ASH 2021 Is Packed With Practice-Changing Hematologic Cancer Data

Omar Nadeem, MD

Not only is the 2021 ASH Annual Meeting bursting with more than 5000 abstracts unveiling pivotal data across a range of hematologic malignancies and disorders, but the conference will be held as a hybrid format after going fully virtual in 2020.

The long-awaited meeting will take place from December 10 to 14, 2021 in Atlanta, Georgia, and is unveiling findings with CAR T-cell therapy, combinations with monoclonal antibodies, kinase inhibitors, and many more across subtypes in lymphoma, leukemia, and multiple myeloma, just to name a ew.

OncLive^® sat down with experts specializing in multiple myeloma and non-Hodgkin lymphoma on what they believe are the top studies being presented at the 2021 ASH Annual Meeting and how their findings have the potential to change clinical practice.

MULTIPLE MYELOMA

Omar Nadeem, MD @OmarNadeemMD

Clinical Director, Myeloma Cellular Therapies Program; Physician; Instructor in Medicine, Harvard Medical School

Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance (Abstract 79)

In the primary analysis of the phase 2 GRIFFIN trial (NCT02874742), which had a median follow-up of 13.5 months, the combination of daratumumab (Darzalex) plus lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD; D-RVd) showed a stringent complete response (sCR) rate of 42.2% at the end of post-autologous stem cell transplant (ASCT) compared with 32.0% with RVd alone (1-sided P = .068).¹ The responses were found to deepen at a median 27.4-month follow-up at 63.6% vs 47.4%, respectively (2-sided P = .0253).²

At the 2021 ASH Annual Meeting, investigators will present further efficacy and safety findings from GRIFFIN with a median follow-up of 38.6 months.

“This study highlights the efficacy of quadruplet-based induction therapy for newly diagnosed multiple myeloma using the combination of daratumumab, bortezomib, lenalidomide and dexamethasone with stem cell transplantation and maintenance therapy with either daratumumab/lenalidomide or lenalidomide alone.

This updated analysis after 24 months of maintenance continue to show stringent complete response rates favoring the quadruplet regimen [66% vs 47.4%; P = .0096]. Furthermore, much higher rates of minimal residual disease negativity [MRD; 10-5] were observed in the quadruplet arm vs triplet arm [64.4% vs 30.1%, P <.0001] along with higher rates of sustained MRD negativity lasting at least 12 months [44.2% vs 12.6%; P <.0001]. The median progression-free survival [PFS] was not reached in either arm but trended towards favoring D-RVd [36-month PFS rate 88.9% vs 81.2%].

This trial continues to support the enhanced efficacy of quadruplet induction over triplet induction in newly diagnosed multiple myeloma patients with longer follow up.”

High prevalence of monoclonal gammopathy in a population at risk: the first results of the PROMISE study (Abstract 152)

In this screening study (NCT03689595), investigators sought to determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS)—which is seen in approximately 3% of the general population—in those who are at high risk of multiple myeloma, and to also identify the clinical variables of those who test positive for MGUS.

To be eligible for enrollment, individuals had to be aged 40 years or older with an additional multiple myeloma risk factor. The interim screening data, which will be presented during the meeting, includes the first 2960 participants on study.

“The PROMISE study is the first nationwide screening study for individuals with high risk of developing multiple myeloma, defined as African Americans and those with first-degree relatives diagnosed with hematologic malignancy or precursor condition to multiple myeloma.

A total of 7622 individuals have been screened to date utilizing both a novel high-sensitivity Exent MALDI-TOF mass spectrometry [MS] and conventional methods including SPEP/IFX with serum free light-chain analysis. Significantly higher rates of monoclonal gammopathy of undetermined significance were seen in the high-risk cohort age older than 50 years compared with previously reported incidence, and detection was higher via MS [13%] compared with conventional methods (6%).

Furthermore, MS also detected lower-level monoclonal gammopathies termed monoclonal gammopathies of indeterminate potential [MGIP], which were lower than the limit of detection identified for the conventional methods [<0.2g/L]. MGIP was detected in around 28% of individuals aged 50 and above.

This study highlights the higher incidence of monoclonal gammopathies seen in high-risk population and introduce a new lower-level monoclonal gammopathy of indeterminate potential that is associated with aging.”

Screening for monoclonal gammopathy of undetermined significance: a population-based randomized clinical trial: first results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study (Abstract 156)

Related to screening for MGUS, the iStopMM study (NCT03327597) is a population-based screening trial in an effort to identify those with MGUS who could receive early treatment for multiple myeloma and lymphoproliferative disorders. In the randomized clinical trial, patients with MGUS were randomized to 1 of the 3 arms: patients are not contacted (arm 1); are followed based on current guidelines (arm 2); or are followed with a more intensive diagnostic and monitoring strategy (arm 3). Participants who progress are offered early treatment, and all participants on study answered questionnaires focused on quality of life and mental health.

“The iSTopMM study is a large population-based screening study from Iceland that also included a randomized trial component of follow-up and treatment strategies. Participants diagnosed with MGUS were randomized to 1 of the 3 study arms: arm 1 where participants are not contacted; arm 2 where individuals are followed based on current guidelines; and arm 3 where individuals are followed with a more intensive diagnostic and monitoring strategy.

