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Bridging the Gaps in Hematologic Malignancies

Dr Chari on Current Unmet Needs to Address in Multiple Myeloma Treatment

Ajai Chari, MD, director, Multiple Myeloma Program, professor, clinical medicine, University of California, San Francisco (UCSF), UCSF Helen Diller Family Comprehensive Cancer Center, discusses current unmet needs that remain to be addressed in the treatment of patients with multiple myeloma and highlights what oncologists should know about the current treatment paradigm for this disease.

The current unmet needs in multiple myeloma encompass various patient populations, including elderly patients and those with persistent renal issues, renal failure, frailty, extramedullary disease, plasma cell leukemia, central nervous system relapse, and functional high risk, such as early relapses beyond the expected, Chari begins. These are critical areas requiring focused attention, he adds. Addressing these needs may pose challenges in conducting large, randomized studies, but there's value in incorporating dedicated cohorts within larger phase 3 trials to target these subgroups, such as the frail elderly or patients with renal failure, Chari reports. Although achieving substantial patient sample sizes might be challenging, even smaller cohorts comprising 20 to 30 patients can provide valuable insights into efficacy and safety profiles, facilitating progress in the field, he notes.

Furthermore, in the context of induction therapy, CD38 inhibitors plus lenalidomide (Revlimid) and dexamethasone are commonly considered, with possible inclusion of proteasome inhibitors for transplant-eligible and high-risk elderly patients, he continues. Therefore, adopting triplet or quadruplet regimens for broader patient groups is imperative, Chari says, adding that although transplantation remains a consideration, lenalidomide maintenance therapy with or without additional agents is a recognized treatment approach.

Regarding CAR T-cell therapy, ciltacabtagene autoleucel (cilta-cel; Carvykti) has generated promising results, but concerns persist regarding associated Parkinsonism and cranial neuropathies, he expands. Nonetheless, there's anticipation for the emergence of newer CAR T-cell therapies and bispecific antibodies, with potential combinations offering intriguing prospects, Chari adds. As these therapies advance, there's a growing interest in transitioning them to community settings, according to Chari. Although still in early development stages, it's essential to eventually extend access to these products beyond specialized treatment centers to ensure widespread benefits for patients with myeloma, he concludes.

Ajai Chari, MD, discusses unmet needs in multiple myeloma, as well as what oncologists should know about the current treatment paradigm for this disease.

Tycel Phillips, MD, discusses efforts to clarify and refine the treatment paradigm of patients with mantle cell lymphoma.

Dr Phillips on Efforts to Clarify and Refine Management Approaches in Relapsed/Refractory MCL

Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses highlights from the 2024 

® Bridging the Gaps in Hematologic Malignancies meeting, and expands on efforts to clarify and optimize the role of current approaches to the treatment of patients with mantle cell lymphoma (MCL).

During the MCL session of the Bridging the Gaps in Hematologic Malignancies meeting, there was extensive discussion of ongoing challenges in managing MCL, both in the United States and globally, Phillips begins. The session also placed particular emphasis on evolving treatment paradigms in the frontline setting, he explains, adding that there remains considerable disagreement regarding the optimal induction regimen and the role of transplantation in patient management.

The development of novel treatments in the relapsed/refractory setting may be improving prospects for patients, he continues. Notably, CAR T-cell therapies have great potential in this space, pending their approval for associated indications, Phillips reports. These therapies include 

lisocabtagene maraleucel (liso-cel; Breyanzi).

 Brexu-cell gained FDA approval in July 2020 based on findings from the phase 2 ZUMA-2 trial, and liso-cel is currently being evaluated in the phase 1 TRANSCEND NHL 001 trial (NCT02631044) for patients with relapsed/refractory mantle cell lymphoma.

The emergence of bispecific antibodies and BTK inhibitors further enriches the therapeutic armamentarium in MCL, Phillips says. However, the question of treatment sequencing and the potential for treatment reuse remain pertinent, he adds.

