Chimeric antigen receptor T-cells, bispecific antibodies, and antibody-drug conjugates for multiple myeloma: An update.

Patients with multiple myeloma who are refractory to currently available effective therapies have short expected survival. Modalities harvesting the knowledge of the immune characteristics and microenvironment of myeloma such as chimeric antigen receptor (CAR) T-lymphocytes, bispecific antibodies (bsAbs), and antibody-drug conjugates (ADCs) have shown potential in early phase trials. Based on data from phase 2 studies, idecabtagene vicleucel (ide cel), an anti-B-cell maturation antigen CAR T-product and belantamab mafodotin (belamaf), an ADC are currently approved in the relapsed/refractory setting. bsAbs have shown promise with quick and deep responses. In this review, we summarize the available evidence on these treatments from clinical trials.

Pharmacokinetics of High-Dose Propylene Glycol-Free Melphalan in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation.

High-dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). Evomela (propylene glycol-free melphalan HCl [PG-Free Mel]; Spectrum Pharmaceuticals, Irvine, CA) was approved by the US Food and Drug Administration as conditioning therapy for ASCT in MM in 2 daily 100-mg/m2 doses for a total dose of 200 mg/m2. In this phase II, open-label study PG-Free Mel (Evomela) conditioning was given at single dose of 200 mg/m2 on day -2 pre-ASCT to establish pharmacokinetic (PK) parameters and safety. Twenty-four patients (median age, 64 years) were enrolled between August 2016 and February 2017. Myeloablation followed by successful neutrophil engraftment occurred at a median of 10 days in all patients. Peak melphalan concentration was observed at 10 minutes after infusion, whereas there was considerable variation in the maximum plasma concentration (Cmax) and area under concentration time curve (AUC). Median Cmax was 7380 ng/mL (interquartile range [IQR], 6522 to 8027). Similarly, median AUC was 533,552 ng/mL∙min (IQR, 450,850 to 662,936). PG-Free Mel had an acceptable safety profile regardless of the exposure, with no mortality and an overall response rate of 96% and a very good partial response rate of 75%. In conclusion, although PG-Free Mel at a single dose of 200 mg/m2 was safe, considerable PK variability was observed with the highest quartile having an ~3-fold higher AUC than the first quartile, suggesting that strategies for higher targeted exposure could be explored in future trials to optimize clinical benefit.

Efficacy of VDT PACE-like regimens in treatment of relapsed/refractory multiple myeloma.

Experience with intensive chemotherapy for relapsed/refractory multiple myeloma (RRMM) using VDT PACE regimen and its modifications (VDT PACE-like regimens: VPLRs) outside TOTAL THERAPY trials is limited. We analyzed the outcomes of 141 patients with RRMM who received VPLRs at our center between 2006 and 2017 in an intent-to-treat analysis. Median age was 59.7 years and 66.7% of patients were male. A median of 2.2 years (range 0.02-11.4) separated diagnosis of myeloma and inititation of VPLR. High-risk cytogenetics were present in 52.4% patients. Patients received a median of 4 (range 1-14) prior therapies, including stem cell transplant (SCT) in 66.7% patients. Ninety-five (67.4%) patients received VDT PACE, 20 (14.2%) patients received VD PACE and 26 (18.4%) patients received other VPLRs. Patients received a median of 1 cycle (range 1-9) of VPLR. We observed ≥ minimal response in 68.4%, ≥ partial response (PR) in 54.4% and ≥ very good PR in 10.3% patients. Median progression-free survival was 3.1 months (95% CI, 1.9-3.9) and median overall survival (OS) was 8.1 months (CI, 6.2-9.9). One-hundred and sixteen (82.3%) patients received some therapy after VPLR; 71 (61.2%) received systemic chemotherapy, while 45 (38.8%) underwent SCT. Median OS for those who received SCT after VPLR was 15.1 months (CI, 10.3-20.8). Age ≥ 60 years (hazard ratio [HR] 2.3 [CI, 1.4-3.7]; P = 0.0008) and R-ISS III stage (HR- 2.4 [CI, 1.3-4.0]; P = 0.003) predicted shorter OS in patients receiving VPLR. VPLRs are effective in heavily pre-treated RRMM. In fit patients, SCT can be used to consolidate the response to VPLR.

Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials.

Outside of clinical trials, experience with daratumumab-based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43-93) years. High-risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1-14) and time to first DCT from diagnosis was 4.3 years (range, 0.4-13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty-two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and "other" DCTs, respectively. Overall response rate was 47%. Median follow-up was 5.5 months (95% CI, 4.2-6.1). Median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta-refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1-2.4] vs 3.1 [95% CI, 2.1-NR] vs 5.9 [95% CI, 5.0-NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1-6.0] vs 8.2 [95% CI, 4.6-NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7-5.9] vs NR [95% CI, NR-NR]; P = .002). Non-hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.

A Curious Case of "Septic Shock".

BACKGROUND: Takayasu arteritis, also known as "pulseless disease," causes proximal occlusion of the lumen of large arteries of the neck and arm, leading to impalpable pulses and "pseudohypotension." This may misdirect the management plan for a patient in the emergency setting if the presence of vascular occlusion is not previously known. CASE REPORT: We describe a young woman who presented to the emergency department (ED) with fever. On evaluation, she had shock, which was not responsive to a fluid bolus. Bedside Rapid Diagnostic Test was positive for Plasmodium vivax, and a diagnosis of severe vivax malaria was made. She was started on intravenous artesunate and vasopressors in view of her persistent hypotension in the face of a normal central venous pressure. A thorough examination at that time revealed palpable lower limb pulses with feeble upper limb pulses. Vasopressors were tapered while monitoring lower limb blood pressure. Computed tomographic angiogram confirmed the diagnosis of Takayasu arteritis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Hypotension and shock are regularly encountered in the ED. Occlusive arterial disease involving upper limbs can mimic refractory shock, leading to potentially harmful and unnecessary interventions. Emergency physicians should be aware of this possibility. A simple routine of quickly checking all peripheral pulses would help them avoid this pitfall.

Pulmonary and Ear, Nose and Throat (ENT) Involvement in ANCA-Associated Vasculitis at Diagnosis-Experience from a Tertiary Care Centre in North India.

BACKGROUND AND AIMS: There is paucity of data on pulmonary and ENT involvement in ANCA associatd vasculitis from India. We aimed to review the pattern of lung and upper respiratory tract involvement in patients with AAV diagnosed at our centre. METHODS: A retrospective review of all AAV patients between January 2007 and June 2014 was done. A complete clinical evaluation for Pulmonary and ENT involvement was done. Advanced investigations including computed tomography (CT) bronchoscopy and nasal endoscopy were done when indicated. Proportion of involvement was noted and different variables among patient groups were compared. RESULTS: 92 patients (median age 42 years; 60% female) of AAV were included. Clinical and/or radiological evidence of lung involvement was seen in 70 (76.1%) patients. Diffuse alveolar haemorrhage was present in 6 (60%) patients with MPA and 7 (10.1%) patients with GPA (p=0.002). ENT involvement was present in 55 (59.8%) patients and was more in GPA (p=0.000). Absence of renal involvement [p=0.047] and absence of GI involvement [p=0.012] were associated with ENT involvement in GPA. CONCLUSION: Pulmonary involvement was common in GPA, MPA and CSS, ENT involvement was almost characteristic of GPA. DAH was common in MPA. Population based and multicentre studies are needed to assess the true burden of organ involvement in AAV in the Indian population.

Mode of progression in smoldering multiple myeloma: a study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Mode of Progression in Smoldering Multiple Myeloma: A study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Natural history of multiple myeloma with de novo del(17p).

We compared the outcomes of 310 patients with newly diagnosed multiple myeloma with del(17p) detected by FISH to patients with high-risk translocations (HRT) (n = 79) and standard-risk (SR) cytogenetics (n = 541). The median progression-free survival (PFS) following initial therapy for the three groups was 21.1, 22, and 30.1 months, respectively (P = 0.437- del(17p) vs. HRT); the median overall survival (OS) was 47.3, 79.1, and 109.8 months, respectively, (P = 0.007- del(17p) vs. HRT). PFS and OS for patients with relative loss of 17p (n = 21) were comparable to other patients with del(17p). The PFS was similar between the del(17p) and HRT groups when stratified for age, ISS stage or treatment. The OS of del(17p) and HRT groups were similar in presence of advanced age, ISS III stage or if patients did not receive a proteasome-inhibitor containing induction. ISS III stage, high LDH and HRT, but not the percentage of cells with del(17p) predicted shorter OS in patients with del(17p). The median OS for low (ISS I, normal LDH and no HRT), intermediate (neither low nor high-risk) and high-risk (ISS III and either elevated LDH or coexistent HRT) groups among del(17p) patients were 96.2, 45.4, and 22.8 months, respectively, allowing further risk stratification.