This study demonstrated a 4.9% incidence of MGUS which was age dependent [2.3%, 6.2%, and 12.9% diagnosed in age groups 40-59, 60-79, and 80-103 years, respectively]. The prevalence of MGUS was higher in males, 5.9% vs 4.1% [P <.0001]. The randomized trial component demonstrated that a higher number of patients were diagnosed with lymphoproliferative disorders in the more intensive follow-up arm, suggesting benefit for early screening and enhanced monitoring.”

Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. final primary endpoint analysis of the Master trial (Abstract 481)

In the Master trial (NCT03224507), investigators sought to determine whether the combination of daratumumab, carfilzomib (Kyprolis), lenalidomide and dexamethasone (D-KRd) would show clinical activity and tolerability in patients with newly diagnosed multiple myeloma. Investigators also utilized MRD through next-generation sequencing (NGS) as a way to inform the use and duration of Dara-KRd posttransplant and treatment cessation in patients who have confirmed MRD negativity.

“The Master trial is studying the induction regimen of daratumumab, carfilzomib, lenalidomide and dexamethasone with autologous stem cell transplantation and MRD-guided consolidation therapy and treatment cessation in newly diagnosed [patients with] multiple myeloma. The patients would receive anywhere between 0 to 8 cycles of Dara-KRD consolidation depending on their MRD status, which was evaluated by NGS [ClonoSEQ].

A total of 123 patients have been enrolled, of which 84 [71.2%] have entered a monitoring phase after they achieved confirmed MRD negativity. The rates of MRD negativity were similar in patients with 0, 1, and 2+ high-risk chromosomal abnormalities [HRCA; 78% vs 82% vs 79%]. However, nearly all patients with 0 or 1 HRCA on observation with MRD surveillance remain free of [International Myeloma Working Group] progression compared with 27% with 2+ HRCA who have progressed.

This trial is one of the first to study MRD surveillance after treatment cessation and it will be important to see in which patients treatment can be safely stopped. The role of MRD to guide therapy will be an important research question going forward and more trials are needed for us to properly utilize MRD testing in routine clinical practice.”

Updated results from CARTITUDE-1: Phase 1b/2 Study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor t cell therapy, in patients with relapsed/refractory multiple myeloma (Abstract 549)

The BCMA-targeted CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) will have updated results from CARTITUDE-1 (NCT03548207) with a median follow-up of 18 months in patients with heavily pretreated relapsed/refractory multiple myeloma. Previously, the agent showcased deep and durable clinical activity in this study at a median 12.4-month follow-up, with a 97% objective response rate (ORR) and a 67% sCR.³

In November 2021, the FDA had extended the Prescription Drug User Fee Act target date for the biologics license application that was seeking the approval of cilta-cel for use in adult patients with relapsed and/or refractory multiple myeloma. The new decision date for the application is February 28, 2022.

“The CARTITUDE-1 trial is evaluating the use of cilta-cel in patients with relapsed and refractory multiple myeloma. The update of this study with longer median follow-up, 18 months, continues to demonstrate significant activity with 80.4% of patients achieving a sCR and 91.8% achieving MRD negativity (10^-5) in evaluable patients. Encouragingly, the median duration of response [DOR] was 21.8 months and the 18-month progression-free and overall survival rates were 66% and 80.9%, respectively. Cytokine release syndrome occurred in 94.8% of patients and was mostly low grade in nature. Importantly, there were no new CAR T-cell–associated neurotoxicity reported since the previous update.

Cilta-cel continues to demonstrate promising activity in this heavily pretreated patient population. The median DOR of nearly 22 months and no new safety concerns particularly at is relates to neurological toxicity is encouraging with longer follow-up.”

NON-HODGKIN LYMPHOMA

Andrew M. Evens, DO, MSc, FACP

Andrew M. Evens, DO, MSc, FACP @DrAEvens

Associate Director (Clinical Services), Rutgers Cancer Institute of New Jersey; System Director of Medical Oncology; Oncology Lead for RWJBarnabas-Rutgers Medical Group, RWJBarnabas Health; Associate Vice Chancellor, Clinical Innovation & Data Analytics, Rutgers Biomedical and Health Sciences; Attending Physician, Robert Wood Johnson University Hospital

A large multicenter real-world evidence (RWE) analysis of autoimmune (AI) diseases and lymphoma: histologic associations, disease characteristics, survival, and prognostication (Abstract 50)

This retrospective analysis includes 785 patients with a lymphoma diagnosis and preexisting AI disease across 14 North American institutions with 694 having complete data. Investigators sought to identify associations of AI diseases with lymphoma histologic subtypes, while also evaluating prognostic and survival information.

“In a large, multicenter, RWE retrospective analysis of adult patients with lymphoma and a preexisting AI disease, we identified several novel histologic associations of AI diseases with lymphoma histologic subtypes. For patients with diffuse large B-cell lymphoma [DLBCL] with antecedent AI disease, complete cessation of immune suppression during frontline therapy appeared to be associated with improved survival.

