Dana Farber

An interim analysis of the phase 2 ZUMA-5 trial revealed that patients with follicular lymphoma and marginal zone lymphoma (MZL) derived significant and potentially durable responses with the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta), explained Caron Jacobson, MD.

The results, which were presented at the 

, showed that at a median follow-up of 15.3 months, axi-cel led to an overall response rate (ORR) of 93% (n = 96) and a complete response (CR) rate of 80% (n = 77) in patients with follicular lymphoma and MZL.

Moreover, in the follicular lymphoma cohort (n = 80), 80% of patients who achieved a CR (n = 65) remained in remission at follow-up.

In terms of safety, grade 3 or higher cytokine release syndrome (CRS) occurred in 8% of patients, and grade 3 or higher neurologic events were reported in 17% of patients.

“This is an early look at the data,” said Jacobson. “There are a lot of patient samples, correlative science to draw on, and patient disease characteristics to look at in terms of their associations with response and toxicity. All of that needs to come. However, from the early look of these data, the key take-home messages are the efficacy and adverse effect profile.”

In October 2017, axi-cel received regulatory approval for the treatment of patients with large B-cell lymphoma who have not responded to or who have relapsed after at least 2 prior treatments.

, Jacobson, medical director of the Immune Effector Cell Therapy Program and physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discussed the initial ZUMA-5 findings and the next steps with axi-cel in follicular lymphoma and MZL.

: How was the ZUMA-5 trial designed, and what type of patients were enrolled?

: ZUMA-5 is a phase 2, open-label clinical trial, so every patient enrolled received the same therapy. The trial included patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma. Specifically, these patients had follicular lymphoma or MZL. The planned accrual was 125 patients with follicular lymphoma and 35 patients with MZL.

At the 2020 ASCO Virtual Scientific Program, interim data were presented on all 125 patients with follicular lymphoma and 16 patients with MZL.

These patients [had seen at least 2 lines of therapy]. Their prior treatments must have included chemoimmunotherapy with a CD20-directed antibody and an alkylating agent.

The median number of prior lines of therapy was 3, so for the majority of patients, [axi-cel] was their fourth line of therapy. Moreover, this was a heavily pretreated patient population; about 70% of patients had at least 3 prior lines of therapy.

In addition, this was a high-risk patient population. Patients had high tumor bulk by Groupe d'Etude des Lymphomes Folliculaires criteria and high-risk Follicular Lymphoma International Prognostic Index scores.

The number of patients who had progressed within the first 2 years after their first line of therapy was approximately 50%, making this a particularly high-risk group of patients.

Were high-risk patients the focus on the planned accrual population?

No, but patients in their third- or later-line of treatment tend to be an [innately] higher-risk patient population. Many patients with follicular lymphoma will have remissions for several years from their first- or second-line therapy. Additionally, many of these patients can be observed for a number of years. Therefore, calling on patients who already require a third line of therapy highlights a higher-risk group.

What did the results of the interim analysis show?

These were inspiring results. For patients with follicular lymphoma, the ORR was 95%. The percentage of patients who went into a CR was 81%. The median follow-up of the follicular lymphoma cohort was about 15.3 months. At that time, 80% of patients who had [achieved] a CR, were still in response.

This is early follow up for an indolent disease. We know patients can relapse many years after therapy, but the remissions look promising and durable.

The MZL cohort was smaller with 16 patients. Patients were required to have 1 month of follow-up so that we had at least 1 scan to look at for efficacy. The primary [end point] was response rate by independent radiology review. When the central radiology review looked at the pretreatment scans, they found that some of these patients did not meet measurable disease criteria.

The ORR was closer to 81% with a CR rate in the range of 70%. Additionally, 19% of patients were non-evaluable because they were not felt to have measurable disease prior to getting CAR T-cell therapy.

The numbers look a little bit worse [than the follicular lymphoma cohort], largely due to the fact that 19% of patients were not evaluable. No patients had progressive disease in that cohort.

