Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened versus clinically detected MGUS differ. We compared the progression risk between screened versus clinical MGUS cohorts and assessed whether the MGUS detection method impacted risk prediction of established clinical factors (score). We included 379 screened MGUS from the Olmsted County population based study and 1384 MGUS patients diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened versus clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% CI 8.3-14.8]) versus clinical (10.1% [95% CI 8.6-11.8%]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI 0.6-1.2) screened versus 1.0 (95% CI 0.9-1.2) clinically detected MGUS patients experienced disease progression for every 100 person years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction=0.217) and did not add to known risk factors for progression (likelihood ratio test, p=0.839). Here we show that progression risk among patients with screened versus clinically detected heavy-chain MGUS was similar. Future studies are needed to assess if tailored follow-up of screened MGUS patients affects clinical outcomes.

A Prognostic Survival Model Incorporating Patient-Reported Outcomes for Transplant-Ineligible Patients With Multiple Myeloma.

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.

Comparing the clinical trial efficacy versus real-world effectiveness of treatments for multiple myeloma: a population-based study.

Not available.

Cancer-specific mortality in multiple myeloma: a population-based retrospective cohort study.

Survival has improved in patients diagnosed with multiple myeloma (MM) over the last two decades; however, there remains a paucity of data on the causes of death in MM patients and whether causes of death change during the disease trajectory. We conducted a retrospective population-based study to evaluate the rates of MM-specific versus non-MM cause of death and to identify factors associated with cause-specific death in MM patients, stratified into autologous stem cell transplant (ASCT) and non-ASCT cohorts. A total of 6,677 patients were included, 2,576 in the ASCT group and 4,010 in the non-ASCT group. Eight hundred and seventy-three (34%) ASCT patients and 2,787 (68%) non-ASCT patients died during the follow-up period. MM was the most frequent causes of death, causing 74% of deaths in the ASCT group and 67% in the non-ASCT group. Other cancers were the second leading causes of death, followed by cardiac and infectious diseases. Multivariable analysis demonstrated that a more recent year of diagnosis and novel agent use within 1 year of diagnosis were associated with a decreased risk of MM-specific death, whereas a history of previous non-MM cancer, older age, and the presence of CRAB criteria at diagnosis increased the risk of non-MM death. Our data suggests that despite improvement in MM outcomes in recent years, MM remains the greatest threat to overall survival for patients. Further advances in the development of effective MM therapeutic agents in both ASCT and non-ASCT populations and patient access to them is needed to improve outcomes.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

INTRODUCTION: Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. METHODS AND OBJECTIVE: We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. RESULTS: We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. CONCLUSION: Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

A phase 1/2 of carfilzomib and melphalan conditioning for autologous stem cell transplantation for multiple myeloma (CARAMEL).

In this phase 1/2 study, carfilzomib was added to high-dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days -6, -5, -2, and -1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days -4 and -3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4-88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3-4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Effect of Donor Age and Donor Relatedness on Time to Allogeneic Hematopoietic Cell Transplantation in Acute Leukemia.

Relapse after allogeneic hematopoietic cell transplantation (HCT) for acute leukemia can be reduced when pursued early after first complete remission. The impact of donor age and donor relatedness on the time from diagnosis to transplant in patients with acute leukemia was examined to clarify the design of future prospective studies that can address optimal donor choice. Files of 100 consecutive patients undergoing transplantation for leukemia were reviewed. Recipients of related donors (RDs) and unrelated donors (UDs) were not significantly different in terms of recipient gender, age, underlying diagnosis, disease risk index, graft source, or donor HLA match. UDs were significantly younger than RDs (median age, 29 versus 51, P < .001). Multivariate linear regression revealed that when controlling for age of donor and recipient, the time from diagnosis to transplant was 35% longer with UDs compared with RDs (P = .018). No significant correlation was observed between donor and recipient age on length of time to transplant (P = .134 and P = .850, respectively), when controlling for other variables. The steps in UD procurement that contribute most to the longer time to transplant relate to activating the donor workup and scheduling the donor workup before cell collection. Understanding sources of delay in the transplant process will help transplant centers and UD registries reduce the time to transplant for patients with acute leukemia and will provide necessary insight for the design of prospective controlled studies that can address optimal donor choice.

Prevalence of geriatric impairments and frailty categorization among real-world patients with multiple myeloma: a prospective cohort study (MFRAIL).

