Therapy In Multiple Myeloma Patients Research Articles

Clinical and economic implications of using daratumubab with lenalidomide in the 1st and 2nd lines of therapy for multiple myeloma patients

Objective: to assess clinical and economic implications of adding daratumumab (Dara) to the “lenalidomide + dexamethasone” (Rd) treatment program in early lines of therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy (HDCT) with subsequent autologous hematopoietic stem cell transplantation (autoHPSCT).Material and methods. Partitioned survival model was developed to compare overall survival in the treatment programs of MM patients in the 1st to 3rd lines of therapy. The following treatment options were included in the analysis: 1st line – Dara+Rd; 2nd line – “carfilzomib + lenalidomide” (K+Rd) or “ixazomib + lenalidomide” (Ixa+Rd) triplets; 3rd line – pomalidomide (Pom+dex) and Rd+(Dara+Rd)+(Pom+dex) versus Rd+(K/Ixa+Rd)+(Pom+dex/Dara). Probabilities of transition between health states (progression-free, progressed disease, and death) were based on published clinical data. Lifetime direct healthcare costs and incremental cost-effectiveness ratios (ICERs) per 1 life year gained were calculated from a Russian health care perspective. The indicator of the difference in costs between current and expected practice was used in budget impact analysis.Results. Dara+Rd combination increased life expectancy by 1.04 years (+16.05%) and 0.95 years (+14.57%) per patient, and in the target population (n=955) by 995.48 and 903.40 years for (Dara+Rd)+(K+Rd)+(Pom+dex) and (Dara+Rd)+(Ixa+Rd)+(Pom+dex) treatment programs, respectively, compared to Rd use in the 1st line. The ICER per 1 life year gained for Dara+Rd in 1st line therapy was 8.95 mln rubles for (Dara+Rd)+(K+Rd)+(Pom+dex) and 8.41 mln rubles for (Dara+Rd)+(Ixa+Rd)+(Pom+dex). It's lower than the median ICER of 13.64 million per 1 life year gained for antitumor drugs used to treat cancer of lymphatic and hematopoietic tissues (reference ICER). Dara+Rd triplet is used in 2nd line therapy after Rd, the number of life years gained in the target population due to greater efficacy is higher by 291.50 years compared with K+Rd and by 203.93 years compared with Ixa+Rd. The ICER per 1 life year gained for Dara+Rd is also lower than the ICER reference value: 9.25 mln rubles versus 13.64 mln rubles. The budget impact analysis showed that using Dara in early stages of MM therapy does not increase drug provision costs in the target population.Conclusion. The obtained results allowed to conclude that it is economically feasible to add Dara to the 1st and 2nd lines of therapy in lenalidomide treatment programs for MM patients who are not candidates for HDCT with autoHPSCT.

An Illustrative Case of Daratumumab-associated Leukoencephalopathy: A Rare but Important Complication of Anti-CD38 Therapy in Multiple Myeloma Patients (P6-5.021)

An Illustrative Case of Daratumumab-associated Leukoencephalopathy: A Rare but Important Complication of Anti-CD38 Therapy in Multiple Myeloma Patients (P6-5.021)

Impact of Genetic Polymorphisms in NF-ĸB2 and TRAF3 Genes on Response to Bortezomib-Based Therapy in Multiple Myeloma Patients.

Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for normal cell function, plays a pivotal role in myeloma pathophysiology, especially with the advent of bortezomib (BTZ). Dysregulation of the UPP has implications ranging from developmental abnormalities to cancer. This study aimed to delineate the clinical characteristics of newly diagnosed multiple myeloma patients and investigate the influence of single nucleotide polymorphisms (SNPs) in NF-ĸB2 and TRAF3 genes on the risk and treatment response to bortezomib-based chemotherapy. Conducted at JIPMER, Pondicherry, this prospective study enrolled 184 participants, comprising cases and controls. DNA extraction from peripheral blood samples was followed by SNP analysis through Real-time Polymerase Chain Reaction. Patients were categorized into Good and Poor responders, and SNP associations with treatment response, response rates, and survival outcomes were assessed using chi-square and Kaplan-Meier analyses. The median age of participants was 55 years, with backache being the most prevalent symptom (66.3%). Hypercalcemia (22%), renal failure (8.7%), and bone fractures (45.7%) were also observed, alongside high prevalence of anemia. Notably, the frequency of the TRAF3 rs12147254 A allele was lower in cases compared to controls (31% vs. 49%, P-value=0.002). Poor responders exhibited higher frequencies of the GA+AA genotypes in TRAF3 rs12147254 (OR-3.882(1.629-9.251), P-value-0.002) and NFKB2 rs1056890 (OR-3.308(1.366-8.012), P-value-0.008) when compared to good responders. The GA+AA genotype in TRAF3 rs11160707 SNP correlated with improved progression-free survival. The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.

Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients

BackgroundBortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study. MethodsTreatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0. ResultsTotal 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44). ConclusionsPolymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.

Response Of Bortezomib, Cyclophosphamide And Dexamethasone Induction Chemotherapy In Multiple Myeloma Patients Presenting To Combined Military Hospital Rawalpindi

Objective: To determine the response rate and tolerability of Bortezomib, Cyclophosphamide and Dexamethasone (VCD) induction therapy in multiple myeloma patients. Study Design: Prospective longitudinal study Place and Duration of Study: Department of Oncology, Combined Military Hospital, Rawalpindi Pakistan, from Mar to Sep 2020. Methodology: Patients of either gender aged >20-65 years, newly diagnosed cases of multiple myeloma, Durie-Salmon stage II/III, were included. Patients were given Bortezomib, Cyclophosphamide and Dexamethasone induction therapy for a 21-day cycle. Response rate and tolerability were measured. Results: A total of 147 patients were included in the study. There were 75(51%) male and 72(49%) female.The overall response rate was seen in 93(63.3%) patients, complete response was seen in 30(20.4%), and partial response was seen in 63(42.9%) patients. The overall response rate was significantly associated with age, myeloma type, and Karnofsky's performance status (p-value<0.001). Conclusion: The novel sequential 3-drug combination of Bortezomib, Cyclophosphamide and Dexamethasone is safe and well tolerated for multiple myeloma patients. The results of the current study increase evidence of a moderately high response rate with Bortezomib, Cyclophosphamide and Dexamethasone induction therapy.

Does Systemic Hematological Therapy Influence the Course of Paraproteinemic Keratopathy?

The purpose of this article is to evaluate the course of paraproteinemic keratopathy (PPK) in patients undergoing systemic therapy for the underlying hematological disease. Baseline and follow-up examinations included hematological work-up, best-corrected visual acuity, slit-lamp biomicroscopy, and in vivo confocal laser scanning microscopy (IVCM). We included 22 patients with bilateral PPK (aged 68 ± 10.4 years, 11 males). Ten patients with multiple myeloma (MM) underwent on-label systemic therapy. During follow-up, we observed a regression of corneal opacities in three patients under slit-lamp examination and under IVCM, while PPK remained unchanged in seven patients. In three patients with monoclonal gammopathy of ocular significance (MGOS), systemic therapy was initiated off-label to reduce the serum paraprotein load before penetrating keratoplasty (PKP). These patients showed no signs of PPK recurrence for up to 24 months after PKP. In one patient without systemic therapy, a recurrence in corneal grafts occurred within 12 months of PKP. In eight patients without systemic therapy, PPK remained stable. In conclusion, systemic therapy for MM patients reduced corneal opacity in 30% of treated patients. Furthermore, systemic therapy performed before PKP in patients without conventional systemic therapy indication (MGOS) likely postpones PPK recurrence in the corneal graft.

Multiple myeloma and Chagas disease: qPCR as a marker for preemptive antiparasitic therapy: a case reports series and review.