Again, the follow-up time is very short. Most patients had a 6-month follow-up, so the duration of response curves were truncated early. I would say the data are immature in terms of durability of response in the MZL cohort.

Were the adverse effect (AE) profiles in the 2 cohorts consistent with what we know of axi-cel?

Interestingly, the safety profile was a little bit better in the follicular lymphoma cohort, so much so that it potentially raises the question of whether [axi-cel] could be dosed in the outpatient setting. About 23% of patients had no CRS whatsoever. Among those patients who did, the median onset [of CRS] was 4 days as opposed to 2 days with axi-cel in large-cell lymphoma. Additionally, only 7% of patients had high-grade CRS.

Similarly, with neurologic toxicity, 15% of patients with follicular lymphoma had high-grade neurologic toxicities. Both of these numbers are about half of what we [expect] with axi-cel in large-cell lymphoma.

The MZL cohort had a slightly higher incidence of CRS and higher-grade neurologic toxicity that was more aligned with what we see in diffuse large B-cell lymphoma (DLBCL). However, the median time to onset [of CRS] was about 4 days. Therefore, it was the same degree of toxicity, but occurred later than what we are used to seeing [in DLBCL].

What are the next steps for this research?

The data need to mature. We are still enrolling patients with MZL. The next important end point for the follicular lymphoma cohort is the 12-month analysis to [determine whether] these responses are durable.

The ZUMA-5 trial is designed as a pivotal study for axi-cel. [An FDA approval] would lead to an expanded indication for axi-cel among our patients with lymphoma. On top of that, if the durability proves to be robust and the safety profile continues to be reproducible, we could start thinking about designing clinical trials with axi-cel or other CAR T-cell therapies in earlier lines of therapy, particularly for patients who are higher risk, such as those who progress early after initial chemoimmunotherapy.

Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: a phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). 

. 2020;38(suppl 15):8008. doi:10.1200/JCO.2020.38.15_suppl.8008

Articles

Caron Jacobson, MD, discusses the initial ZUMA-5 findings and the next steps with axicabtagene ciloleucel in follicular lymphoma and marginal zone lymphoma.

Axi-Cel Elicits Encouraging Activity in Indolent Follicular Lymphoma, Marginal Zone Lymphoma

Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center; institute physician at Dana-Farber Cancer Institute; and RJ Corman Professor of Medicine at Harvard Medical School, discusses the patient population analyzed in the first-in-human phase 1 trial of the CELMoD CC-92480.

Of the 76 patients analyzed in this study, the median age was 66 years, with the oldest patient treated on the studyaged 78 years, says Richardson. Because this was a relapsed/refractory patient population, and these patients had received all other classes of drugs that are available to them with no success. Furthermore, the majority of patients enrolled on the study had International Staging System stage II and III disease, and 40% of patients had extramedullary disease, which is an indicator of poor prognosis, adds Richardson. Investigators also examined cytogenetics, although those data are currently pending.

What is very important with regard to this study, is that the median number of prior therapies was 6, but ranged between 2 and 13 prior therapies, says Richardson. The vast majority of these patients were refractory lenalidomide (Revlimid) and pomalidomide (Pomalyst), as well as to proteasome inhibition and CD38 monoclonal antibody therapy. Approximately 70% were refractory to monoclonal antibodies and 79% were refractory to pomalidomide. These numbers underscore how heavily pretreated the patient population was, says Richardson. In fact, more than half of the patients met the triple-class refractory criteria, making this a particularly poor-prognosis group, concludes Richardson.

Videos

Paul G. Richardson, MD, discusses the patient population analyzed in the first-in-human phase 1 trial of the CELMoD CC-92480.

Dr. Richardson on First-In-Human Phase 1 Trial With CC-92480 in R/R Myeloma

Ursula A. Matulonis, MD, professor of medicine, Harvard Medical School, medical oncologist, chief of the Division of Gynecologic Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses final data from the phase 2 KEYNOTE-100 trial with pembrolizumab (Keytruda) in advanced recurrent ovarian cancer.

