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Multiple myeloma didactics 2023 updates.pptx
- 1. C NCCN UPDATES IN MULTIPLE MYELOMA Highlights on the Presentation of Dr. Shaji Kumar Mary Anne Lorraine Kua, Year-II
- 2. NCCN 2022 Tackled on: A. Advances in Transplant-Eligible, Newly Diagnosed Disease B. To Transplant or Not? C. Maintenance Therapy Improves PFS D. Transplant-Ineligible Disease E. Treatment of Relapsed Disease F. Highly Refractory Disease G. Supportive Care
- 3. General Treatment Principles a) Patients should receive at least a triplet regimen (2 drug classes and steroids) if they can tolerate it. b) Patients with poor performance status or who are frail can be started on a 2-drug regimen, with a third drug added once performance status improves. c) A new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months. d) Clinical trials with these triplet regimens primarily included patients who were naïve or sensitive to the novel drug in the doublet comparator arm. e) Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy that does not contain the drug they are progressing on. • Frailty assessment should be considered in older adults. See NCCN Guidelines for Older Adult Oncology. f) Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem cell reserve prior to stem cell harvest in patients who may be candidates for transplant. g) Consider harvesting peripheral blood stem cells after several cycles of therapy prior to prolonged exposure to lenalidomide and/or daratumumab in patients for whom transplant is being considered.
- 5. A. Advances in Transplant-Eligible,Newly Diagnosed Disease •phase II GRIFFIN trial •Dara+ VRd CD38 antibody bortezomib/lenalidomid e/dexamethasone (VRd) • 64% were MDR-negative (vs 30% VRd) • 54% reduction in disease progression • no differences in overall survival (OS)
- 6. A. Advances in Transplant-Eligible,Newly Diagnosed Disease P: newly diagnosed multiple myeloma I: RVd + maintenance therapy with daratumumab and lenalidomide (2yrs) C:RVd + maintenance therapy with lenalidomide O: PFS, MRD negativity M: randomized phase II Daratumumab /RVd RVd PFS Longer MRD negativity rates 64% 30% Complete response 83% 60% Risk Reduction to disease Progression or death 55% - Estimated 48-month progression-free survival rate 87.2% 70% Median progression-free survival was not reached in either treatment arm
- 7. A. Advances in Transplant-Eligible,Newly Diagnosed Disease •Can the treatment duration be shortened? P: newly diagnosed multiple myeloma I: Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. C: No Consolidation O: MRD negativity (< 10–5) Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance. M: multicenter, single-arm phase II MASTER trial
- 8. B. To Transplant or Not? • IFM 2009 trial compared up-front ASCT with additional cycles of VRd • Despite a 3-drug induction regimen, ASCT • still improved PFS by almost 1 year (median PFS, 47.3months vs 35.0 months for VRd alone) • hazard ratio [HR], 0.70; 95% CI, 0.59–0.83; P 5.0001 • OS differences were not seen • Transplant is an effective therapy as part of initial treatment, but it is reasonable to delay.