Discussions during the MCL session also centered on strategies to improve outcomes for high-risk patients and enhance the identification of this subgroup, he expands. Efforts to minimize the use of cytotoxic chemotherapy in favor of more effective and durable therapies garnered attention, Phillips states. Numerous studies are showing that chemotherapy yields limited and transient responses, potentially fostering the emergence of resistant clones, he adds. Thus, there's a collective focus on refining patient management strategies to optimize outcomes in this challenging patient population, Phillips concludes.

Dr Chari on the Bridging the Gaps in Hematologic Malignancies Meeting

Ajai Chari, MD, director, Multiple Myeloma Program, professor of clinical medicine, University of California, San Francisco (UCSF), UCSF Helen Diller Family Comprehensive Cancer Center, discusses the 2024 

® Bridging the Gaps in Hematologic Malignancies meeting, highlighting the topics that were covered at the meeting regarding the treatment of patients with multiple myeloma.

Chari quips that doctors who treat multiple myeloma often have differing views on how to approach various treatments across different settings. Thus, attending the meeting, he shares that he anticipated a lack of consensus on various topics. Although there were indeed areas where consensus was lacking, it was pleasantly surprising to find some unexpected points of agreement among the key opinion leaders present, Chari explains.

Beginning with discussions on newly diagnosed multiple myeloma, it was generally agreed that anti-CD38–based quadruplets are commonly utilized for induction therapy, with most clinicians favoring stem cell collection, he expands. The consensus also leaned toward recommending transplant, especially for patients deemed to have high-risk disease, with near unanimous agreement among attendees on this point, Chari states. For patients who are transplant-ineligible, there appeared to be clear consensus on the use of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone, possibly incorporating a proteasome inhibitor (PI) for select high-risk subgroups, he elucidates. 

However, significant controversy arose regarding post-transplant maintenance therapy, with lenalidomide being the most utilized agent, he continues. Disagreement centered on whether to incorporate daratumumab or a PI for high-risk patients and the optimal duration of daratumumab therapy, Chari reports. Additionally, in early relapse cases, there was a preference for anti-CD38 monoclonal antibodies based on data from the phase 3 IKEMA study (NCT03275285), he says. Furthermore, while most practitioners preferred switching treatment classes, concerns were raised about the suitability of carfilzomib (Kyprolis), particularly for elderly patients with cardiac comorbidities, Chari states

The meeting also highlighted considerable interest in early T-cell redirection with CAR T-cell therapies, along with ongoing discussions about effective sequencing strategies for bispecifics and CAR Ts, he explains. Moreover, there was apprehension regarding newer toxicities associated with some of these agents, such as motor dysfunction and cranial neuropathies, for which clinical experience remains limited, Chari concludes.

Ajai Chari, MD, discusses the 2024 OncLive® Bridging the Gaps in Hematologic Malignancies meeting, highlighting the treatment of multiple myeloma.

Tycel Phillips, MD, discusses unmet needs for patients with relapsed/refractory mantle cell lymphoma.

Dr Phillips on Unmet Needs in Patients With Relapsed/Refractory MCL

Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses unmet needs for patients with relapsed/refractory mantle cell lymphoma (MCL), highlighting the need for more effective treatment options for this patient population.

Phillips begins by stating that the patients who have high-risk MCL are the ones with the most unmet needs. Even trials such as the single-arm phase 2 WINDOW-1 (NCT02427620) and WINDOW-2 (NCT03710772) trials lack comprehensive data, Phillips explains. Notably, the WINDOW-1 trial evaluated ibrutinib (Imbruvica) plus rituximab (Rituxan) and hyper-CVAD consolidation therapy in newly diagnosed young patients with MCL, and the WINDOW-2 trial investigated ibrutinib plus rituximab followed by venetoclax (Venclexta) and hyper-CVAD consolidation therapy in the same newly diagnosed patient population.

