings offer further support for the use of Carvykti in earlier lines of therapy.
Please be sure to listen to hear what myeloma experts had to say as they recap each day’s clinical research and discuss what these findings mean for myeloma patients here.
We look forward to more clinical updates in the months ahead!
Day 2 of IMS brought us some recent findings covering a mix of different drug combinations for both newly diagnosed and relapsed/refractory myeloma. Let’s dig into a big day of updates in myeloma treatment.
Revlimid is a key drug in the treatment of newly diagnosed patients with multiple myeloma. Unfortunately, due to the extensive use of Revlimid (lenalidomide)-containing regimens in the frontline setting and Revlimid-maintenance therapy, patients may develop resistance to treatment early in the disease course. Refractoriness is defined as no response to primary therapy (lenalidomide in our case) or progression within 60 days of the last dose.
Pomalyst (Pomalidomide) is approved for the use in patients who have previously received at least 2 drugs to treat multiple myeloma, including a proteasome inhibitor and Revlimid and have demonstrated disease progression on or within 60 days of completion of the last therapy. The combination of Pomalyst-Velcade (bortezomib), and dexamethasone (PVd) is a preferred option in patients who have received one ore more prior therapies, including those who have received Revlimid and Velcade.
In the first abstract, researchers from Turkey reported updates from the phase 3 OPTIMISMM, which has previously shown that PVd significantly prolonged progression-free survival (that is the length of time during and after treatment in which a patient is living with a disease that does not get worse) compared to Vd (11 vs 7 months). Participants enrolled in OPTIMISMM had a diagnosis of RRMM and had received 1-3 prior lines of therapy, including at least one round of Revlimid.
Their findings showed that patients who received PVd achieved a median overall survival (that is the length of time a patient survives) of 36 months compared with 32 months among patients treated with Vd. The most common side effects with PVd were low white blood cell counts (54%), burning/tingling in the hands and feet, also known as peripheral neuropathy (48%), and low platelet counts (40%). The researchers conclude that PVd is effective in patients for whom Revlimid is no longer a treatment option, including Revlimid-refractory patients after 1 prior line of therapy.
Venetoclax is a selective small‐molecule inhibitor of BCL‐2 that is FDA-approved for the treatment of chronic lymphocytic leukemia and has shown to be effective in treating myeloma patients with a translocation of chromosomes 11 and 14 (t[11;14]). An early phase clinical study showed that combination of venetoclax with plus Kyprolis (carfilzomib) and dexamethasone (VenKd) in RRMM showed an overall response rate (ORR) of 92% in patients who had a t(11;14).
In this abstract, Dr Jonathan Kaufman reported initial safety and efficacy data in patients with t(11;14) RRMM treated with one of 2 doses of Ven (400 or 800 mg) combined with Kyprolis and dexamethasone (Ven400Kd or Ven800Kd) compared to Kd alone. Their findings showed that patients treated with VenKd 400mg or VenKd 800mg achieved an ORR of 89% and 95%, respectively. Most common side effects observed were diarrhea, nausea, vomiting and fatigue. The incidence of side effects was higher with the higher dose of venetoclax.
This trial is ongoing and additional results will shed light on the clinical potential of venetoclax for the treatment of patients with t(11;14).
Iberdomide, Velcade, and Dexamethasone (IberVd) in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM)
Iberdomide is a novel, potent oral cereblon E3 ligase modulator (CELMoD™) with a dual function: activate the immune system and directly kill myeloma cells by inducing the destruction of tumor-promoting proteins known as ikaros and aiolos.
In this abstract, researchers from Canada presented results from an early phase clinical trial that evaluated iberdomide in combination with Velcade and dexamethasone (IberVd). This combination has shown promising preliminary efficacy and safety in patients with RRMM in an early phase clinical trial.
Patients in the trial had untreated symptomatic NDMM, no autologous stem cell transplant planned, nor ineligibility due to age or comorbidities. Their findings showed:
The researchers concluded that IberVd showed high efficacy with deep responses in transplant ineligible patients with NDMM. The safety profile was manageable with no new safety signals, and no pts discontinued due to AEs. These findings support further assessment of iberdomide combinations in the frontline setting.
Be sure to hear what myeloma experts Dr. Sagar Lonial and Dr. Keith Stewart, had to say about the day’s presentations here.
Stay tuned for more updates from the final day at IMS 2023!
Renowned myeloma doctors and researchers from all over the world gathered in Athens, Greece at the 20th International Myeloma Society (IMS) Annual Meeting to present and discuss the latest advances in multiple myeloma research. Highlights from today included the use of risk factors to better predict minimal residual disease negativity, new findings on sustained MRD negativity with Sarclisa, Kyprolis, Revlimid, and dexamethasone in patients with high-risk myeloma, the latest results on mezigdomide, a novel cereblon E3 ligase modulator (CELMoD™) for the treatment of relapsed/refractory multiple myeloma, and the long-term benefits of using Zometa (zoledronic acid) for protection of bone disease in myeloma.
Minimal residual disease (MRD) is an important topic in the field of multiple myeloma, in large part because we have very active treatment regimens that can induce deep and sustained responses in most patients, something that was not possible just several years ago. Measuring MRD refers to counting the number of multiple myeloma cells that remain in a patient after a course of therapy is completed. Achieving MRD negativity (that is, no disease detected after treatment) in clinical trials is associated with a significantly longer time before disease progression (progression-free survival [PFS]) and overall survival; however, to date, there has been limited data on the role of sustained MRD negativity to inform whether to stop treatment. It is important to identify risk-factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreatment and to test these hypotheses in clinical trials prior to adopting in clinical care.
Researchers from Spain reported their findings from an analysis of transplant-eligible MM patients enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials who achieved MRD negativity.
The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) score of 3 and ≥0.01% of detectable circulating myeloma cells. Patients who achieved MRD negativity after induction (less than 6 months after starting treatment) had significantly lower risk of MRD resurgence and/or PD than those who achieved MRD negativity after 6 months from starting treatment.
The researchers conclude this model could be used in clinical trials to predict the risk of MRD resurgence and/or PD among patients achieving undetectable MRD to avoid undertreatment of transplant-eligible MM patients.
Specific cytogenetic abnormalities can be predictive of high risk of poor prognosis in patients with multiple myeloma; these include the presence of gain or amplification of chromosome arm 1q21 (gain/amp[1q21]), deletion of chromosome 1p (del[1p]), deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]), translocation of chromosomes 14 and 16 (t[14;16]), and translocation of chromosomes 14 and 20 (t[14;20]). MRD negativity has recently emerged as a potential surrogate for longer survival, regardless of a patient’s cytogenetic risk. Information from recent clinical trials suggests that extended intensified treatment can help achieve MRD negativity in patients who may have one or more of these high-risk features, which may lead to improved outcomes.
In the next abstract, researchers from Germany presented their findings from the phase 2 GMMG-CONCEPT trial that evaluated Sarclisa, Kyprolis, Revlimid, and dexamethasone (Isa-KRd) as induction therapy in high-risk multiple myeloma. Patients with high-risk multiple myeloma were defined by ISS stage 2 or 3 and any of del17p, t(4;14), t(14;16), or >3 copies 1q21 (amp1q21). Findings from this study were recently published in the Journal of Clinical Oncology (link). The authors showed that the combination of Isa-KRd resulted in high MRD negativity rates in patients with newly diagnosed, high-risk multiple myeloma, regardless of their transplant status.
Researchers reported:
The authors conclude that Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status.
Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD™) designed to activate the immune system and directly kill myeloma cells by inducing the destruction of tumor-promoting proteins known as ikaros and aiolos. CELMoDs are oral (taken by mouth) medications that have many similarities to immunomodulatory agents or IMiDs, but CELMoDs can be used even in patients who have relapsed after treatment with immunomodulatory agents.
In this abstract, researchers from Spain presented their findings from an early phase clinical trial that evaluated mezigdomide, a novel cereblon E3 ligase modulator (CELMoD™), in combination either Velcade and dexamethasone (MeziVd) or Kyprolis and dexamethasone (MeziVd) in relapsed/refractory multiple myeloma (RRMM) who had previously received the standard of care – a combination of three classes of drugs — and in some cases had been treated with BCMA targeting treatment, including CAR T-cell therapy. Results of the early phase trial were published online by the New England Journal of Medicine (link). Data reported from participants who received MeziVd was divided into two groups: MeziVd at varying doses (0.3, 0.6, 1.0mg) or 1.0mg of mezigdomide (MeziVd-1.0mg).
Researchers reported overall response rates (ORR) of 75% with MeziVd (either 0.3, 0.6, or 1.0mg of mezigdomide), 84% with MeziVd-1.0mg, and 85% with MeziKd.
The most frequent treatment-related side effects were low white blood cell counts (36%) and low platelet counts (21%) with MeziVd; low white blood cell counts (58%) and all infections (34%) with MeziVd-1.0mg; and low white blood cell counts (41%) and all infections (30%) with MeziKd.
With longer follow-up, MeziVd and MeziKd continued to show promising efficacy at all dose levels tested with a manageable safety profile in patients with RRMM. Future clinical trials will continue to examine the potential of this novel CELMoD in combination with other treatments.
Up to 85% of people with multiple myeloma experience bone disease. In some people, myeloma may cause thinning and weakening of the bones to the point where holes are formed in the bone, which can lead to pain or fractures. Even more patients will experience bone complications at some time point in their course of disease.
Progression of bone disease can be inhibited by treatment with Zometa. Zometa has been shown to increase quality of life and overall survival in myeloma patients, however Zometa is also associated to osteonecrosis of the jaw. The best length of treatment with Zometa is yet uncertain, as previous studies followed myeloma patients for up to 2 years.
In the final abstract, researchers from Denmark examined if treatment of myeloma bone disease up to 4 years with Zometa was safe and effective. Their findings showed that four years of monthly Zometa are superior to two years treatment in protection against progressive bone disease in multiple myeloma. The incidence of osteonecrosis of the jaw after 4 years was 4% and not significantly different between the two treatment groups. These results shed light on the clinical potential of long-term use of Zometa in protection of bone disease in myeloma.
Be sure to hear what myeloma expert, Dr. Saad Usmani, had to say about the day’s presentations here.
Stay tuned for more updates from IMS 2023!
