A Panel Discussion from the Total Health 2023 Community Cases Atlanta Conference
September is Blood Cancer Awareness month, and at the recent Total Health Community Cases Conference held in Atlanta, Georgia, a panel discussion on Hematologic Cancers featured case presentations focusing on different clinical scenarios in multiple myeloma, with commentary on the practical and patient management aspects of the different drug therapies. Multiple myeloma is a blood cancer originating in the plasma cells, a type of white blood cell that normally produces antibodies. The discussion was moderated by Dr Nisha Joseph, MD, from Emory University, and also featured Dr Sara Scott, PharmD, from Emory Winship Cancer Institute and Roseann Pruitt, PA, from Emory University.
Case 1: Management Strategies for ‘Smoldering’ Myeloma
The first case reviewed featured a patient found to have elevated total protein level on his routine lab work with his primary care physician. He was otherwise well with no fatigue, bone pain, or clinical symptoms, and no relevant family history. Upon further workup, he is found to have clinical features consistent with smoldering myeloma, with 30% bone marrow plasma cells (BMPC) on biopsy, and no evidence of lytic bone disease on his positron emission tomography (PET) scan, with, as Dr Joseph suggested, “an overall small burden of disease”.
A key feature in the management of this patient, as Dr Joseph explained, is the choice for observation versus surveillance. She noted that smoldering myeloma is an asymptomatic “precursor” state, and historically, the risks and toxicity associated with treating such patients was too high relative to the overall benefit of the treatment, so the standard of care was generally observation. By comparison, in the modern era, as Dr Joseph noted, therapies are more effective and less toxic, and there are also better clinical models to predict which patients are at high risk, and therefore will benefit most from treatment. For example, the Mayo Clinic 2018 clinical criteria identified three key features that predicted progression to symptomatic myeloma, including 1) an “M-spike” of over 2 g/dL, 2) a BMPC over 20%, and 3) a free light chain ratio (FLCr) of > 20. As such, if the patient has 0, 1, or 2 to 3 of these clinical features, this classifies them as low, intermediate, or high risk for progression to symptomatic myeloma. The difference in overall prognosis among these three risk groups is significant, with an approximately 9 to 10 years in time to progression (TTP) for the low risk group, versus a 2 to 3 year TTP for the high risk group.
For the patient considered in the first case, his M-spike was 1.5 g/dL, his FLCr was 58, and his BPMC was 30%, so he would be classified as high risk, with 2 of the 3 criteria fulfilled. Dr Joseph reviewed data from the QuiRedex Phase III trial, examining the use of lenalidomide, an immunomodulatory drug, in combination with dexamethasone (known as the ‘Rd’ regimen) versus observation for patients with smoldering multiple myeloma (SMM). The results showed a significant benefit in both TTP (P<0.0001) and overall survival (OS; P=0.024) for patients treated with Rd versus observation. While there were limitations to these trial results, Dr Joseph also showed data from the PETHEMA trial, with a nearly 11-year follow up, which also showed a significant benefit of Rd in both TTP and OS. Another important finding that that emerged from this trial was that early treatment of SMM did not cause relapses to become more drug resistant; there was no significant difference in OS from the time of progression for patients treated with Rd (median 6.4 years) versus those treated with observation alone (median 4.7 years).
Additional data which Dr Joseph reviewed from the Eastern Cooperative Oncology Group (ECOG) E3A06 Trial, which randomized 180 SMM patients to either lenalidomide monotherapy or observation, showed a 91% versus 66% progression-free survival (PFS) for patients in the respective treatment groups. The benefit was most pronounced in the high-risk (Mayo Clinic 2018) group, with a less clear benefit in the intermediate and low risk groups for lenalidomide monotherapy, and the authors concluded that this therapy should be limited to a total of 2 years. She outlined the current practice at her center for SMM, which is based on early, low-intensity therapy with a limited duration for high risk patients (Box 1).
Box 1: Smoldering Multiple Myeloma (SMM) – Risk Factors and Treatment Options*
Risk Factors (2018 Mayo Clinic Criteria)
Low = No risk factors Intermediate = 1 risk factor High = 2-3 risk factors
*Note: All SMM patients should receive definitive imaging such as PET-CT or MRI; High risk SMM patients should be referred for ASCT and stem cell collection; Curative clinical trials are underway with good responses, but no major PFS benefit as yet.