Multiple myeloma (MM) associated with Chagas disease is rarely described. This disease and its therapy suppress T cell and macrophage functions and increase regulatory T cell function, allowing the increase of parasitemia and the risk of Chagas Disease Reactivation (CDR). We aimed to analyze the role of conventional (cPCR) and quantitative Polymerase Chain Reaction (qPCR) for prospective monitoring of T. cruzi parasitemia, searching for markers of preemptive antiparasitic therapy in MM patients with Chagas disease. Moreover, we investigated the incidence and management of hematological diseases and CDR both inside and outside the transplant setting in the MEDLINE database. We found 293 studies and included 31 of them. Around 1.9-2.0% of patients with Chagas disease were reported in patients undergoing Stem Cell Transplantation. One case of CDR was described in eight cases of MM and Chagas disease. We monitored nine MM and Chagas disease patients, seven under Autologous Stem Cell Transplantation (ASCT), during 44.56±32.10 months (mean±SD) using parasitological methods, cPCR, and qPCR. From these patients, three had parasitemia. In the first, up to 256 par Eq/mL were detected, starting from 28 months after ASCT. The second patient dropped out and died soon after the detection of 161.0 par Eq/mL. The third patient had a positive blood culture. Benznidazole induced fast negativity in two cases; followed by notably lower levels in one of them. Increased T. cruzi parasitemia was related to the severity of the underlying disease. We recommend parasitemia monitoring by qPCR for early introduction of preemptive antiparasitic therapy to avoid CDR.

T-cell redirection therapy after allogeneic stem cell transplantation in multiple myeloma: When the cure fails!

Allogeneic stem cell transplant remains an option for patients with myeloma. Given the unfortunate inevitability of the majority of patients, relapsing salvage therapy options are needed. Although there is a potential concern for subsequent T-cell redirection therapy in these patients, Hammons etal. provide a retrospective look at patients treated this way with no new significant adverse safety or efficacy signal. Commentary on: Hammons etal. Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation. Br J Haematol 2024;204:887-891.

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

Age-Based Comparison of Stem Cell Transplantation during the First Line of Therapy for Multiple Myeloma Patients

Background High-dose chemotherapy followed by stem cell transplantation (SCT) has been the standard first-line therapy for eligible multiple myeloma (MM) patients for over three decades. However, most studies evaluating SCT in MM have focused on patients under 65 years old, despite the increasing number of older patients diagnosed with MM. Retrospective data suggest that SCT can offer good survival outcomes with acceptable toxicities in patients over 65. This registry retrospective study aims to compare the time to next treatment (TTNT) of SCT versus non-SCT treatments in MM patients, assessing those aged <65 and ≥65 years old. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1279 patients with multiple myeloma. Patients were categorized into two groups based on age at the start of their first line of therapy (<65 and ≥65). Kaplan-Meier ‘Time to Next Treatment’ (TTNT) R analysis was employed to compare patients who underwent stem cell transplant (SCT) and those who did not (NSCT) within each age group. SCT patients received a high-dose melphalan preparative regimen (140-200 mg/m2). Age groups were also subclassified by high-risk cytogenetics, using mSMART staging by fluorescence in situ hybridization (FISH), and Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1279 MM patients, of whom 830 (64.9%) were <65 and 449 (35.1%) were ≥65. The <65 group had a mean age of 55±7, whereas the group ≥65 had a mean age of 70±5. 52.5% were female. The majority of patients were White (78.2% in the <65 group and 81.77% in ≥65), with other relevant groups including Blacks (5.8% in the <65 group and 4.2% in the ≥65 group), and Hispanics or Latinos (4.0% in the <65 group and 2.8% in the ≥65 group). The median year of diagnosis was 2018 (2006-2022).R-ISS staging was available for 664 patients and not dissimilar between groups ( p = 0.69): in the <65 group, 159 (37.2%) patients were classified as R-ISS stage I, 188 (44.0%) patients stage II, and 81 (18.9%) patients stage III. In the ≥65 group, 81 (34.3%) were stage I, 118 (50.0%) stage II, and 37 (15.7%) stage III. 1196 patients had mSMART staging available, of whom, patients with high-risk, double, and triple hit, represented 15.9%, 4.6%, and 0.4%, respectively. Age group high-risk characteristics proportions were not dissimilar ( p = 0.7). In the <65 group, 69.2% had a transplant during their first line of therapy, while in the ≥65 group, 48.8% had a transplant. For patients aged <65, the mean TTNT was 32.5 mo (SD 25) in the SCT group, and 16 mo (SD 21.6) in the NSCT group. For patients aged ≥65, the mean TTNT was 28.6 mo (SD 18.9) in the SCT group, and 16.5 mo (SD 18.3) in the NSCT group. The TTNT survival at 4 years was significantly higher in patients that experienced an SCT in both groups, <65 (SCT=40%, NSCT=18%, p = <0.0001) and ≥65 (SCT=43%, NSCT=14%, p = <0.0001). Conclusions Our findings add to the compelling evidence that SCT demonstrates favorable outcomes in both age groups of MM patients. The mean TTNT difference of SCT vs NSCT observed in the <65 group is 16.5 mo, and in the ≥65 group, it is 12.1 mo. Furthermore, patients who underwent SCT in both age groups had significantly higher TTNT survival rates at 4 years, doubling the rates to 40% in the <65 group and 43% in the ≥65 group, emphasizing the substantial benefits of SCT as a first-line therapy for multiple myeloma. These results contribute to the growing body of evidence supporting the efficacy and acceptability of SCT in the management of multiple myeloma across all age groups. It also emphasizes the importance of considering SCT as a viable treatment option for eligible MM patients, including those aged 70 and above, to improve long-term outcomes.

Age-Based Comparison of Dara-Rvd, Krd and Rvd Induction Therapies during the First Line of Therapy for Multiple Myeloma Patients

Background Since the development of proteasome inhibitors, the combination of lenalidomide (R), bortezomib (V), and dexamethasone (d) for induction has been the standard of care when treating patients with multiple myeloma. This combination has been shown to improve the clinical outcomes and quality of life of multiple myeloma patients. More recently, new generations of proteasome inhibitors, such as carfilzomib (K), and the development of monoclonal antibodies have created new opportunities for treatment that provide better outcomes with fewer side effects. The addition of daratumumab (Dara) to the RVd induction therapy has shown more potent results, increasing response rates and outcomes. However, there is a lack of evidence about the influence that age may have on the efficacy of these therapies. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1100 patients with multiple myeloma. Patients were categorized into two groups based on age (<65 and ≥65). We compared ‘Time to Next Treatment’ (TTNT) among patients who received DaraRVd, KRd, or RVd as induction therapy. The analysis was conducted using Kaplan-Meier curves in R. Age groups were also subclassified by high-risk cytogenetics according to mSMART staging by fluorescence in situ hybridization (FISH), and the Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1100 patients with MM, of which 718 patients (65.3%) were age <65 and 382 patients (34.7%) were age ≥65. The <65 group had a median age of 55±7, and the ≥65 group had a median age of 70±5. The majority of patients were female (n=586, 53.3%). The median year of diagnosis was 2018 (2009-2022). In the <65 group, the majority of patients were White (88%), and other big groups were Blacks (5.8%), and Hispanics or Latinos (2.6%). Similarly, in the ≥65 group, the majority of patients were White (93.0%), and other big groups were Blacks (3.3%), and Hispanics or Latinos (2%). In the <65 group, 55 patients had DRVd as induction therapy, 77 KRd, and 586 RVd. In the ≥65 group, 38 patients received DRVd as induction therapy, 39 KRd, and 305 RVd. R-ISS staging was available for 588 patients. In the <65 group, 139 patients (36.7%) were classified as R-ISS stage I, 170 patients (44.8%) stage II, and 70 patients (18.5%) stage III. In the ≥65 group, 75 patients (35.9%) were stage I, 104 patients (49.8%) were stage II, and 30 patients (14.3%) were stage III ( p=0.37). mSMART staging was available for 1035 patients, of whom patients with high-risk, double, and triple hit represented 16.2%, 5.0%, and 0.3%, respectively ( p = 0.35). Regarding stem cell transplant (SCT), 571 patients (51.9%) underwent SCT. In the <65 group, 404 patients (56.3%) received SCT; of those, 18 (32.7%) received DRVd, 21 (53.3%) KRd, and 345 (58.9%) RVd. In the ≥65 group, 167 patients (43.7%) received SCT; of those, 12 (31.6%) received DRVd, 23 (59%) KRd, and 132 (43.3%) RVd as induction therapy. For patients aged <65, the median TTNT was not yet reached for the DRVd group, 33 mo for the KRd group, and the RVd group was longer at 48 mo ( p=0.049). For patients aged ≥65, the median TTNT was not yet reached for the DRVd group, and 54 mo for the KRd group, which did not significantly differ from the RVd group, which had a median TTNT of 47 mo (p=0.52). Conclusion This study found that in the <65 age group, RVd induction therapy led to a longer TTNT compared to KRd, while in the ≥65 age group, KRd showed a longer TTNT than RVd. When considering the SCT usage rate, which increases TTNT by at least 12 months on average, KRd did not significantly improve outcomes over RVd in both age groups. However, when evaluating KRd induction, it's worth noting that KRd showed an improved outcome with a longer TTNT in the ≥65 age group compared to the <65 age group, despite toxicity concerns. These results align with the ENDURANCE trial, which also indicated that KRd did not significantly improve outcomes in standard-risk patients compared to VRd. Though the TTNT for the DRVd group is yet to be reached, the current trend suggests promising results for DRVd as a first-line therapy over KRd and RVd in both age groups. Nevertheless, further research is needed to validate and gain better insight into these observed trends.

A Pilot Study to Determine the Safety and Efficacy of Repeated Hyperbaric Oxygen Therapy in Multiple Myeloma Patients Undergoing High-Dose Therapy and Autologous Stem/Progenitor Cell Transplantation

Background Serum erythropoietin (EPO) negatively impacts hematopoietic stem cell homing and engraftment. Hyperbaric oxygen (HBO) therapy can reduce serum EPO in healthy volunteers and when given prior to stem cell infusion may improve engraftment after hematopoietic stem cell transplant (HSCT). We previously performed a phase II trial randomizing patients with multiple myeloma undergoing high dose melphalan and autologous HSCT 1:1 between a single HBO treatment and no HBO. HBO was given as 100% oxygen, 2.5 ATA for a total of 90 min, in a single treatment on Day 0 prior to the transplant. A total of 99 patients were enrolled with 52 randomized to HBO. HBO significantly reduced EPO levels for the first 24 hours after auto transplant, but EPO levels quickly rebounded by 48 hours after transplant. We hypothesized multiple HBO treatments will keep EPO levels low during the duration of stem cell homing (i.e: the first 72 hours after HSCT) and may improve neutrophil and NK cell recovery. Methods We performed a pilot study to evaluate the safety and tolerability of multiple HBO treatments during autologous HSCT. Patients with multiple myeloma undergoing autologous HSCT were eligible. Patients received HBO therapy, consisting of hyperbaric oxygen at 2.5 ATA for a total of 90 minutes breathing 100% oxygen on days 0 (prior to HSCT), 1, and 2 of transplant. The primary objective of this pilot study was to determine the safety of repeated HBO therapy in the setting, as defined by treatment limiting toxicity (TLT) including occurrence of seizure disorder, pneumothorax, death, or any irreversible grade Ill or any grade IV toxicity within 24 hours of HBO therapy. Secondary objectives were to determine the effects of multiple HBO therapy on neutrophil count recovery and the effect of multiple HBO on serum EPO. Results 10 patients have been enrolled that are evaluable for the primary objective. All patients had multiple myeloma and 4 were female. 9/10 patients successfully completed all 3 HBO treatments and 1/10 completed HBO on days 1 and 2 only because of ear pain on day 0. No patients experienced treatment limiting toxicity. The median times to neutrophil and platelet engraftment was 12 days (range 11-14) and 16 days (range 14-28), respectively. The median length of hospitalization was 13 days (range 12-16). Febrile neutropenia occurred in 3/10 patients with just one incidence of documented infection. This was significantly less than the rate of febrile neutropenia in patients receiving a single treatment of HBO or no HBO (81% and 47%, respectively, p<0.05). 3 patients required red blood cell transfusion and 5 platelet transfusion. Conclusions Multiple HBO treatment were well tolerated without treatment limiting toxicity during autologous HSCT for multiple myeloma.

Inflammatory Biomarkers and Outcomes in Multiple Myeloma Patients after CAR T-Cell Therapy

Introduction: CAR T-cell therapy is an effective tool for the treatment of multiple myeloma but produces a systemic inflammatory response which can manifest as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurologic toxicities, and hyperferritinemia. Understanding the factors associated with these complications can help clinicians better evaluate their patients' candidacy for CAR T-cell therapy. In this study, we assessed whether baseline values of inflammatory biomarkers were associated with outcomes after CAR T-cell therapy. Methods: We retrospectively reviewed multiple myeloma patients who underwent CAR T-cell therapy with commercial products or on clinical trials at The Mount Sinai Hospital between 2017 and 2023. We gathered data on lab parameters that we felt were indicative of patients' baseline inflammatory status including C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, absolute lymphocyte count (ALC), and absolute neutrophil count (ANC). Baseline data were collected prior to lymphodepletion. Outcomes of interest were occurrence and maximum grade of CRS and ICANS, occurrence of delayed neurotoxicity, attainment of peak ferritin ≥5000 within 30 days of infusion, progression-free survival (PFS), and overall survival (OS). Univariate logistic regression was used to assess the association between baseline labs and CRS, ICANS, delayed neurotoxicity, and peak ferritin ≥5000. Ordinal logistic regression was used to assess the baseline labs' association with maximum grade of CRS and ICANS, while proportional cox regression was used to assess their association with OS and PFS. The percentage of bone marrow plasma cells pre-CAR T, which we used as a surrogate for tumor burden, was included as a covariate on multivariable analyses. Results: A total of 101 patients treated with CAR T cells were included - 45 with ciltacabtagene autoleucel, 37 with idecabtagene vicleucel, and 19 with other products on clinical trials. Median age was 63 (range 37-82), median baseline marrow plasma cells percentage was 5% (range 0%-95%), and median follow-up was 11.9 months. Patients had a median (IQR) CRP of 4.0 mg/L (1.8, 11.8), ferritin of 174 ng/mL (68, 364), D-dimer of 0.6 mcg/L (0.4, 1.2), fibrinogen of 397.0 mg/dL (334.0, 477.5), ALC of 0.8 x10 3/µL (0.5, 1.1), and ANC of 2.7 x10 3/µL (1.9, 3.6). CRS occurred in 88.2% of patients (3.9% grade ≥3), ICANS in 15.7% (all grade <3), and delayed neurotoxicity in 5.9% (all grade <3). Increased baseline fibrinogen and ferritin were significantly associated with inferior OS even after adjusting for covariates (p-values 0.031 and 0.010, respectively). Every 143 mg/dL increase in fibrinogen increased the hazard of death by 83.7%, while every 500 ng/mL increase in ferritin increased the hazard of death by 27.5%. Patients with higher baseline CRP had a trend towards inferior OS (30.2% increased hazard of death per 20 mg/L CRP increase, p = 0.055). Baseline CRP, D-dimer, fibrinogen, ferritin, ALC, and ANC were not associated with PFS. Higher baseline ALC was associated with both increased odds of ICANS (110.2% increased odds of ICANS for every 0.5 x10 3/µL increase in ALC, p = 0.019 on multivariable analysis) and increased grade of ICANS (p = 0.023 on multivariable analysis). None of the assessed biomarkers were associated with peak ferritin ≥5000 (aside from baseline ferritin), occurrence of CRS, maximum grade of CRS, or delayed neurotoxicity. Conclusion: Although CAR T-cell therapy is a highly effective treatment option for patients with multiple myeloma, outcomes of infused patients can be highly variable. Serologic biomarkers like fibrinogen and ferritin are routinely assessed in patients undergoing CAR T-cell therapy and could offer value as predictors of outcomes. We found that higher fibrinogen and ferritin values at baseline were associated with inferior OS after CAR T-cell therapy, even after controlling for tumor burden. Higher baseline ALC was also associated with higher risk of ICANS and higher grade of ICANS, an important toxicity to consider for patients receiving CAR T. Baseline fibrinogen, ferritin, and ALC may be incorporated into assessments of the risk of CAR T-cell therapy for multiple myeloma patients.

Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially dependent on MCL-1 and in plasma cells from patients.

A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.

Predicting neutropenia dynamics after radiation therapy in multiple myeloma patients receiving first-line bortezomib-based chemotherapy – a pilot study

Predicting neutropenia dynamics after radiation therapy in multiple myeloma patients receiving first-line bortezomib-based chemotherapy – a pilot study

P-291 Outcomes of third-line therapy in multiple myeloma patients: a report from the Canadian myeloma research group (CMRG)

P-291 Outcomes of third-line therapy in multiple myeloma patients: a report from the Canadian myeloma research group (CMRG)

Lenalidomide plus Dexamethasone Combination as First-Line Oral Therapy of Multiple Myeloma Patients: A Unicentric Real-Life Study.

Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.2%) were alive, and 22 were still in treatment with Len/Dex. Among 73 evaluable patients who received at least two cycles, the overall response rate was 71% (N = 52). The disease control rate, defined as any level of clinical response to therapy, occurred in 71 patients (97%). We reported one or more adverse events of grade 3 or 4 (G3/4) in 65.2% (N = 58) of patients, with a prevalence of hematological toxicity (24 patients), leading to an overall discontinuation of treatment in two cases. In univariate analysis, high ISS, high serum β2-microglobulin, and creatinine clearance <30 mL/min negatively impact OS, while the depth of response positively impacts OS. Moreover, G3-4 anemia, ISS, frailty score, and ECOG negatively impacts PFS. In conclusion, elderly and more frail patients benefit from the Len/Dex combination also in the era of monoclonal antibodies, ensuring an increased PFS and OS in patients where the therapeutic choice is often limited and usually not very effective.

The quantification of circular RNA 0007841 during induction therapy helps estimate the response and survival benefits to bortezomib-based regimen in multiple myeloma.

Circular RNA_0007841 (Circ_0007841) facilitates multiple myeloma (MM) progression and resistance of the bortezomib by experimental studies, while its clinical implication in MM patients is still unclear. This study intended to evaluate the longitudinal change and prognostic role of circ_0007841 expression in MM patients receiving bortezomib-based induction therapy. In this prospective study, bone marrow plasma cell (BMPC) samples were gained from 97 MM patients at diagnosis and after bortezomib-based induction therapy, and from 30 healthy controls (HCs) proposing BM donation. Then, circ_0007841 expression in BMPC samples was measured by reverse transcription-quantitative polymerase chain reaction. Additionally, MM patients were followed up for a median of 29.4months. Circ_0007841 expression was increased in MM patients compared to HCs (P < 0.001), but it was decreased after bortezomib-based induction therapy in MM patients (P < 0.001). Moreover, circ_0007841 expression at diagnosis was associated with the presence of t (4; 14) (P = 0.034), while its expression after bortezomib-based induction therapy was linked with higher revised international staging system stage (P = 0.025) in MM patients. Interestingly, circ_0007841 expression after bortezomib-based induction therapy was lower in MM patients who achieved complete remissions (P = 0.001) and overall responses (P = 0.002) compared to those who did not. Prognostically, circ_0007841 expression after bortezomib-based induction therapy (over the median vs. below the median) independently predicted shorter progression-free survival (hazard ratio (HR): 2.497, P = 0.002) and overall survival (HR: 3.107, P = 0.008) in MM patients. Circ_0007841 quantification during induction therapy may reflect the response and survival benefits to bortezomib-based regimen in MM patients.

Cellular immunity in the era of modern multiple myeloma therapy.

Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.

Feasibility of cryocompression for bortezomib-induced peripheral neuropathy (BIPN) among patients with multiple myeloma (MM).

e24147 Background: BIPN is a dose-limiting side effect of bortezomib therapy occurring in over three-quarters of bortezomib-treated patients and results in increased morbidity secondary to decreased quality of life and increased mortality due to treatment discontinuation or dose-reduction. Cryocompression therapy acts at the level of the nerve and does not limit bortezomib anti-tumor activity, making it ideal for clinical testing in patients with BIPN. This study evaluated the feasibility of cryocompression therapy in MM patients with BIPN. Methods: MM patients with Common Terminology Criteria for Adverse Event (CTCAE) Grade 1-3 BIPN who previously received a bortezomib-containing regimen (Arm 1) or were currently receiving a bortezomib-containing regimen (Arm 2) were enrolled at a Comprehensive Cancer Center outpatient clinic. Patients were instructed to complete daily home cryocompression treatments on non-dominant hand and foot for 30 continuous minutes for 8-weeks. Primary outcome was compliance measured by device-recorded data and defined as completion of at least 25 of 30 minutes, 60% of prescribed treatment days. Change in patient reported symptoms was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 questionnaire. Proportion of compliant patients was calculated. Spearman’s rank correlation coefficients were used to evaluate the association between treatment compliance and QLQ-CIPN20 scores. Here we report on Arm 1. Results: 12 patients (median age 63.9+11.8 years, 41.7% female, 66.7% white, 25.0% black) participated in Arm 1. 75% of patients were compliant. The mean proportion of treatment-compliant days was 65.8% (95% CI 46.5% – 85.0%). Patient-reported BIPN symptoms improved with QLQ-CIPN20 total and sensory sub scores of 39.2+9.2 and 22.5+4.7 at baseline, 33.7+6.2 and 19+3.5 at week 4, and 34.1+7.8 and 19.9+5.5 at week 8. This accounted for a statistically significant decline in total QLQ-CIPN20 score at week 4 (-5.9+9.1, p = 0.035), week 8 (-4.6+5.0, p = 0.020), and sensory sub score at week 4 (-3.5+3.4, p = 0.008) and week 8 (-2.6+3.5, p = 0.050). There was no correlation between compliance and change in total QLQ-CIPN20 score (r = -0.31, p = 0.380) or sensory sub score (r = -.054, p = 0.109) in the per protocol analysis (N = 10). Using a last-time-point available analysis, no correlation was observed for total QLQ-CIPN20 score (r = -0.44, p = 0.149) but a moderate-to-strong inverse correlation was observed between amount of cryocompression use and change in QLQ-CIPN20 sensory sub score (r = -0.62, p = 0.031). Conclusions: Cryocompression therapy is feasible in MM patients with BIPN who previously received a bortezomib-containing regimen. The observed biologic gradient with greater improvement in patient-reported sensory neuropathy with longer duration of cryocompression treatment supports the rationale and further study. Clinical trial information: NCT03870451 .