Impact of acquired del(17p) in multiple myeloma.

The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Elevated cardiac biomarkers and echocardiographic left ventricular dysfunction at admission in patients with dengue fever: report from a tertiary care center in Northwest India.

Cardiac involvement is not an uncommon manifestation in dengue fever and diagnosing it has always been a challenge to physicians owing to its constellation of clinical features and lack of standard screening methods. We studied the prevalence of cardiac involvement among fifty sequential adult patients of dengue fever admitted in our emergency department, PGIMER, Chandigarh, India, who were assessed clinically and classified based on the severity. They were studied for possible cardiac involvement by means of point-of-care testing for serum cardiac biomarkers (quantitative troponin-I, creatinine kinase - MB Isoform and cardiac myoglobin) and two-dimensional transthoracic echocardiogram (2D-echo). Evidence of myocardial involvement was present in 16% and 30% patients based on 2D-echo and biomarker testing respectively. On univariate analysis, the presence of cardiac symptoms (p = 0.009) and of shock (p = 0.003) showed statistically significant association with biomarker elevation. However, this and evidence of myocardial dysfunction by 2-D echo showed poor inter-correlation.

Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma.

The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy-nine (26%) patients had an elevated PCPI (>0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P < .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials.

Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria.

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45-72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63-3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11-2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55-2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

Evaluation of Bortezomib-Induced Neuropathy Using Total Neuropathy Score (Reduced and Clinical Versions) and NCI CTCAE v4.0 in Newly Diagnosed Patients With Multiple Myeloma Receiving Bortezomib-Based Induction.

BACKGROUND: Bortezomib-induced peripheral neuropathy (BiPN) is a dose-limiting adverse effect of bortezomib-based therapy for multiple myeloma (MM). The reporting of BiPN is variable because of the use of different neuropathy scales. Most investigators use the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). PATIENTS AND METHODS: We prospectively evaluated the incidence of BiPN in treatment-naive patients with MM receiving weekly cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in 28-day cycles using 3 neuropathy scores: Total Neuropathy Score-reduced (TNSr) and -clinical (TNSc), and NCI CTCAE v4.0. RESULTS: Twenty-six patients received CyBorD. Twenty patients completed follow-up. The rates of occurrence of BiPN were as follows: TNSr - 55% (n = 11), TNSc - 40% (n = 8), and NCI CTCAE - 45% (n = 9). All 3 scales showed worsening after treatment (P < .01). When compared to BiPN by TNSr, sensitivities for NCI CTCAE and TNSc were 77.8% and 88.9%, respectively. Specificity was 63.3% for both NCI CTCAE and TNSc. Among 12 patients who did not have BiPN by NCI CTCAE scale, 41.7% (n = 5) and 16.7% (n = 2) patients satisfied the criteria for BiPN by TNSr and TNSc, respectively. The higher detection rate of neuropathy by TNSr and TNSc is probably due to increment in scores that are allotted for increase in anatomic extent of sensorimotor involvement, unlike the NCI CTCAE scale, which requires functional limitation for increase in grade. CONCLUSION: NCI CTCAE may be suboptimal in comparison to TNSr and TNSc in assessment of BiPN because it may miss worsening neuropathy without functional limitation.

Hypereosinophilia in a Young Patient: Occam's Razor or Hickam's Dictum?

Hypereosinophilia is an uncommon clinical problem encountered in hematology practice. While most of such cases are secondary or reactive, a significant fraction of cases are due to clonal myeloproliferative disorders. We report a young patient who presented with marked hypereosinophilia and was investigated extensively for its cause. Finally a common tropical infection was responsible for such marked eosinophilia fulfilling the principle of Occam's razor. The case emphasizes the need to search for treatable reactive causes even in presence of marked hypereosinophilia in a tropical country.