- 9. C. Maintenance Therapy? • Maintenance therapy after induction and ASCT improves both PFS and OS • Patients with high-risk features: outcomes after maintenance remain inferior to those achieved in standard-risk patients • single-agent lenalidomide as maintenance therapy P: newly diagnosed multiple myeloma <65y/o I: with lenalidomide + carfilzomib maintenance C: with lenalidomide maintenance O: Rates of MRD negativity M: multivariate analysis of RCT
- 11. C. Maintenance Therapy Improves PFS • CASSIOPEIA trial • After 2 yrs of Daratumumab: • median PFS was 46.7 months • MRD negativity rates were 47.1% and 58.6%, respectively (P,.0001) P: 18–65y/o newly diagnosed multiple myeloma ECOG 0-2, 111 European practice centers given after bortezomib/thalidomide/dexamethasone I: 2 years of daratumumab maintenance C: no maintenance O: MRD negativity M: two-part, open-label, randomised, phase 3 trial
- 12. C. Maintenance Therapy Improves PFS • Based on these and other phase II/III trials • Proposal: risk-adapted approach to managing newly diagnosed myeloma • Standard-risk patients receive induction with VRd for 4 cycles, and then 1. Proceed to ASCT >> Lenalidomide (preferred) (or) 2. receive 4 more cycles of VRd >> Lenalidomide, then with ASCT on disease progression. • High-risk patients • those with double- or triple-hit disease, del17p, gain 1q, t(4:14), or t(t:16)— • will receive 4 cycles of Dara-VRd, >>> then ASCT • Maintenance: bortezomib and lenalidomide
- 14. D. Transplant-Ineligible Disease • Patients who are not candidates for ASCT often receive VRd or VRd ‘lite’ P: 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation I: daratumumab + lenalidomide +dexamethasone (Dara-Rd) C:lenalidomide + dexamethasone (Rd) O: PFS, risk of disease progression or death M: randomized, open-label, phase 3 trial, • At 48 months, the median PFS was not reached for Dara-Rd and was 34.4 months for Rd alone • Mortality was reduced by 32% (P 5.0013). • Recommendation for Standard-risk patients: • Dara-Rd, (or) • if that regimen cannot be used using VRd ‘lite’ with continuous therapy (for daratumumab + lenalidomide +dexamethasone (Dara-Rd) lenalidomide + dexamethasone (Rd) risk of disease progression or death significantly lower negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells) 24.2% 7.3% median follow-up of 28.0 months (range, 0 to 41.4), disease progression or death 26.4% 38.8% alive without disease progression at 30 months 70.6% 55.6% median progression-free survival not reached in the daratumumab group 31.9 months (95% CI, 28.9 to not reached) Mortality Reduction 32% higher incidence of neutropenia and pneumonia
- 15. E. Treatment of Relapsed Disease 1. Duration of initial response 2. Triplets (2 active classes 1 dexamethasone) are preferred over doublets, with >=1 drug from a non- refractory class 3. For drug and dose selections, consider performance status, age, and comorbidities 4. Prior and residual toxicities from previous therapies 5. Patients should be treated to maximum response and maintained on one drug until disease progression or intolerability.
- 16. “A key factor in selecting therapy is whether the patient is refractory to lenalidomide,”
- 20. F. Treatment Options for Highly Refractory Disease •PFS 4 months •OS : 1 year 1.Selinexor 2.Belantamab mafodotin-blmf 3.CAR T-cell therapies targeting B-cell maturation antigen (BCMA) 4.T-cell engagers 5.CELMoDs 6.Venetoclax
- 21. F. Treatment Options for Highly Refractory Disease
- 22. F. Treatment Options for Highly Refractory Disease 1. Selinexor o a nuclear transport protein inhibitor o as a new option in early Relapse P: newly diagnosed multiple myeloma I: selinexor/ carfilzomib/dexamethasone C: bortezomib+dexamethasone (Vd) O: M: randomized, active comparator-controlled, open-label, multicenter study, phase 3
- 23. F. Treatment Options for Highly Refractory Disease 2. Belantamab mafodotin-blmf, an antibody–drug conjugate DREAMM2 trial P: >=18 years ECOG 0-2 RRMM with disease progression after 3 or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 I: belantamab mafodotin C: - O: until disease progression or unacceptable toxicity M: ongoing open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
- 24. 3. CAR T-Cell Therapy • elicited VGPRs in 94.9% of patients and stringent complete responses in 82.5%. • 2-year PFS was 71.0% (95% CI, 57.6–80.9) (90% sustained MRD negativity) • OS rate was 74.0% a) Idecabtagene vicleucel b) Ciltacabtagene autoleucel