Returning to the case, she noted that the patient was treated with lenalidomide for a 2 year period through January of 2022 and remains on observation at present. The patient also had a good response to treatment, with normalization of his M-spike and FLCr, and, despite some evidence of progression in his most recent lab work, Dr Joseph noted the patient will continue to be observed.
The panelists then discussed some key issues in treatment with this patient, including tolerability and dose modifications, supportive care measures, and clinical trial options. Fatigue, gastrointestinal toxicity, rash, and cytopenias (drop in blood cell counts) are the primary toxicities associated with lenalidomide that must be monitored, and are the primary reasons for dose reduction. It was noted that dose may also have to be reduced if the patient has renal dysfunction. A distinctive rash may occur and there may also be some diarrhea associated with lenalidomide treatment; if present, it was noted that any diarrhea should be managed with bile acid sequestrant type agents such as colestipol. Although less common, thrombotic events may also occur, and depending on the patient’s existing risk factors, drug therapy with anticoagulants may be indicated. With regard to clinical trial options, it was noted that no trials are available for low risk SMM, as the benefit does not outweigh the risks. However, the panelists noted that trials are available at Emory University for both intermediate and high risk SMM patients.
Case 2: Newly Diagnosed Multiple Myeloma (NDMM)
The second case featured a 72-year old patient with acute onset back pain after sneezing. The patient was found to have an acute compression fracture at her L1 vertebra, a finding consistent with lytic bone disease. Upon further workup, she was found to have 10-15% BMPC, and multiple lytic lesions in her ribs, thoracic vertebra, and pelvic bones. Dr Joseph noted this to be a patient presenting with symptomatic, newly diagnosed multiple myeloma (NDMM), and she had clinical features of hypercalcemia, anemia, lytic bone disease, and renal dysfunction. She suggested that this is a patient suitable for a stem cell transplant because of her age, good functional status, and limited comorbid conditions.
Dr Joseph outlined the typical treatment strategy for a transplant eligible NDMM patient such as this, which involves the use of between 4 and 6 cycles of cytotoxic induction therapy, followed by an autologous stem cell transplant (ASCT), and then maintenance therapy until disease progression. Dr Joseph noted “the first remission is really our opportunity for the longest [remission]”, and as such, the overall goal of this intensive treatment is to induce as long of an initial progression free survival period as possible (termed a ‘PFS1’), while at the same time limiting the overall toxicity for the patient (Box 2). Dr Joseph noted that, while there are now many drugs available for multiple myeloma, the optimal initial treatment for this patient would be one that induces a “deep response” in the patient, and limits any overlapping toxicities of the drug regimen used.
Dr Joseph explained that the standard of care (SOC) regimen, had historically been a triple regimen of ‘RVd’ (for Revlimid [lenalidomide], Velcade [bortezomib], and dexamethasone), which in one study, was associated with an impressive median OS of 11 years across the entire cohort of MM patients. More recently, a 4-drug ‘quad’-regimen, consisting of an anti-CD-38 monoclonal antibody (Daratumumab) + RVd regimen (D-RVd) was compared with the triple RVd regimen in the Phase II GRIFFIN study. The results of this trial showed deep patient responses over time, with a difference of 64% versus 30% at the end of study for patients in the D-RVd and RVd groups, respectively, and a 4-year PFS rate of 87.2% and 70.0%, respectively (hazard ratio [HR]=0.45; P=0.032), corresponding to a 55% reduction in the risk for progression or death with the D-RVd regimen.
Returning to the case, Dr Joseph suggested that the optimal induction regimen for the patient would be D-RVd, based on the GRIFFIN results, and that this has become SOC at her center, particularly for standard-risk NDMM patients. She noted that this patient received D-VRd for 4 cycles and achieved a complete response, after which she underwent ASCT, with a complete response, and she has continued on maintenance lenalidomide to date, with good disease control.