First, there was a very small trial with nivolumab (Opdivo) conducted in 2015, which showed a 15% response rate albeit in a small cohort of 20 patients, says Matulonis. Then, single-agent avelumab (Bavencio) data were published in 2019, in which agent was reported to induce a response rate of just under 10%.

Now, updated data from the KEYNOTE-100 trial have been published in the 

with over 30 months median follow-up. In this trial, single-agent pembrolizumab was evaluated in 376 patients with advanced recurrent ovarian cancer. The overall response rate with the agent was approximately 8%. Although that does not appear to be very significant at first glance, it's important to remember that patients who have predominantly platinum-resistant ovarian cancer, single-agent chemotherapy response rates also quite low, says Matulonis. In fact, in some instances, response rates of single-agent chemotherapy in the platinum-resistant setting is 0%, concludes Matulonis.

Ursula A. Matulonis, MD, discusses final data from the phase 2 KEYNOTE-100 trial with pembrolizumab (Keytruda) in advanced recurrent ovarian cancer.

Dr. Matulonis on Final Data From KEYNOTE-100 in Recurrent Ovarian Cancer

Ursula A. Matulonis, MD, professor of medicine, Harvard Medical School, medical oncologist, chief of the Division of Gynecologic Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses final data from the phase 2 KEYNOTE-100 trial with pembrolizumab (Keytruda) in advanced recurrent ovarian cancer.

First, there was a very small trial with nivolumab (Opdivo) conducted in 2015, which showed a 15% response rate albeit in a small cohort of 20 patients, says Matulonis. Then, single-agent avelumab (Bavencio) data were published in 2019, in which agent was reported to induce a response rate of just under 10%.

Now, updated data from the KEYNOTE-100 trial have been published in the 

Ursula A. Matulonis, MD, discusses final data from the phase 2 KEYNOTE-100 trial with pembrolizumab (Keytruda) in advanced recurrent ovarian cancer.

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; senior physician at Dana-Farber Cancer Institute; and assistant professor of medicine at Harvard Medical School, discusses the unmet need with regard to effectively preventing central nervous system (CNS) recurrence in HER2-positive breast cancer.

In the early disease setting, the field continues to do a better job of curing patients with HER2-positive disease, with the addition of pertuzumab (Perjeta), T-DM1 (ado-trastuzumab emtansine; Kadcyla), and sometimes neratinib (Nerlyx), says Tolaney. However, despite these advances, some patients still recur after these treatments. Interestingly, in the phase 3 KATHERINE study, 5% of disease-free survival events observed were CNS recurrences, notes Tolaney. In fact, no benefit with T-DM1 over trastuzumab was observed with regard to preventing those recurrences.

The field is left with the unmet need of trying to decrease CNS recurrences, and it begs the question of how that need can be addressed. Some have hypothesized that using a TKI, such as tucatinib (Tukysa), could potentially address this need, based on the activity observed with the agent in the metastatic setting, says Tolaney.

To this end, an arm in the COMPASS trial is enrolling patients with residual disease after preoperative HER2-directed therapy and randomizing them to receive T-DM1 or T-DM1 with tuctanib. It will be interesting to know whether the addition of tucatinib will help improve overall events and decrease rates of CNS recurrence in patients with HER2-positive disease, concludes Tolaney.

Sara M. Tolaney, MD, MPH, discusses the unmet need with regard to effectively preventing central nervous system recurrence in HER2-positive breast cancer.