- 25. F. Treatment Options for Highly Refractory Disease 4. Bispecific T-cell engagers : bispecific antibodies is that they are quite effective in patients who have been exposed to 5 -6 prior lines of therapy Drug MoA Trial Effect Teclistamab targets BCMA MajesTEC-1 trial 62.0% of triple class–refractory patients experienced response 41.9% achieved MRD negativity Talquetamab targets GPRC5D MonumenTA L-1 trial VGPRs in 53% Cevostamab targets FcRH5 VGPRs in 33.3%
- 26. 5. Venetoclax • Improved PFS overall • The subgroup analysis found a strong benefit in the t(11;14) group and the BCL2-high group • Venetoclax is recommended in the NCCN Guidelines for t(11;14 disease) alone. • increased mortality was observed in the Ven group P: RRMM who had received 1-3 prior lines of therapy and were either sensitive or naïve to proteasome inhibitors. I: Ven 800 mg/day + bortezomib and dexamethasone C: Placebo + bortezomib and dexamethasone O: PFS, overall response rate and OS M: Phase 3, randomized, double-blind, multicenter
- 27. 6. CELMoDs Iberdomide • potent novel • effective in disease refractory to other IMiDs (lenalidomide, pomalidomide) and to BCMA- targeting agents • In CC-220-MM-001 (Iberdomide + dexamethasone ) • ORR: 26.2% • Disease control rate: 79.4% BCMA-targeting therapy, these rates were 25.0% and 75.0% • ORR: 25% • Disease control rate: 75%
- 28. G. Supportive Care for VTE
- 29. G. Supportive Care for VTE
- 30. G. Supportive Care for VTE
- 32. Thank you.
Editor's Notes
- Many new treatments for multiple myeloma have been FDA approved in the past few years, but their optimal use is still being explored. As patients become refractory to one treatment, and then another, questions remain regarding proper sequencing. Do intensive regimens take the place of transplant?
- Recent improvements in induction therapy include the addition of a CD38 antibody to bortezomib/lenalidomide/ dexamethasone (VRd). In the phase II GRIFFIN trial, the addition of daratumumab to VRd (Dara-VRd) in the induction and consolidation cycles and to lenalidomide for maintenance produced more and deeper responses.1 After 2 years of maintenance, 64% of the patients who received Dara-VRd were minimal residual disease (MRD)–negative compared with 30% who received VRd, which translated into a 54% reduction in disease progression. Progression free survival (PFS) curves are now starting to separate, with no differences in overall survival (OS) yet.
- The study noted that After 2 years of maintenance therapy, the MRD negativity rate continued to favor daratumumab/RVd vs RVd (64% vs 30%, P = <.0001). Additionally, 44% of patients who received daratumumab/RVd achieved sustained MRD negativity of 12 months or more, compared to 14% of patients in the RVd arm. Treatment with daratumumab/RVd also resulted in higher stringent complete response rates at all time points in the study, with the highest rates occurring following 2 years of maintenance therapy (67% vs 48%, P = .0079, respectively). Complete response or better rate was 83% in the daratumumab/RVd arm vs 60% in the RVd arm (P = .005). At the conclusion of the final analysis, after a median follow-up of 49.6 months, a 55% reduction in the risk of disease progression or death was observed in patients in the daratumumab/RVd arm; an estimated 48-month progression-free survival rate of 87.2% was observed in the daratumumab/RVd arm, compared to 70% in the RVd arm. Median progression-free survival was not reached in either treatment arm. In addition, after extended follow-up, no new safety concerns were observed.
- With these effective regimens, can the treatment duration be shortened? This question was tackled by the phase II MASTER trial, which examined discontinuing therapy (ie, daratumumab/carfilzomib/lenalidomide/dexamethasone [Dara-KRd]) based on MRD negativity. Under an MRD-guided approach, patients either received more cycles of Dara-KRd as consolidation or they did not. Almost all patients achieved at least a very good partial response (VGPR), and 80% achieved MRD negativity. At 2 years, PFS exceeded 90% in patients with 0 or 1 high-risk feature, and OS essentially reached 100%. However, relapse was still common among patients with >2 high-risk features, despite this intensive treatment approach. ================================ Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10–6, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%). Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.