Finally, there were a small number of select patients with DLBCL who garnered long-term disease-free survival using reduction of immune suppression plus or minus rituximab [Rituxan] as frontline therapy, similar to the treatment paradigm in posttransplant lymphoproliferative disorders.”

A multi-institution analysis of relapsed lymphoma occurring during pregnancy including pharmacokinetics with antenatal checkpoint inhibitor therapy (Abstract 2457)

Currently, data are limited on patients who receive a diagnosis of lymphoma during pregnancy, and there are several challenges and questions associated with optimal management of these patients to avoid risks to the patient and fetus. In the retrospective analysis, investigators evaluated patients with relapsed lymphoma during pregnancy between 1989 and 2021 across 10 academic centers to get information on disease characteristics, treatment, obstetric complications, and fetal outcomes.

“We performed a detailed retrospective analysis of patients diagnosed with relapsed lymphoma during pregnancy across 10 academic centers worldwide. Overall, treatment was deferred in the majority of patients, though it was well tolerated by those who received antenatal therapy during pregnancy.

Furthermore, there were relatively few obstetrical or fetal complications for patients who received antenatal treatment. Finally, use of antenatal nivolumab [Opdivo] checkpoint inhibitor therapy in 1 patient with relapsed Hodgkin lymphoma was safe, effective, and associated with expectant maternal pharmacokinetics.”

Real world evidence (RWE) of safety, efficacy, and outcomes of CD19 CAR-T therapy in 20 patients with solid organ transplant (SOT)-related post-transplant lymphoproliferative disorder (PTLD; Abstract 38530)

Patients with PTLD are generally treated with single-agent rituximab and a reduction of immunosuppression; for patients who do not respond, those who do not respond then receive sequential chemoimmunotherapy. In patients with relapsed disease, however, optimal therapy is unclear, including the use of CAR T-cell therapy in a patient population with relapsed/refractory SOT-related PTLD.

“We analyzed 20 adults with relapsed/refractory SOT-associated PTLD who received CD19 CAR-T therapy in a multicenter, retrospective, RWE analysis. We found that rates of CAR T–related cytokine release [syndrome] and neurologic events appeared comparable with previous non-PTLD CAR T-cell data.

Furthermore, 50% of SOT-PTLD patients obtained a complete remission [CR], with approximately one-third of patients sustaining long-term remission, and achievement of CR was a critical factor associated with survival. Finally, with abrogation of immunosuppression prior to CAR T-cell therapy, and careful resumption post-therapy, organ preservation was achieved in most patients.”

Kevin David, MD

Kevin David, MD

Director, Lymphoma Program, Rutgers Cancer Institute; Attending Physician, Robert Wood Johnson University

Older patients with primary central nervous system lymphoma (PCNSL): real world evidence (RWE) of prognostication and outcomes with post-induction therapy (Abstract 1428)

Post-induction treatment patterns and outcomes were evaluated across 20 US academic centers in this large, retrospective study—of which David is the lead author on—based on RWE in older patients with primary central nervous system lymphoma. Treatment challenges in this patient population have proven to be challenging to date, due to frailty, comorbidities, and complexities.

“Consolidative autologous stem cell transplant may benefit a subset of older patients with primary CNS lymphoma who have had a response to initial induction therapy, but is not applicable to all patients due to comorbidities and frailty. Maintenance strategies appeared to improve outcomes and should be more robustly studied in future prospective investigations.”

Phase II study of venetoclax in combination with obinutuzumab and bendamustine in patients with high tumor burden follicular lymphoma as frontline therapy (PrECOG 0403; Abstract 8140)

The approach with combining the BCL-2 inhibitor with venetoclax (Venclexta) with obinutuzumab (Gazyva) and bendamustine stemmed from the high prevalence of BCL-2 expression in follicular lymphoma, and also that BCL-2 inhibition is thought to be synergistic with chemotherapy. At the 2021 ASH Annual Meeting, investigators will present the end-of-induction outcomes in patients with treatment-naïve follicular lymphoma who were treated with the triplet regimen in the PRE0403 trial (NCT03113422).

“The combination of bendamustine, obinutuzumab, and venetoclax used in this study had a high response rate in patients with untreated follicular lymphoma, but significant infectious complications were seen. If this regimen is to further investigated, modifications in dosing of components such as venetoclax should be considered.”

Outcomes and treatment patterns in patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy (Abstract 884)

To date, there has not been a standard approach to treatment in patients with relapsed/refractory B-cell lymphoma who experience disease progression on CD19-directed CAR T-cell therapy. In a multicenter, retrospective analysis, investigators sought to identify treatment outcomes and patterns in this patient population to provide guidance on first-line salvage therapy upon progression on CAR T-cell therapy.

“Outcomes in patients with diffuse large B-cell lymphoma who experience disease progression after CAR T-cell therapy are poor. Recently developed novel therapies may provide short-term benefit, but improved treatments are needed to achieve long-term responses in these very refractory cases.”

References

1. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288
2. Kaufman JL, Laubach JP, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): Updated analysis of Griffin after 12 months of maintenance therapy. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; virtual. Abstract 549.
3. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8