Dr. Tolaney on CNS Recurrence in HER2+ Breast Cancer

The clinical need to identify patients with 

ex14)-mutated non—small cell lung cancer (NSCLC) and understand the characteristics of these cancers has grown in light of the recent regulatory approval of capmatinib (Tabrecta) in this indication, said Mark M. Awad, MD, PhD.

 was based on findings from the phase 2 GEOMETRY mono-1 study,

 in which capmatinib led to a 67.9% objective response rate (95% CI, 47.6-84.1) in treatment-naïve patients with 

The FoundationOne CDx assay was simultaneously approved as a companion diagnostic for capmatinib to detect tumor mutations that lead to 

During the 2020 ASCO Virtual Scientific Program, Awad presented findings from a study in which 60,495 samples from patients with NSCLC underwent next-generation sequencing—based hybrid-capture genomic profiling to identify 

ex14 skipping alterations and potential acquired resistance mechanisms.

ex14 alterations were found in 2.3% of samples. Moreover, 32% of 

 co-amplifications were present in 12% of cases.

Additionally, potential acquired resistance mechanisms such as secondary 

"Since this is a relatively new target in lung cancer, it's been more important to try to understand the characteristics of these cancers, to see what other mutations may be present within the genome, and identify the other factors that may regulate response or resistance to immunotherapy or targeted therapies," said Awad. "By understanding resistance mechanisms, perhaps we can design better trials to delay [their] emergence. Then, if we do encounter acquired resistance, we can develop strategies to overcome those mechanisms."

, Awad, clinical director of the Thoracic Oncology Treatment Center and physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, discussed the findings from the study, the importance of identifying patients with 

ex14 mutations, and the importance of understanding acquired resistance in NSCLC.

: What was the rationale for conducting this study?

: This was a collaboration with Foundation Medicine where, in over 60,000 patients with NSCLC, we found 

ex14 mutations in over 1300 cases. This is an important and emerging subset of lung cancer to identify, especially now because we have an FDA-approved targeted therapy for patients with 

Could you discuss the data that led to the approval of capmatinib for patients with 

Over the years, many drugs have gone through clinical development for patients with 

-dysregulated cancers. Some of these drugs include agents such as crizotinib (Xalkori), tepotinib (Tepmetko), and savolitinib. In May 2020, capmatinib became the first FDA-approved drug for patients with 

That approval was based on data from the GEOMETRY mono-1 study in patients with 

ex14-mutant NSCLC who had not previously received a MET inhibitor. Based on the response rate and progression-free survival [seen in the GEOMETRY mono-1 study], we know drugs such as [capmatinib] have the potential to make meaningful differences for our patients.

What were the objectives of the analysis you conducted?

We had several goals for this study. We know many different types of mutations can be identified that can impact 

ex14, some of which lie in the flanking intronic sequences. One of the goals of this study was to see if certain mutations correlated more with other co-mutations or genomic abnormalities.

We were also looking to develop a better sense of factors, such as PD-L1 expression and tumor mutational burden, in this molecular lung cancer subtype.

In patients who had serial biopsies and underwent sequencing, we also tried to identify putative mechanisms of acquired resistance to MET kinase inhibitors with the hope that, by developing a greater understanding of acquired resistance mechanisms, we might be able to develop drugs to either overcome or, ideally, prevent resistance.

What do we know about acquired resistance to MET inhibitors?

What we found in this study, as well as what has been recently described in some other work in this space, is that mechanisms of resistance in 

ex14-mutant NSCLC are varied and can be complex.

Some patients develop on-target acquired resistance mutations. This means that 

 mutates again, leading to secondary mutations within the MET kinase domain. This is particularly seen in certain recurring positions, such as D1228, Y1230, L1195, and others. We also see a subset of patients who develop acquired amplification of the 

Additionally, we see a number of possible off-target resistance mechanisms or bypass track activations, such as amplification of wild-type 

 or other MAP kinase pathway molecules. This increases the complexity of resistance mechanisms in this subtype of lung cancer. Hopefully, we'll develop a strategy to develop improved therapies and prevent resistance from emerging.

What are the key findings from this study?