- “When disease control is achieved, the next question is whether to proceed to autologous stem cell transplantation. [ASCT] or to continue with some form of maintenance,” Dr. Kumar said. To this end, the IFM 2009 trial compared up-front ASCT with additional cycles of VRd, with ASCT available upon relapse. Despite a 3-drug induction regimen, ASCT still improved progression free survival by almost 1 year (median PFS, 47.3 vs 35.0 months for VRd alone; hazard ratio [HR], 0.70; 95% CI, 0.59–0.83; P5.0001), though OS differences were not seen. “This provides a clear message that transplant is an effective therapy as part of initial treatment, but it is reasonable to delay transplant to the time of first relapse if desired,” he commented. Similarly, the FORTE trial examined KRd induction followed by ASCT and demonstrated prolonged PFS over other carfilzomib-based approaches.5 The IFM 2009 and FORTE trials validated that, in transplant-eligible disease, the preferred induction approach is with a proteasome inhibitor, lenalidomide, and dexamethasone along with early transplant, if possible, he said.
- Maintenance therapy after induction and ASCT has become incorporated into clinical care, because it improves not only PFS but also OS. For patients with high-risk features, however, outcomes after maintenance remain inferior to those achieved in standard-risk patients. As a result, recent studies have attempted to improve upon single-agent lenalidomide as maintenance therapy. In the FORTE study, a maintenance regimen of carfilzomib 1 lenalidomide improved PFS compared with lenalidomide alone among all patient subgroups, including those with high-risk features.
- Similarly, all patient subsets in the CASSIOPEIA trial benefited from 2 years of daratumumab maintenance after bortezomib/ thalidomide/dexamethasone.8 Compared with the observation group, for which the median PFS was 46.7 months, for those receiving daratumumab, median PFS was not reached (P,.0001). MRD negativity rates were 47.1% and 58.6%, respectively (P,.0001). Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2–39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]–NE) with daratumumab versus 46·7 months (40·0–NE) with observation only (hazard ratio 0·53, 95% CI 0·42–0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.
- Based on these and other phase II/III trials, the researchers proposed a risk-adapted approach to managing newly diagnosed myeloma. Under this algorithm, standard-risk patients receive induction with VRd for 4 cycles, and proceeded to ASCT (preferred) or receive 4 more cycles of VRd, with ASCT on disease progression. Both approaches involve lenalidomide as maintenance. High-risk patients—those with double- or triple-hit disease, del17p, gain 1q, t(4:14), or t(t:16)—will receive 4 cycles of Dara-VRd, then proceed to ASCT (possibly tandem, in the absence of MRD negativity). Maintenance therapy for these patients is bortezomib and lenalidomide.
- Patients who are not candidates for ASCT often receive VRd or VRd ‘lite’ , in which tolerability is improved through dose modifications. The recent MAIA trial randomly assigned patients to daratumumab/lenalidomide/dexamethasone (Dara-Rd) versus Rd alone. The study randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. The percentage of patients who were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells) was more than 3 times as high in the daratumumab group as in the control group (24.2% vs. 7.3%, P<0.001) . Negative status for minimal residual disease was associated with longer progression-free survival than positive status, regardless of the trial . All the patients who were negative for minimal residual disease had a complete response or better. At a median follow-up of 28.0 months (range, 0 to 41.4), disease progression or death had occurred in 26.4% in the daratumumab group and 38.8% in the control group). The Kaplan–Meier estimate of the percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group. The median progression-free survival was not reached in the daratumumab group and was 31.9 months (95% CI, 28.9 to not reached) in the control group. The hazard ratio for disease progression or death in the daratumumab group as compared with the control group was 0.56 (95% CI, 0.43 to 0.73; P<0.001) ------ At 48 months, the median PFS was not reached for Dara-Rd and was 34.4 months for Rd alone (HR, 0.53; 95% CI, 0.43–0.66; P,.0001). Mortality was reduced by 32% as compared to Rd alone (P5.0013). “Based on this, for standard-risk patients, we would recommend Dara-Rd, or if that regimen cannot be used, using VRd ‘lite’ with continuous therapy (for 12 months) followed by lenalidomide maintenance until disease progression,” “For high-risk patients, given that data are limited on Dara-Rd, we prefer to use VRd. Of course, consideration can be given to using the quadruplet combination and to reduce doses if patients are able to tolerate it. And we would strongly consider using a proteasome inhibitor 1 lenalidomide for maintenance until disease progression. For high-risk patients, the critical thing is to get them to achieve a deep response, preferably MRD negativity.”
- Patients who are transplant-eligible and those who are transplant-ineligible, however, continue to experience relapse. Today, these patients are often “more remote” from their diagnosis (~5 years), have been off therapy for a while, and thus are “in better shape” when relapse first occurs,. The researchers base the treatment on the timing and number of prior relapses, according to the following principles: “A key factor in selecting therapy is whether the patient is refractory to lenalidomide,” he said, noting that most patients today receive lenalidomide maintenance. With this in mind, Dr. Kumar proposed a rational approach to first and later relapses (Figure 1). “In essence, for the first 2 to 3 relapses, we have the ability to mix and match 3 different monoclonal antibodies, 3 different proteasome inhibitors, and 2 different immunomodulatory drugs (IMiDs) to create regimens that are non–crossresistant,”
- “A key factor in selecting therapy is whether the patient is refractory to lenalidomide,” he said, noting that most patients today receive lenalidomide maintenance. With this in mind, Dr. Kumar proposed a rational approach to first and later relapses (Figure 1).
- “In essence, for the first 2 to 3 relapses, we have the ability to mix and match 3 different monoclonal antibodies, 3 different proteasome inhibitors, and 2 different immunomodulatory drugs (IMiDs) to create regimens that are non–crossresistant,”
- With multiple lines of treatment possible, a triple class– refractory subset of patients (often those with high-risk genetics) is increasingly being seen. A recent study has shown the median progression free survival for this group of patients to be 4 months, with an overall survival of 1 year. Treatment options for highly refractory patients include several approved drugs: selinexor, a nuclear transport protein inhibitor (list selinexor/ carfilzomib/dexamethasone as a new option in early Relapse) In the phase II BOSTON trial, selinexor 1 bortezomib/ dexamethasone led to a median PFS of 13.9 versus 9.5 months for bortezomib/dexamethasone alone (HR, 0.70; P5.0075).11 Selinexor has also successfully been combined with carfilzomib, pomalidomide, and daratumumab. The NCCN Guidelines list selinexor/ carfilzomib/dexamethasone as a new option in early relapse.
- With multiple lines of treatment possible, a triple class– refractory subset of patients (often those with high-risk genetics) is increasingly being seen. A recent study has shown the median progression free survival for this group of patients to be 4 months, with an overall survival of 1 year. Treatment options for highly refractory patients include several approved drugs: selinexor, a nuclear transport protein inhibitor (list selinexor/ carfilzomib/dexamethasone as a new option in early Relapse) In the phase II BOSTON trial, selinexor 1 bortezomib/ dexamethasone led to a median PFS of 13.9 versus 9.5 months for bortezomib/dexamethasone alone (HR, 0.70; P5.0075).11 Selinexor has also successfully been combined with carfilzomib, pomalidomide, and daratumumab. The NCCN Guidelines list selinexor/ carfilzomib/dexamethasone as a new option in early relapse.
