Tandem Autologous Stem Cell Transplantation Does Not Benefit High-Risk Myeloma Patients In The Maintenance Era: Real-world Results From The Canadian Myeloma Research Group Database.

BACKGROUND: In patients with multiple myeloma, the presence of high-risk cytogenetic abnormalities is associated with worse disease control and survival. Autologous stem cell transplant does benefit these patients. Tandem transplantation has been explored as a means to deepen responses and further improve survival however, its role remains controversial. This is particularly true in the era of novel agent induction and post-transplant maintenance therapy. OBJECTIVES: The aim of this study was to use the Canadian Myeloma Research Group database (CMRG-DB) and examine a large cohort of real-world patients comparing the outcomes of tandem versus single ASCT specifically in high-risk patients receiving novel agent-based induction and post-transplant maintenance. STUDY DESIGN: The data for this study was derived retrospectively from a comprehensive national-level database of Canadian patients with multiple myeloma. High-risk cytogenetics were defined as presence of del17p, t(4;14) or t(14;16). Those receiving allogeneic transplant were excluded. Tandem transplantation was defined as a second ASCT performed consecutively without interim relapse or progression after first ASCT. Those with relapse or progressive disease within three months of completing a first transplant were excluded. We compared response depth, progression free and overall survival based on single or tandem transplantation procedures. The impact of covariates of interest was also assessed. RESULTS: 381 patients with high-risk cytogenetics were identified. 242 received single and 139 patients received tandem transplants. All received post-transplant maintenance. The most common induction regimen for these patients was cyclophosphamide, bortezomib, and steroids (CyBorD, 87%). Forty-one patients (10.8%) required reinduction prior to first ASCT. The best overall responses at any time were 98.3% (90.5% ≥ VGPR) and 98.6% (89.9% ≥ VGPR) in the single and tandem ASCT groups respectively. Survival outcomes were similar with the median PFS for single or tandem ASCT of 35.2 and 35.3 months (p=0.88) and the median OS were 92.6 and 88.9 months respectively (p=0.72). No statistically significant differences were seen based on type of cytogenetic abnormality or type of maintenance. This was confirmed on multivariate analysis. CONCLUSION: In the real-world setting, tandem ASCT does not improve outcomes for MM patients with high-risk cytogenetics. This may be driven by the use of effective pre- and post-ASCT therapies. The development of more potent induction and consolidation along with current nearly ubiquitous continuous maintenance therapies until disease progression does not support the use of a second high dose procedure.

Long-term follow-up of outcomes including progression-free survival 2 in patients with transplant-ineligible multiple myeloma in the real-world practice: A multi-institutional report from the Canadian Myeloma Research Group (CMRG) database.

Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to evaluate the outcomes in newly diagnosed transplant-ineligible patients using bortezomib/lenalidomide-based regimens in the Canadian real world as well as their outcomes in the second line. The Canadian Myeloma Research Group Database (CMRG-DB) is a national database with input from multiple Canadian Centres with now up to 8000 patients entered. A total of 1980 transplant ineligible patients were identified in the CMRG-DB between the years of 2007-2021. The four most commonly used induction regimens are bortezomib/melphalan/prednisone (VMP) (23%), cyclophosphamide/bortezomib/dexamethasone (CyBorD) (47%), lenalidomide/dexamethasone (Rd) (24%), and bortezomib/lenalidomide/dexamethasone (VRd) (6%). After a median follow-up of 30.46 months (0.89-168.42), the median progression-free survival (mPFS) and median overall survival (mOS) of each cohort are 23.5, 22.9, 34.0 months, and not reached (NR) and 64.1, 51.1, 61.5 months, and NR respectively. At the time of data cut-off, 1128 patients had gone on to second-line therapy. The mPFS2 based on first-line therapy, VMP, CyBorD, Rd, and VRd is 53.3, 48.4, 62.7 months, and NR respectively. The most common second-line regimens are Rd (47.4%), DRd (12.9%), CyBorD (10.3%), and RVd (8.9%) with a mPFS and a mOS of 17.0, 31.1, 15.4, and 14.0 months and 34.7, NR, 47.6, 33.4 months, respectively. This study represents the real-world outcomes in newly diagnosed transplant-ineligible myeloma patients in Canada. The spectra of therapy presented here reflect the regimens still widely used around the world. While this is sure to change with anti-CD38 monoclonal antibodies now reflecting a new standard of care in frontline therapy, this cohort is reflective of the type of multiple myeloma patient currently experiencing relapse in the real-world setting.