There is limited knowledge regarding the prevalence of geriatric impairments and frailty among patients with multiple myeloma (MM) in a real-world setting. This study evaluated the distribution of frailty profiles among 116 patients with newly diagnosed or relapsed MM, using four common frailty scales. The proportion of patients classified as frail varied significantly, ranging from 15.5% to 56.9%, due to differences in how frailty was operationalized between each frailty measure. Functional, cognitive, and mobility impairments were common overall and irrespective of performance status. Analyses between frailty and treatment selection (dose reduction and doublet vs. triplet therapy) demonstrated significant differences in non-steroid MM drug dose reductions between frail vs. non-frail patients, as scored by the International Myeloma Working Group (IMWG) Frailty Index and Simplified Frailty Score (p < .05). A standardized approach to frailty assessment that is practical in application, and beneficial in guiding treatment selection and minimizing treatment related toxicity is necessary to provide optimal tailored care.

Treatment Pattern, Healthcare Resource Utilization and Symptom Burden Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study.

PURPOSE: This study aims to describe the treatment patterns, outcomes, health care utilization and symptom burden of triple class exposed (TCE) relapsed/refractory patents with multiple myeloma (MM) receiving a subsequent line of treatment (LOT). METHODS: This is a retrospective observational cohort study using administrative databases in Ontario, Canada. Outcomes were captured for TCE patients receiving a subsequent LOT and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), health care utilization, palliative care referral, and patient reported symptoms. RESULTS: Of the 16,777 patients diagnosed with MM between 2007-2021 in Ontario, 1358 (8%) patients were classified as TCE. Among the TCE MM patients, 489 (36%) received a subsequent LOT. The two most commonly administered therapies post TCE were carfilzomib/dexamethasone (n = 111, 22%) and pomalidomide/dexamethasone(n = 95, 19%). Median TTNT was 1.7 months (95%CI 1.2-2.4 months) and median OS 12.8 months (95%CI 10.8-16.5). Healthcare utilization was high with 276 (56%) of patients evaluated in an emergency department (ED) or admitted to hospital. There was high symptom burden as reported by patients with moderate-severe impairment in well-being, fatigue, pain and drowsiness noted in greater than 25% of the cohort. Palliative care referrals rates were low with only 10% (n = 48) patients referred to palliative care. Among the patients that died during study follow up, the majority died in hospital (n = 147,44%). CONCLUSION: Our study reports one of the largest series of real-world TCE patients published and demonstrates the poor outcomes of TCE patients receiving a subsequent LOT.

Quadruplet regimens for patients with newly diagnosed multiple myeloma: A systematic review and meta-analysis.

Quadruplet regimens (anti-CD38 monoclonal antibodies (mAbs) with proteosome inhibitor (PI) and immunomodulatory (IMID) drugs) are increasingly being investigated in newly diagnosed multiple myeloma (NDMM). The objective of our study was to conduct a systematic review and meta-analysis to measure the efficacy and toxicity of quadruplet regimens utilized in NDMM. Embase, Medline, Web of Science, Cochrane Library, clinical trial registries, and meeting libraries from inception to January 24, 2024, in addition to ASCO conference abstracts 2024 were searched using terms reflecting MM and component of the quadruplet regimen. Included studies were randomized controlled trials (RCTs) that compared backbone regimens consisting of a PI and IMID versus the same regimen plus an anti-CD38 mAb in NDMM. We identified seven RCTs including 3716 patients. Compared to triplets, quadruplets increase the overall response rate (ORR, relative risk [RR] 1.03, 95% confidence interval [CI] 1.01-1.05), and progression free survival (PFS, hazard ratio [HR]] 0.55, 95% CI 0.46-0.66). Quadruplets increase the rates of minimal residual disease (MRD) negativity at 10-5 (RR 1.39, 95% 1.23-1.58) and at 10-6 (RR 1.62, 95% CI 1.36-1.94). Quadruplets improve overall survival (OS, HR 0.65, 95% CI 0.53-0.79). There was a slight increase in the rates of grade 3-4 infections (RR 1.22 [95% CI 1.07-1.39]) noted with quadruplets compared to triplets. Overall, in this meta-analysis quadruplets were associated with improved efficacy including ORR, MRD negativity, PFS and OS with a slight increase in infection rates. Quadruplet regimens represent a new standard of care particularly in transplant eligible NDMM.

Predictors and Impact of Timing of Disease Progression Following Primary Therapy in Multiple Myeloma.

In multiple myeloma (MM) significant variation in progression-free survival (PFS) and overall survival (OS) is observed. We examined the outcomes of 1557 MM patients stratified into short (<2 years), medium (between 2 and 5 years) and long (>5 years) PFS. Short PFS occurred in 758 patients (48.7%), medium in 561 patients (36.2%), and long in 238 patients (15.3%). Median post-progression PFS was 9.2 months (95% CI: 8.1-11.0) in the short PFS and 33.1 months (95% CI: 29.0-42.1; P < .001) in the long PFS group. Median post-progression OS was 26.6 months (95% CI: 23.9-29.8) in the short PFS and 87.8 months (95% CI: 71.3- NR; P < .001) in the long PFS. Worse survival in the short PFS was irrespective of high risk (HR) fluorescence in situ hybridization (FISH) features, defined as deletion 17p and/or translocation t(4;14), t(14;16), t(14;20). In a multivariable analysis short PFS was associated with HR FISH, extramedullary plasmacytoma, plasma cell labeling index ≥2% at diagnosis, nonimmunoglobulin G isotype, treatment without autologous stem cell transplantation and achieving less than very good partial remission. In conclusion, the duration of the PFS significantly influences survival, regardless of HR cytogenetic features. Therefore, it should be considered an important parameter for risk stratification in patients experiencing a relapse.

Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy.

Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable "off-the-shelf" treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.

An atlas of the bone marrow bone proteome in patients with dysproteinemias.

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

An atlas of the bone marrow bone proteome in patients with dysproteinemias.

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

Redefining attrition in multiple myeloma (MM): a Canadian Myeloma Research Group (CMRG) analysis.

While most patients diagnosed with multiple myeloma (MM) receive initial therapy, reported attrition rates are high. Understanding attrition rates and characteristics of patients not receiving subsequent therapy is useful for MM stakeholders. We performed an analysis of attrition rates in a large disease-specific database of patients with newly diagnosed MM who received at least one line of therapy between Jan 1/10-Dec 31/20. Attrition was defined as failure to receive a subsequent line of therapy despite progression of MM or due to death. A total of 5548 patients were identified, 3111 autologous stem cell transplant (ASCT) patients and 2437 non-ASCT. In the ASCT cohort, the attrition rate was 7% after line 1, 12% after line 2, and 23% after line 3. In non-ASCT patients, the attrition rate was 19% after line 1, 26% after line 2, and 40% after line 3. Death was the dominant contributor to attrition across all cohorts, with a minority of patients alive with progressive disease in the absence of further therapy at each line. Multivariable analysis identified older age, shorter time to progression, and inferior response as independent risk factors for attrition. Our data show that attrition rates increase with each line of therapy and are higher in non-ASCT patients but are appreciably lower than previously reported. This study supports a revision of the previous definition of attrition, demonstrating that most patients who do not receive subsequent therapy are either continuing their current therapy and/or are in remission off-treatment rather than being irreversibly lost to attrition.

Outcomes after biochemical or clinical progression in patients with multiple myeloma.

Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P < .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P < .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P = .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P = .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P = .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P = .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

The Role of Belantamab Mafodotin, Selinexor, and Melflufen in Multiple Myeloma.

PURPOSE OF REVIEW: Multiple myeloma (MM) is a hematologic malignancy of plasma cells that remains incurable with currently available therapies including proteosome inhibitors, immunomodulators, monoclonal antibodies, corticosteroids, and alkylators, in addition to autologous stem cell transplantation in patients who are eligible. Novel therapeutics are therefore required to improve patient outcomes. The goal of this paper is to review the role of three new agents in the MM treatment landscape: belantamab mafodotin, selinexor, and melflufen. RECENT FINDINGS: All three agents have demonstrated clinical activity in patients with MM. Belamaf is the first FDA-approved anti-BCMA targeted agent, showing single-agent response rates of 60% and higher response rates of 48-100% in combinations. The majority of patients treated with belamaf experience corneal toxicity which remains the main challenge with its use; however, fortunately, the vast majority of patients recover. Selinexor is also FDA approved for the treatment of relapsed MM, with single-agent response rates of 26% and combination rates of 48-65%. Gastrointestinal side effects are common with selinexor use, with roughly 65% of patients experiencing nausea, 50% anorexia, 35% vomiting, and 42% diarrhea, the majority of which are grades 1-2. Both agents have a plethora of ongoing clinical trials with data forthcoming on various combinations with standard backbone agents as well as additional novel treatments. While melflufen showed promising initial data showing single-agent response rates of about 30%, inferior survival outcomes in patients previously treated with ASCT in the phase 3 OCEAN study lead to early termination of the trial and subsequent removal from the US market. Belamaf, selinexor, and melflufen are active agents to treat myeloma. Belamaf and selinexor are current options for the treatment of relapsed multiple myeloma with improved response rates and durability when used in triplet combinations. The optimal timing of use and treatment combinations of both agents in the context of additional immunotherapeutics entering the MM landscape requires further study. Many prospective studies are in development and promise to afford further clarity in the near future.