In this analysis of over 1300 patients with 

ex14-mutant NSCLC, we conducted a very comprehensive description of the co-mutational analyses within these cancers. We found that, although these cancers tend to have a lower tumor mutation burden compared to 

 wild-type NSCLC, they have very high PD-L1 expression. A large subset, almost half, of patients with 

ex14-mutant NSCLC will have greater than 50% PD-L1 expression. We need to learn a little bit more and develop biomarkers within this subset to identify whether there are certain patients who will benefit from checkpoint inhibitors or not. Hopefully this analysis will help provide a greater framework for looking at some of these immune markers within 

We also saw that several patients with paired biopsies who were sequenced developed new resistance mutations over time at positions D1228, Y1230, L1195, and others, as well as bypass track resistance mechanisms in other MAP kinase pathway proteins or genes, including 

This highlights the complexity of resistance but also a potential path forward for targeting resistance or developing combination strategies to delay the emergence of resistance.

How do you expect these findings to impact clinical practice?

This study showed that these mutations are not uncommon in NSCLC. [

ex14 mutations] represent a small proportion of the total lung cancer population, but there are thousands of these cases in the United States and globally. As such, it is important to test patients for these alterations because we now have targeted therapies that are approved to treat patients with this type of lung cancer.

The other big takeaway is the importance of understanding resistance mechanisms to targeted therapies in this population and other subsets of lung cancer. Through studying resistance mechanisms, we've been able to develop successful strategies to overcome resistance in many cases. That is the hope for this subtype of lung cancer as well.

Wolf J, Seto T, Han JY, et al. Capmatinib (INC280) in 

-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. 

 2019;37(suppl 15; abstr 9004). doi:10.1200/JCO.2019.37.15_suppl.9004

Awad MM, Lee JK, Madison R, et al. Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms. 

. 2020;38(suppl 15; abstr 9511). doi:10.1200/JCO.2020.38.15_suppl.9511

Mark M. Awad, MD, PhD, discusses the findings from the study, the importance of identifying patients with METex14 mutations, and the importance of understanding acquired resistance in NSCLC.
 

Analysis Highlights Acquired Resistance Mechanisms in METex14+ NSCLC

Caron Jacobson, MD, medical director, Immune Effector Cell Therapy Program, and physician, Dana-Farber Cancer Institute, assistant professor of medicine, Harvard Medical School, discusses the safety profile of axicabtagene ciloleucel (axi-cel; Yescarta) in relapsed/refractory indolent non-Hodgkin lymphoma (iNHL).

An interim analysis of the phase 2 ZUMA-5 trial presented at the 2020 ASCO Virtual Scientific Program showed that axi-cel elicited significant and durable clinical benefit in patients with relapsed/refractory follicular lymphoma and marginal zone lymphoma (MZL).

Axi-cel had a favorable safety profile in the cohort of patients with follicular lymphoma. As such, axi-cel could be considered for outpatient dosing, pending further positive results, says Jacobson.

About 23% of patients with follicular lymphoma did not experience any-grade cytokine release syndrome (CRS) and of those who did, 7% was grade 3 or higher, says Jacobson. Notably, the median time to onset of CRS was around 4 days compared with 2 days in large-cell lymphoma. Additionally, 15% of patients in this cohort experienced grade 3 or higher neurologic toxicities. 

Among patients with MZL, the rates of high-grade CRS and neurologic events were 13% and 38%, respectively, says Jacobson. These findings are in line with what has been observed in large-cell lymphoma.

Caron Jacobson, MD, discusses the safety profile of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma.

Dr. Jacobson on the Safety Profile of Axi-Cel in Relapsed/Refractory Indolent Lymphoma

Associate Director of the Brigham and Women’s Hospital/Dana-Farber Cancer Institute’s Amyloidosis Program

Attending Physician, the Jerome Lipper Multiple Myeloma Center,

Systemic amyloidosis is a heterogenous family of diseases characterized by deposition of fibrillary aggregates of a precursor protein in target organs, such as the heart and kidneys (

 The identity of the amyloidogenic precursor protein, such as transthyretin (TTR) or immunoglobulin light chain (AL), dictates the pattern of organ deposition and clinical presentation and determines the therapeutic approach (ie, chemotherapy or chemoimmunotherapy for AL versus TTR stabilizer or gene silencing for TTR amyloidosis).

 AL amyloidosis is the most common form of systemic amyloidosis and is characterized by rapidly progressive organ failure and eventually patient demise, if not promptly recognized and treated. The pathogenetic mechanism in AL amyloidosis is deposition of fibrils of misfolded immunoglobulin free light chains (FLC), typically produced by clonal plasma cells and, less often, B cells.

The FLC is λ in 75% of cases and a small pool of Ig light chain variable (IGVL) genotypes underlies most AL amyloidosis cases, suggesting that amyloidogenicity is an intrinsic characteristic of the amino acid sequence of the FLC.

 Progression of AL amyloidosis from precursor plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) can occur and hematologists must carefully monitor these patients for signs or symptoms concerning AL amyloidosis.

Epidemiologic studies suggest that AL amyloidosis is not a rare disease, but rather underdiagnosed.

 The vague nature of early symptoms, such as fatigue and weight loss, contributes to diagnostic delay, potentially causing irreversible organ damage and high risk of early mortality. There is no FDA-approved treatment for AL amyloidosis; however, chemotherapy targeting plasma cells, such as cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD), and/or autologous stem cell transplant, are standard of care and can elicit deep and durable hematologic responses.

Figure 1. Histopathologic Appearance of Cardiac Amyloidosis (Click to Enlarge)

Figure 2. Histopathologic Appearance of Renal λ Light Chain AL Amyloidosis (Click to Enlarge)

Figure 3. Critical Areas of Research Effort in AL Amyloidosis (Click to Enlarge)

With the FDA approval of inotersen (Tegsedi) and patisiran (Onpattro) for hereditary TTR amyloidosis (ATTR)-related neuropathy and tafamidis (Vyndamax) for ATTR-related cardiomyopathy, it has become even more critical to accurately distinguish ATTR versus AL amyloidosis.

 Significant epidemiological and clinical overlap exists for ATTR and AL amyloidosis and an expedited, careful diagnostic work up with definitive confirmation of precursor amyloid protein via liquid chromatography and mass spectrometry (LC-MS) or immunogold on tissue biopsy is thus critical.

Research efforts to identify MGUS/SMM patients at high risk for AL amyloidosis transformation include the study of serum FLC N-glycosylation via LC-MS and in vitro fibrillogenic competition assay with circulating FLC.

 The SAVE clinical study (NCT02741999) evaluates asymptomatic patients with a provisional diagnosis of λ light chain MGUS/ SMM to identify IGVL genotypes associated with highest risk of amyloidogenicity and ensure patients are screened accordingly.

 Innovative molecular imaging modalities detecting AL fibrils in a highly specific manner are being investigated as a tool to assess amyloid deposition and distribution even before overt clinical manifestations.

The major hurdle in treating patients with AL amyloidosis using multiple myeloma (MM)-directed chemotherapy is decreased tolerance, particularly in patients with advanced cardiomyopathy or nephrotic syndrome, rather than lack of efficacy. As a single agent, the CD38-targeting antibody daratumumab (Darzalex) has shown unprecedented effectiveness in inducing rapid and profound hematologic responses in patients with heavily pretreated AL amyloidosis, but large volume infusion and high steroid dosing limited tolerability.

 Excitingly, the FDA approved the subcutanous formulation of fixed dose daratumumab and and hyaluronidase-fihj (Darzalex Faspro) for all previously approved indications of intravenous daratumumab.

The ANDROMEDA trial (NCT03201965), a phase 3, randomized trial comparing CyBorD alone or in combination with subcutaneous daratumumab, closed to accrual in August 2019. Data on the 28 patients enrolled in the safety run-in phase showed an overall response rate of 96% with 82% of those very good partial responses or better, including 36% complete responses.