Against vivisection: Charcot and Pitres' discovery of the human motor cortex and the birth of modern neurosurgery and of the surgical treatment of epilepsy.

This article addresses the discrepancy between Edouard Hitzig's and David Ferrier's findings on the cortical localization of movements in animals and Jean-Martin Charcot's findings in humans. The results of Hitzig's and Ferrier's vivisections were criticized by experimentalists in England and France as discordant, irreproducible, and inconclusive, and they were rejected by clinicians as irrelevant. Charcot addressed the gap between animal and human motor function by correlating motor deficits and focal epileptic seizures in patients to their autopsy findings. By this method he discovered the functional organization of the human motor cortex and produced the first accurate human motor brain map. Ferrier, William Osler, and Hughlings Jackson acknowledged Charcot's findings, and his findings guided the first neurosurgeons in localizing and resecting intracranial mass lesions presenting with focal epileptic seizures. Although his contributions in these fields have been neglected by modern historians, Charcot made significant contributions to the neurobiology of the human motor system, to epileptology, and to the birth of modern neurosurgery.

The collaboration of Francis Forster and Wilder Penfield in the management of a girl with 'reflex epilepsy'.

In the era after World War II, Francis (Frank) Forster (1912-2006) became a preeminent American neurologist and epileptologist, with international prominence in the study of reflex epilepsy. Forster's interest in reflex epilepsy began with a chance observation of the condition, in 1946, in a four-year-old girl. When medical measures failed to control her somatosensory-evoked seizures, Forster recommended surgery, and then facilitated transfer to Canadian neurosurgeon Wilder Penfield (1891-1976) at the Montreal Neurological Institute. Forster traveled to Montreal for the child's surgery. The surgery on February 27, 1948, proved to be curative for the child, and Forster's interactions with Penfield and epileptologist Herbert Jasper (1906-1999) made a lasting impression. This study reviews the medical and surgical history of this case, which strongly influenced Forster's career.

Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma.

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities in multiple myeloma. However, FISH is a targeted analysis that can be challenging due to the genetic complexity of myeloma. The aim of this study was to evaluate the potential of optical genome mapping (OGM) to detect clinically significant cytogenetic abnormalities in myeloma and to provide larger pangenomic information. OGM and FISH analyses were performed on CD138-purified cells of 20 myeloma patients. OGM successfully detected structural variants (SVs) (IGH and MYC rearrangements), copy number variants (CNVs) (17p/TP53 deletion, 1p deletion and 1q gain/amplification) and aneuploidy (gains of odd-numbered chromosomes, monosomy 13) classically expected with myeloma and led to a 30% increase in prognosis yield at our institution when compared to FISH. Despite challenges in the interpretation of OGM calls for CNV and aneuploidy losses in non-diploid genomes, OGM has the potential to replace FISH as the standard of care analysis in clinical settings and to efficiently change how we identify prognostic and predictive markers for therapies in the future. To our knowledge, this is the first study highlighting the feasibility and clinical utility of OGM in myeloma.

Real-world results of autologous stem cell transplantation in newly diagnosed multiple myeloma: a report from the Canadian Myeloma Research Group database.

Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients as part of initial therapy. Using the Canadian Myeloma Research Group (CMRG) national database, we examined the details and outcomes of ASCT performed as first-line therapy in eligible Canadian MM patients between 2007 to 2021. We included 3821 patients with 72% receiving CyBorD induction and 2061 patients receiving maintenance, consisting of lenalidomide +/- steroids in 78.3%. The median PFS and OS for patients given a single ASCT were 35.4 and 126 months. Those receiving a second induction regimen had significantly inferior outcomes, although when maintenance was used, results were comparable regardless of the number of induction regimens administered (median PFS 55.3 vs 51.1 months [p = 0.11]; median OS 158.6 vs not yet reached [p = 0.13]). Consolidation patients had a longer median PFS (55.3 vs 34.4 months [p = 0.001]), but no significant gain in median OS (p = 0.065). Patients who received lenalidomide-based maintenance experienced a median PFS of 53.7 months and OS of 159 months. In the multivariable analysis, use of any type of maintenance therapy vs no maintenance was associated with a lower risk of progression (HR 0.52 (95% CI 0.47-0.57)) and death (HR 0.58 (95% CI 0.51-0.67)). This real-world study demonstrates that, overall, first-line treatment sequence in transplant-eligible patients produces a median OS of ≥10 years. It also highlights the contribution of post-ASCT maintenance, particularly lenalidomide given until progression.

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.

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.

Selinexor-Based Triplet Regimens in Patients With Multiple Myeloma Previously Treated With Anti-CD38 Monoclonal Antibodies.

BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

Young Myeloma Patients: A Systematic Review of Manifestations and Outcomes.

Multiple myeloma usually affects older adults. However, younger patients constitute a significant subset as approximately 10% of cases occur in subjects younger than 50 years old. Young patients, who are underrepresented in the literature, are diagnosed during their most productive years of life, urging the need for tailored treatment approaches. This literature review aims to report recent studies specifically addressing young patients with a focus on characteristics at diagnosis, cytogenetics, treatments, and outcomes. We searched PubMed for studies involving young patients with multiple myeloma ≤50 years old. The time span of our literature review search was from 1 January 2010 to 31 December 2022. Overall, 16 retrospective studies were analyzed for this review. Young patients with multiple myeloma tend to have less advanced disease, more frequent light chain subtypes, and survive longer compared to their older counterparts. However, available studies included a limited number of patients; the newest revised international staging system was not used to stratify patients, cytogenetics varied from one cohort to another, and most patients did not receive contemporary triplet/quadruplet treatments. This review emphasizes the need to perform contemporary, large-scale retrospective studies to improve knowledge regarding the presentation and outcomes of young myeloma patients in the era of modern treatments.

A Phase II, Open-Label Study of an Accelerated Infusion Rate of Daratumumab in Patients With Relapsed and Refractory Multiple Myeloma.

INTRODUCTION/BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody initially approved as a single agent for the treatment of relapsed and refractory multiple myeloma. The infusion-related reactions (IRRs) commonly seen with intravenous daratumumab have been managed by prolonging the first infusion, temporarily stopping/slowing the rate if reactions occur and using adequate pre- and post-infusion medications. Several retrospective studies have evaluated shorter infusions after ≥ 2 prior doses administered at the standard rates. Although the shorter infusions were well-tolerated, patients in these reports were given heterogeneous daratumumab regimens and had often already received multiple doses at the longer standard rates. PATIENTS AND METHODS: CMRG-009 is a prospective study designed to demonstrate the safety of accelerated daratumumab infusions commencing with the second dose. After an initial dose on Cycle 1 Day consisting of 8 mg/kg over 4 hours, all subsequent doses were given over 90 minutes. RESULTS: No grade 3 IRRs were observed with the 90-minutes infusions. Both the safety profile and anti-myeloma effects were otherwise similar to those observed with other single agent daratumumab studies using longer infusion times. CONCLUSION: This is the first formal prospective trial using infusion times shorter than the standard schedule directly after an initial 4-hours dose. This rapid infusion protocol has resulted in more efficient resource utilization and has become the standard protocol for the use in all intravenous daratumumab regimens in Canada. This approach has been particularly helpful in shortening chair time during the COVID-19 pandemic and providing a useful alternative in jurisdictions without access to subcutaneous daratumumab.

First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium.

Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.

Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study.

BACKGROUND: Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety. METHODS: Patients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W). RESULTS: Overall, 106 patients with RRMM treated with a median of 4 prior lines were included; 25.5% had high-risk cytogenetics, 63.2% were refractory to proteasome inhibitors and immunomodulatory agents, 26.4% were previously exposed to daratumumab, and 84.0% were refractory to their last treatment line. There were no major changes in the safety or pharmacokinetic profile of isatuximab with the addition of cemiplimab. As assessed by investigators, four patients (11.8%) in the Isa arm, nine patients (25.0%) in the Isa + CemiQ2W arm, and eight patients (22.2%) in the Isa + CemiQ4W arm were responders. Though response rates were numerically higher in cemiplimab-containing arms, differences were not statistically significant and did not translate to improved progression-free or overall survival after a median follow-up of 9.99 months. CONCLUSION: Our results suggest a marginal benefit by adding cemiplimab to isatuximab, despite demonstration of target engagement, without additional observed safety issues.

Wilder Penfield and Academic Neurosurgery in North America: 1934-1945.

Wilder Penfield was appointed as Chair of McGill University's newly created Department of Neurology and Neurosurgery in 1930 and Director of the Montreal Neurological Institute (MNI) in 1933. The departmental structure allowed Penfield to develop his own research priorities, and the MNI's clinics and laboratories allowed residents to train in neurosurgery and in basic science under one roof. This paper reviews the research performed by neurosurgical residents under Penfield's direction from 1934 to 1945 and argues that their initiation to laboratory research contributed to the emergence of neuroscience following the Second World War.

Penfield and the Founding of the National Institute of Neurological Diseases and Blindness.

As conceived by Wilder Penfield the Montreal Neurological Institute (MNI) integrated neurology, neurosurgery, and allied disciplines within a single institution, where research and teaching complemented patient care. The MNI's success influenced the creation of the National Institute of Neurological Diseases and Blindness (NINDB), as Pearce Bailey, its first Director, sought to replicate the MNI's clinical and research model. He turned to MNI trainees Maitland Baldwin and Milton Shy to head the NINDB's Surgical and Medical Neurology Branches, respectively. They in turn recruited other MNI trainees who continued their work at the NINDB bringing clinical neuroscience to the USA.

Real-world data on lenalidomide dosing and outcomes in patients newly diagnosed with multiple myeloma: Results from the Canadian Myeloma Research Group Database.

Using the Canadian Myeloma Research Group Database, a retrospective study of 167 newly diagnosed, transplant-ineligible patients with multiple myeloma (MM) that received lenalidomide-dexamethasone as front-line treatment was conducted to understand the impact of lenalidomide dosing. Starting dose modifications were common, 42% of patients started on lenalidomide <25 mg with normal renal function. During treatment course, 35% of patients required further dose reduction. Dose reductions in the first year did not have an impact on progression free survival or overall survival. Further studies need to be conducted to understand the impact of dosing strategies of anti-MM agents in the real world.

Herbert Jasper in Paris and the Origin of Electromyography.

Herbert Henry Jasper was arguably the 20th century's most influential clinical and research electrophysiologist. He initially sought an understanding of the function of the brain through philosophy and psychology as a graduate student, but a chance encounter led to his training in electrophysiology with Louis Lapicque and Alexandre Monnier at La Sorbonne in Paris from 1931 to 1933. There Jasper studied the electrophysiology of the neuromuscular unit in crustaceans, amphibians, and mammals, in the hope of gaining insight into the influence of the cortex and spinal cord on motility. Jasper joined the Department of Psychology at Brown University on his return from Paris, with the intention of pursuing his studies in neuromuscular physiology, but his interest veered to electroencephalography in 1934, when he became aware of Hans Berger's work on electroencephalography. Jasper was recruited to the Montreal Neurologic Institute (MNI) as its electroencephalographer in 1938. As Canada entered the Second World War in 1939, the Canadian Army required an accurate, reliable, and portable apparatus to localize the site of peripheral nerve injuries, to assess their severity, and to guide their intraoperative treatment. Jasper, using his expertise in neuromuscular electrophysiology and André Cipriani, the MNI's electrical engineer, set themselves to the task, and together they built the first clinical electromyograph. The quality of Jasper's electromyographic recordings attracted the attention of James Golseth, a neurologist working with the US Army on peripheral nerve injuries. Golseth tested Jasper and Cipriani's machine on American casualties, and the US Army quickly adopted it for its own use. Following the cessation of hostilities, Jasper, Golseth, and James Fissell, an electrical engineer, developed the first commercial electromyograph based on Cipriani's circuitry. The commercial availability of electromyographs and their widespread use led to the creation of the American Association of Electromyography and Electrodiagnosis in 1953, with James Golseth as its first president. Jasper returned to electroencephalography after the war, but the MNI maintained an active division of electromyography under his direction where the likes of Milton Shy, who with Glen Drager described multiple system atrophy, and the Nobelist David Hubel trained in electrophysiology.