The phase 2 BOVen trial (NCT03824483)—investigating zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax—focused specifically on high-risk patients with MCL, and a phase 2 trial (NCT03863184) assessed acalabrutinib (Calquence), lenalidomide (Revlimid), and rituximab in patients with untreated disease, Phillips continues. Furthermore, despite the introduction of novel regimens, high-risk patients seem to exhibit poor responses, he elucidates, adding that the BOVen trial is still ongoing, leaving uncertainties about its eventual outcome. Phillips shares that he is hopeful BOVen will yield positive results. However, many trials have shown worse outcomes with novel therapies in patients with 

mutations compared with those without, he notes.

A similar trend in clinical outcomes is being observed in patients with blastoid and pleomorphic variants, Phillips expands. These patients generally do not fare as well as most patients with MCL, he states, noting that high-risk patients constitute approximately 20% to 25% of those undergoing initial therapy. However, high-risk patients represent the majority in the relapsed/refractory setting because they experience quicker relapses, necessitating rapid treatment changes, and are likely to succumb to their disease sooner than those with lower-risk disease, Phillips reports. Since the most effective and durable responses often occur during initial treatment for incurable cancers, failing to achieve responses to early lines of therapy sets patients on a challenging treatment course, he concludes.

Dr Phillips on the Treatment Landscape for Patients With MCL

Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses the treatment landscape for patients with mantle cell lymphoma (MCL), highlighting key discussions from the 2024 

® Bridging the Gaps in Hematologic Malignancies meeting.

Phillips begins by saying that his talk centered on non-chemotherapy induction regimens for patients with MCL, which essentially refers to induction regimens devoid of cytotoxic agents. During the presentation, recent and historical trials that evaluated chemotherapy options for patients with MCL were explored, he states. The discussion commenced with the phase 2 WINDOW-1 trial (NCT02427620), which represented an initial investigation into non-cytotoxic chemotherapy induction regimens, he elucidates. This trial examined the efficacy of ibrutinib (Imbruvica) and rituximab (Rituxan) administered for 12 cycles, followed by consolidation therapy with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, allowing patients to receive up to 8 cycles of chemotherapy depending on their initial treatment response to ibrutinib plus rituximab, he reports.

Subsequently, the phase 2 WINDOW-2 trial (NCT03710772) emerged as a completely non-cytotoxic chemotherapy regimen, incorporating ibrutinib, venetoclax (Venclexta), and rituximab, he expands. Additional trials explored combinations such as obinatuzumab (Gazya) with ibrutinib or venetoclax. Notably, the phase 2 BOVen trial (NCT03824483), for which findings were presented at the 2023 ASH Annual Meeting, investigated zanubrutinib (Brukinsa), obinatuzumab, and venetoclax in patients with 

-mutated MCL, he notes. Moreover, the Cornell group presented a study on acalabrutinib (Calquence), lenalidomide (Revlimid), and rituximab at ASH.

However, it's crucial to note that many of these trials have been relatively small, involving single institutions or enrolling a limited number of patients, typically ranging from 20 to 90 individuals, Phillips continues. Consequently, the MCL space is lacking large, randomized trials commonly conducted in Europe, where the standard of care is compared with experimental arms, he reports. Thus, in the United States, there remains a need for further evaluation to determine the placement of these novel non-cytotoxic regimens, he notes. Nonetheless, progress is being made, and it is anticipated that these advancements may eventually render autologous stem cell transplantation obsolete in the management of MCL, possibly within the next year or so, as treatment approaches continue to be refined, he concludes.

Tycel Phillips, MD, discusses the landscape of treatment for patients with mantle cell.


Dr Danilov on Addressing Unmet Needs in Hematologic Malignancies

Alexey Danilov, MD, PhD, hematologist/oncologist, associate director, Toni Stephenson Lymphoma Center, professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses unmet needs for patients with hematologic malignancies that will be addressed at the 2024 

 Bridging the Gaps in Hematologic Malignancies meeting.

Over the past 4 years, there has been significant progress in treating patients with chronic lymphocytic leukemia (CLL) and lymphomas, marked by numerous new drug approvals and the emergence of several promising agents, Danilov begins. As the CLL field transitions away from chemoimmunotherapy, a similar shift is underway in mantle cell lymphoma (MCL), he says. Notably, novel cellular and T-cell engager therapies are advancing in diffuse large B-cell lymphoma, he adds. It's crucial to comprehend how these treatment developments will reshape the management of CLL and lymphomas through the use and sequencing of novel therapies.

In CLL, notable therapeutic advancements include the FDA approvals of BTK inhibitors and BCL-2 inhibitors, with additional BCL-2 inhibitors in development, Danilov continues. However, challenges arise with managing double-refractory CLL, prompting the exploration of new agents such as CAR T-cell therapies, bispecific antibodies, BTK degraders, and noncovalent BTK inhibitors, he explains. Discussions at the Bridging the Gaps in Hematologic Malignancies meeting will delve into research that will further shape the field and address the evolving standard of care, he notes.

For MCL, various phase 1/2 trials have introduced novel therapies into the frontline setting, challenging the traditional approach of chemoimmunotherapy followed by transplant for younger patients, Danilov expands. Understanding how these changes impact treatment strategies and the need for trials to validate the era of targeted therapies in MCL will also be a key focus of the meeting. Additionally, discussions will encompass treatment advancements in relapsed/refractory disease, including improved outcomes with CAR T-cell therapies and bispecific antibodies, he adds.

In DLBCL, recent FDA approvals, along with the integration of CAR T-cell therapy into earlier lines of therapy and advancements in frontline chemoimmunotherapy combinations present new treatment avenues, he explains. Determining optimal sequencing, leveraging emerging data, and designing trials to introduce novel agents into earlier therapy lines will be central topics for discussion at the meeting, Danilov concludes.

Alexey Danilov, MD, PhD, discusses unmet needs in hematologic malignancies to be discussed at the Bridging the Gaps in Hematologic Malignancies meeting.

Dr Saeed on the Use of Pola-R-CHP in Previously Untreated DLBCL

Hayder Saeed, MD, associate member, Malignant Hematology program, Moffitt Cancer Center, discusses key takeaways from his 2024 

® Bridging The Gaps in Hematologic Malignancies meeting presentation on treatment with polatuzumab vedotin-piiq (Polivy) plus rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

Saeed’s presentation is on the topic ‘Pola for Everyone,’ referring to polatuzumab vedotin, an anti-CD79 antibody-drug conjugate. In August 2023, 

 for patients with previously untreated DLBCL not otherwise specified or high-grade B-cell lymphoma who have an International Prognostic Index score of 2 or greater. Notably, this regulatory decision was supported by data from the phase 3 POLARIX trial (NCT03274492), wherein the 2-year PFS rate in patients who received pola-R-CHP (n = 440) was 76.7% (95% CI, 72.7%-80.8%). This approval 

 the 2019 accelerated approval of polatuzumab vedotin plus bendamustine and rituximab in patients with relapsed/refractory DLBCL who had received at least 2 prior therapies.

This presentation regarding the use of pola-R-CHP as frontline treatment for patients with DLBCL stemmed from findings from the POLARIX study showing the advantages of substituting vincristine chemotherapy with polatuzumab vedotin in an all R-CHP regimen, he expands. This study was the first phase 3 trial to demonstrate benefits with pola-R-CHP in this patient cohort and sparked considerable debate because its data sparked a significant shift in treatment standards after many years, Saeed states. In the presentation, Saeed will delve deeper into the trial, its outcomes, and how these outcomes may guide future patient care.

It's crucial to grasp that the study's primary outcomes and findings from subgroup analyses do not necessarily dictate treatment for all newly diagnosed patients with DLBCL, he continues. Understanding the role of subgroup analyses and applying the primary outcomes to all eligible patients is vital for optimal disease management, Saeed concludes.

Hayder Saeed, MD, discusses key takeaways regarding the use of polatuzumab vedotin plus R-CHP in diffuse large B-cell lymphoma.