 The quadruple combination was well tolerated overall and may become frontline, standard of care.

The phase 3 TOURMALINE-AL1 trial (NCT01659658) that randomized patients to receive either ixazomib (Ninlaro) plus dexamethasone or clinician’s choice was closed early due to lack of significant improvement in overall hematologic response. However, patients in the ixazomib arm enjoyed a doubling of hematologic response duration compared with controls (46.5 vs 20.2 months, respectively),suggesting a potential role for ixazomib as maintenance therapy.

Translocation t(11;14) is the most common cytogenetic abnormality in AL amyloidosis and is present in approximately 40% of patients. It is a poor prognostic factor for overall survival and a negative predictive factor of response to bortezomib- containing regimens.

 However, in MM, t(11;14) is a biomarker of high BCL-2 expression and a predictive factor of response to the BCL-2 inhibitor venetoclax (Venclexta).

 Several clinical trials of venetoclax in MM have been halted due to excess mortality from infectious complications noted in patients receiving venetoclax in combination with bortezomib and dexamethasone in the phase 3 BELLINI study (NCT02755597).

As benefits seem to outweigh risks for patients with t(11;14), the amyloidosis community is eagerly awaiting the FDA to lift the hold so that venetoclax can be tested in clinical trials in patients with t(11;14) AL amyloidosis. The BCMA-targeting antibody-drug conjugate belantamab mafodotin and melflufen, a melphalan derivative, showed promising results in MM, and clinical trials are underway or anticipated in AL amyloidosis.

Although overall survival of patients with AL amyloidosis has substantially improved thanks to more effective chemotherapy, early mortality remains largely unaffected and mostly related to delayed diagnosis leading to advanced cardiac dysfunction. Thus, a significant research effort has been funneled toward developing therapeutics to facilitate the reabsorption of deposited amyloid. The antimicrobial doxycycline was shown to rescue cardiomyocyte from direct FLC toxicity and to interfere with fibrillogenesis in preclinical models.

Retrospective and phase 2 studies confirmed that adding doxycycline to standard chemotherapy reduces early cardiac mortality and its use is suggested in patients with AL amyloidosis- related cardiomyopathy in combination with chemotherapy.

 The antifibrillary antibody birtamimab (NEOD001) showed promising results in improving cardiac dysfunction in early-phase clinical studies.

 However, drug development was halted based on lack of benefit in a large phase 3 study.

In a phase 1a/b study enrolling patients with relapsed/refractory AL amyloidosis, CAEL-101, a novel antibody recognizing an epitope solely exposed by misfolded FLC, showed rapid and frequent cardiac and renal responses independently of hematologic response with no patient experiencing organ progression while they were on the study.

 A phase 2/3 study (NCT04304144) of CAEL-101 in combination with CyBorD in patients with treatment-naÏve AL amyloidosis with cardiac dysfunction is currently recruiting.

The upfront use of antifibrillary antibodies and highly effective, combinatory chemotherapy could profoundly affect the natural history of this devastating condition and finally improve early mortality. Together with an effort to educate clinicians to think about amyloidosis in their daily practice, studies focusing on early recognition or diagnosis in high-risk groups such as African Americans and patients with a preexisting MGUS/SMM diagnosis are likely to have a major impact from a public health standpoint.

This is an exciting time for the AL amyloidosis community as patient advocacy groups, academia, pharmaceutical companies, and regulatory agencies are joining in an effort to develop safe and effective treatments for patients with AL amyloidosis.

Clinical research efforts in AL amyloidosis have focused on 3 main areas: (1) early diagnosis; (2) effective chemotherapy; and (3) antifibrillary drugs (

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Immunoglobulin light chain amyloidosis is the most common form of systemic amyloidosis and is characterized by rapidly progressive organ failure and eventually patient demise, if not promptly recognized and treated.

Dana Farber

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