- selinexor, a nuclear transport protein inhibitor (list selinexor/ carfilzomib/dexamethasone as a new option in early Relapse) In the phase II BOSTON trial, selinexor 1 bortezomib/ dexamethasone led to a median PFS of 13.9 versus 9.5 months for bortezomib/dexamethasone alone (HR, 0.70; P5.0075).11 Selinexor has also successfully been combined with carfilzomib, pomalidomide, and daratumumab. The NCCN Guidelines list selinexor/ carfilzomib/dexamethasone as a new option in early relapse.
- Belantamab mafodotin, an antibody–drug conjugate targeting BCMA, has shown efficacy in the DREAMM2 trial as a single agent,12 and is listed in the NCCN Guidelines as an option for patients with late relapse. “Even though the median PFS was only 3 to 4 months, the duration of response for the 30% or so who responded reached almost 1 year. Efficacy seems comparable across all different subgroups and, most importantly, irrespective of prior therapies.” A downside of belantamab mafodotin is ocular toxicity, which requires frequent eye examinations. Lower dosing and less frequent administration are being evaluated to ameliorate this adverse effect. (click) Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
- the introduction of the first CAR T-cell therapy, idecabtagene vicleucel, followed by ciltacabtagene autoleucel— both of which are now recommended for late relapse. Idecabtagene vicleucel proved itself in the pivotal KarMMA trial, with an overall response rate of 73% (81% at the highest dose level) and high MRD negativity rates. Similarly, in CARTITUDE-1, ciltacabtagene autoleucel elicited VGPRs in 94.9% of patients and stringent complete responses in 82.5%. The 2-year PFS was 71.0% (95% CI, 57.6–80.9) (.90% sustained MRD negativity) and the OS rate was 74.0% (95% CI, 61.9–82.7), with medians not reached for either endpoint. “This is a striking improvement compared with what we would have expected from patients who are double-refractory,” Dr. Kumar commented.
- Newer agents have not yet made their way into the NCCN Guidelines but look promising. Bispecific T-cell engagers are of particular interest because their use does not require apheresis and T-cell manipulation. Instead, they are composed of an antibody with 2 specificities: CD3 on T cells, and a tumor-associated antigen (this varies among the agents) on the myeloma cell. Teclistamab, which targets BCMA, is furthest along in development. In the MajesTEC-1 trial, 62.0% of triple class–refractory patients experienced response, with responses deepening over time.15 Of patients who achieved at least a complete response, 41.9% achieved MRD negativity. Talquetamab, which targets GPRC5D, produced $VGPRs in approximately 53% of patients and stringent complete responses in approximately 10% of patients in the MonumenTAL-1 trial.16 Finally, cevostamab, which targets FcRH5, has produced responses in 56.7% of patients, which were at least VGPRs in 33.3%.
- Venetoclax seems particularly promising for patients with t(11;14) or BCL2-high disease. The phase III BELLINI trial found that this drug significantly improved PFS overall (HR, 0.58; P5.0003).18 The subgroup analysis found a strong benefit in the t(11;14) group (HR, 0.12; P5.0014) and the BCL2-high group (HR, 0.37; P5.0005). Venetoclax is recommended in the NCCN Guidelines for t(11;14 disease) alone. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo plus bortezomib and dexamethasone. Cycles 1-8 were 21-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12. Cycles 9 and beyond were 35-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 8, 15, and 22 and dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23.
- Iberdomide is a potent novel CELMoD being developed as a next-generation IMiD. Recent studies have shown iberdomide to be effective in disease refractory to other IMiDs (lenalidomide, pomalidomide) and to BCMA-targeting agents. In CC-220-MM-001, the overall response rate in combination with dexamethasone was 26.2%, and the disease control rate was 79.4%; after BCMA-targeting therapy, these rates were 25.0% and 75.0%, respectively.19 “Clearly, there are multiple new therapies that we hope will be coming into the clinic in the next few years,” he said.
- There has been improved with the addition of recommendations for supportive care management of venous thromboembolism, for which risk is increased in patients receiving multiagent chemotherapy regimens and IMiDs. The management algorithm includes a risk stratification scoring system that allows for the personalization of thromboprophylaxis.