The panelists then discussed some key supportive care issues in treatment with this patient, which relate in part to a depletion of the patient’s B-cell response, which becomes markedly reduced following anti-CD38 therapy with daratumumab. Preventive measures therefore include infection prophylaxis (e.g., herpes/varicella zoster prophylaxis), venous thromboembolism prophylaxis (due to lenalidomide use), use of bone modulating agents (zoledronic acid or denosumab), and pain control while on therapy. The panelists also reviewed their key considerations for transplant eligibility, which include younger age, fitness (“if you can walk a mile a day… that’s good”), organ function (kidney, heart, lungs, etc.), as well as availability of social support once they get home from ASCT. In addition, although D-RVd is preferred regimen, the choice of induction regimen may also be impacted by clinical factors of the patient (e.g., renal function and comorbid conditions). The panelists also reviewed some of the key considerations for dosing of the drugs in the quad regimen, with modifications in dosing for specific drug-related adverse events, such as peripheral neuropathy events associated with bortezomib.
Box 2: Newly Diagnosed Multiple Myeloma (NDMM) – Optimal Induction Regimens
Principles of NDMM Treatment
NDMM Induction Regimens
Case 3: Treatment Refractory Myeloma
The third case featured a 64 year old male patient with a history of relapsed/refractory multiple myeloma (RRMM) and the panelists briefly highlighted data for novel treatment options in such patients. Dr Joseph noted there have been a number of new therapies approved for RRMM over the past 3 years, with many more agents in clinical trials, but the primary agents in this regard include chimeric antigen receptor (CAR)-T Cells, and bispecific T-cell engager (BiTE) therapies, which help to target cancer cells for immune-mediated destruction (Box 3).
Teclistamab was the first-in-class BiTE therapy to be approved in October of 2022, with an overall response rate (ORR) of 63.0%, as seen in the MajestTEC-1 trial. Notably, the vast majority of these responses were deemed as very good partial responses (“VGPR”) or better, which represents a substantive benefit for patients with highly refractory (triple drug class exposed) disease. Elranatamab, a second BiTE approved in mid-2023 based on results from the MagnetisMM-3 trial, achieved a similar ORR of 61% overall, with 56.1% achieving a VGPR or better response. Notably, even patients with more advanced stage and penta-refractory disease achieved impressive rates of response in the trial. Talquetamab, another first-in-class BiTE with a different target molecule, also showed impressive rates of response of over 70% in the MonumenTAL-1 trial, with an ORR of 64.7% even for patients with prior exposure to T-cell redirecting therapies (either CAR-T cells or BiTE therapy). CAR-T cell therapies have been available since 2021 and include Idecabtagene vicleucel (Ide-cel) and Ciltacabtagene autoleucel (Cilta-cel). These agents have shown ORRs of 73% for Ide-cel and 97.9% for Cilta-cel, with a PFS of 12 months and 34.9 months, respectively. While the panelists note that these two therapies have not been directly compared in a trial, they describe the efficacy of these agents, particularly with Cilta-cel, as unprecedented in the highly pre-treated RRMM setting.
The panelists briefly reviewed the major toxicities of these newer agents, particularly cytokine release syndrome, or CRS, which may manifest as fever, hypotension, and multi-organ failure. CRS can occur in 84-95% of patients on CAR-T therapies (with 4-5% severe) and 58-77% of patients on BiTE therapy (with 1-2% severe), and management is typically anti-cytokine therapies like tocilizumab, dexamethasone, and supportive care measures. A second event which may occur is neurotoxicity, which may manifest with symptoms such as headache, encephalopathy, seizures and tremors. This event can occur in 18-21% of patients on CAR-T therapies (with 3-9% severe) and 10-15% of patients on BiTE therapy (with <1% severe), and management is typically with neurologic assessment, anti-seizure prophylaxis, steroids, as well as tocilizumab if occurring concomitantly with CRS. Lastly, some of the lingering issues with novel agents in RRMM which the panel noted were how best to sequence these in patients with refractory disease, issues with accessibility for CAR-T cell therapy, and a need for effective bridging therapy (i.e., to keep patient’s disease under control while CAR-T therapies are in preparation).
Box 3: Relapsed/Refractory Multiple Myeloma (RRMM) – Novel Treatments
Chimeric Antigen Receptor (CAR) T Cells
Bispecific T-Cell Engagers (BiTE)
Idecabtagene vicleucel (Ide-cel)
Ciltacabtagene autoleucel (Cilta-cel)
Speaker Disclosure Information: Dr Nisha S. Joseph lists the following disclosures for this presentation: Research Funding: Novartis, Bristol Meyers Squibb, AstraZeneca, Janssen Oncology. Consultancy: Bristol Meyers Squibb, Janssen Oncology.
You can see the full panel discussion from the Total Health 2023 Community Cases Atlanta Conference here: