Blood cancers

Management of patients with multiple myeloma at Janssen H3 2021

Wednesday, 25 Aug 2021


The Janssen H3 medical education meeting on haematological malignancies was held on 8 May 2021, both virtually and live across six locations in Australia and New Zealand. Chaired by Dr Wojt Janowski of the Calvary Mater in Newcastle, NSW, the fourth session of this meeting opened with a presentation on the treatment of newly diagnosed multiple myeloma from Professor Hang Quach, Director of Clinical Haematology and Clinical Haematology Research at St. Vincent’s Hospital, and Consultant Clinical and Laboratory Haematologist at St. Vincent’s and Epworth Hospitals in Melbourne. Joining the discussion was Professor Andrew Spencer, Head of the Malignant Haematology and Stem Cell Transplantation Service at The Alfred Hospital, Professor of Haematology at Monash University, Head of the Myeloma Research Group and Co-Director of the ACRF Blood Cancer Therapeutics Centre at the Australian Centre for Blood Diseases in Melbourne.

International guest speaker Professor Wee Joo Chng followed with a presentation on the management of multiple myeloma in the relapsed/refractory setting. Professor Chng is the Director of the National University Cancer Institute at the National University Health System in Singapore as well as Group Director of Research Office at the National University Health System, Vice-Dean of Research at the Yong Loo Lin School of Medicine, and the Deputy Director and a Senior Principal Investigator at the Cancer Science Institute of Singapore and the National University of Singapore.

Practical considerations on the use of VRd in newly diagnosed multiple myeloma

Professor Quach began her session with a comment on the “blessing that bortezomib, lenalidomide and dexamethasone [VRd] is now available on the Pharmaceutical Benefits Scheme [PBS] for the upfront treatment of multiple myeloma.” She then gave context for her presentation, stating “a good tool is only ever as good as the user… so it’s important to have this discussion of how to best use VRd for optimal outcomes in patients.”

In transplant eligible patients, the evidence for the use of VRd arises indirectly from two clinical trials, the IFM 2009 and PETHEMA/GEM2012 studies.1,2

Both treatment schedules are shown in Table 1, with Professor Quach noting that “for induction and consolidation, the PETHEMA schedule has 60% more bortezomib and 140% more lenalidomide than the IFM2009 schedule.

Table 1. VRd schedule options in transplant eligible patients

IFM 2009 study schedule PETHEMA/GEM2012 study schedule
3 x VRd –  PBSC collection ASCT – 2 x VRd – R maintenance PBSC collection Post 3, 6 x VRd – ASCT – 2 x VRd – R maintenance
21-day VRd cycle:

  • Bortezomib 1.3mg/m2 IV Days 1, 4, 8, 11
  • Lenalidomide 25 mg PO Days 1–14
  • Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12
28-day VRd cycle:

  • Bortezomib 1.3mg/m2 SC Days 1, 4, 8, 11
  • Lenalidomide 25 mg PO Days 1–21
  • Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12
R maintenance:

  • 12x 28-day cycle
  • Lenalidomide 10 mg (15mg if tolerated from cycle 4) PO Days 1–28
  • PO: by mouth. IV: intravenous.

The challenge for practice is that each trial utilises VRd in a different schedule and for a different number of cycles, leading to variation when the data is translated into the clinic.

The situation is similar for treatment decision making in transplant ineligible patients, with indirect evidence from the SWOGS0777 study of transplant-delayed patients applied to the treatment of transplant ineligible patients.3 As Professor Quach notes, “the optimum schedule of VRd has yet to be explored properly in transplant-ineligible patients”.

Is more better than less?

Professor Quach showed how, despite the different number of VRd cycles, the rate and depth of response was comparable between the two schedules.2,4 With the IFM2009 schedule, best overall response rate was 99%, with a complete response of 59%, whilst the PETHEMA/GEN2012 schedule produced, after consolidation, an overall response rate of 80.5% and a complete response of 50.2%.2,4 Professor Quach noted that “more is not necessarily better.

Where does this leave clinical decision making? Professor Quach recommended consideration of toxicity as well as the capacity for stem cell collection in individuals, factors that “weigh heavily on top of the need to induce a deep response.” She highlighted the potential impact of schedule selection with data on the incidence of grade 3 or 4 peripheral neuropathy,  occurring in around 12% of patients on the 21-day schedule, but only 4% in the 28-day schedule.1,2

Looking at the data in terms of consolidation, Professor Quach expressed the view that “VRd consolidation probably benefits best those who have had inadequate or sub-optimal induction, but its role is questionable in patients who have had adequate and effective induction therapy.”

 Myeloma Australia’s Medical and Scientific Advisory Group updated recommendations

Professor Quach concluded with a presentation on the updated recommendations from Myeloma Australia’s Medical and Scientific Advisory Group (MSAG), shown in table 2.5

Table 2. MSAG recommendation update for VRd as initial treatment of multiple myeloma.5

Transplant eligible patients Transplant ineligible patients
 

  • Autologous stem cell transplant (ASCT) as part of initial treatment remains the standard of care
  • It is not unreasonable for clinicians to adapt a VRd schedule with upfront ASCT to maximise the use of what is available on the PBS to optimise patients’ outcomes – provided there is no unacceptable treatment-emergent toxicity
  • Subcutaneous administration of bortezomib is preferred over IV to minimise peripheral neuropathy
  • It utilising a twice-weekly schedule of bortezomib, vigilance in monitoring for peripheral neuropathy occurring precipitously post-ASCT is required
  • Alternatively, a weekly schedule of bortezomib may be adapted at the outset
  • In elderly patients, minimisation of treatment-related toxicities will improve duration of treatment and correlate with improved survival
    • Frailty assessment is recommended to help choose appropriate induction regimen
  • Current accepted standard of care includes:
    • Enrolment into clinical study if available
    • Continuous lenalidomide and dexamethasone
    • VRd if the patient is deemed fit for twice-weekly bortezomib as per SWOGS0777 study, consider ASCT upfront
    • For frail, elderly patients with renal impairment, doublet bortezomib and dexamethasone may be considered

 

Mobilisation and stem cell transplantation in patients with newly diagnosed multiple myeloma

Professor Spencer opened his presentation with a question – “Is autografting still relevant and do we need to transplant anymore?” Based on the evidence, he concluded that it appears that there is a substantial overall survival benefit, which “tells us that if you can deliver a transplant, you should, and the notion of deferring or ‘umming and ahhing’ should be put to bed, due to the combination of clinical trial data and real world evidence.1

Prof Spencer went on to describe the evidence for differences in cell yields and clinical outcomes when cells are collected via granulocyte colony-stimulating factor (GCSF) in combination with cyclophosphamide, versus GCSF alone. Rees et al. studied patients who had all been treated uniformly at induction (with VRd), and showed that higher CD34 yields can be induced with GCSF + cyclophosphamide, but that the rates of febrile neutropenia and hospitalisations were also higher with this regime. With GCSF alone, peripheral blood stem cell (PBSC) lymphocyte content is higher, with more rapid lymphocyte recovery.6 Professor Spencer noted, “This may actually be very important, particularly when we may be using immune therapies in the context of a prior autograft.”

Exposure to lenalidomide prior to stem cell collection has been shown to be detrimental, with patients requiring more collections, with lower cell yields.7 Presenting data from his own clinic, Prof Spencer described his use of plerixafor to increase the CD34 count. Patients are given GCSF 10µg/kg twice a day, and if peripheral blood CD34 has reached 5–20/µL when measured at day 5, plerixafor is given (maximum 2 doses) and stem cells collected from day 6 onwards. This regime has resulted in more CD34 cells per collection.

Allogeneic transplantation in myeloma – a good idea?

Professor Spencer acknowledged that this topic is“highly contentious and can almost bring haematologists to blows.” He emphasised that “if you’re going to look at allografting in myeloma, you need to look at data long-term.”

Highlighting an Italian study comparing overall survival from time of relapse in patients who received an allograft versus patients who received an autograft8 Prof Spencer noted the significant difference in overall survival for patients who received an allograft, due to the fact that these patients are more salvageable than those who have had an autograph. In fact, he said, “We’ve seen patients who are refractory to a drug, but subsequent to an allograft will then achieve a response to that drug.” This is supported by a 2020 study (Costa et al.), demonstrating improved salvageability with allografting versus autografting.9

Prof Spencer summarised suitable patient criteria for allografting:

  • Frontline disease with two or more high risk features
  • Relapsed disease
  • Biological adversity – a fraction of patients won’t need more than 2 years treatment with currently available therapies
  • Negative measurable residual disease (MRD) – the longer patients remain MRD negative, the greater the likelihood of progression-free survival

Professor Spencer concluded with a final thought on allogeneic transplantation in myeloma – “It is a blunt instrument and I’m hoping it won’t have a role in the next two to three years as we get better immunotherapies. Nevertheless, it can change the natural history in some patients.”

Treatment of multiple myeloma at first relapse

Professor Chng rounded out the fourth session of the meeting with a discussion of treatment choice in patients after their first relapse. He offered the following advice:

  • Switch class of drug if that is an option
  • Triplet therapy is preferred over doublet therapy – doublet therapy is reserved mainly for elderly patients with trouble tolerating triplet combinations
  • For slower biochemical relapse, consider less potent, fast acting oral combinations – beware the cost of newer therapies
  • For patients with more aggressive relapse or high risk features, consider carfilzomib-based or daratumumab-based combinations
  • In patients with predominantly extramedullary disease and relapse, or in younger patients, consider chemotherapy-based salvage such as DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)
  • High risk patients (e.g., del17p or p53 mutations, with extramedullary disease, patients with renal failure or circulating plasma cells) may benefit from allogeneic transplant.

He concluded the session by noting the areas where more research is needed. These include high risk myeloma patients, patients who are refractory to daratumumab, the future role venetoclax will play in the early treatment setting (i.e., following first relapse), and when and how chimeric antigen receptor (CAR) T-cell and Bispecific T-Cell Engager (BiTE)s therapies will fit into the picture in the years to come.

 

Summary

The fourth session of the Janssen H3 medical education meeting on haematological malignancies focussed on multiple myeloma. Professor Quach provided an explanation of the main schedules for VRd and advised that their use be guided by consideration of toxicities and their impact on individual patients.

In his presentation on transplantation, Professor Spencer described how to optimise CD34 cell collection with the addition of plerixafor after GCSF, and contextualised the use of allogeneic stem cell transplant in myeloma. He concluded with the hope that as more immunotherapies come available, allogeneic transplant can be phased out as a treatment option.

Professor Chng ended the session with a brief overview of the treatment options post-first relapse in multiple myeloma, offering advice on treatment strategies for different patient groups.

 

References:

  1. Attal et al. N Engl J Med 2017;376(14):1311-1320.
  2. Rosinol et al. Blood 2019;134(16):1337-1345.
  3. Durie et al. Lancet 2017;389(10068):519-527.
  4. Perrot A, et al. ASH 2020; Abstract #143.
  5. Quach H and Prince HM on behalf of MSAG, Bortezomib, lenalidomide and dexamethasone (VRd) for initial treatment of multiple myeloma, 2020. Available from: https://myeloma.org.au/wp-content/uploads/2020/09/MSAG_clinical_practice_update_JUL20_final.pdf (accessed May 2021).
  6. Rees MJ, et al. Bone Marrow Transplant 2021; online ahead of print. DOI: 10.1038/s41409-021-01300-2.
  7. Kumar S, et al. Leukemia 2007;21:2035-2042.
  8. Giaccone L, et al. Blood 2011;117:6721-6727.
  9. Costa LJ, et al. Bone Marrow Transplant 2020;55:1810-1816.

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