key: cord-0940533-fz9dl12l
authors: Djebbari, Faouzi; Panitsas, Fotios; Sharpley, Faye A.; Rampotas, Alexandros; Larham, Jemma; Moore, Sally; Gooding, Sarah; Kothari, Jaimal; Ramasamy, Karthik
title: Myeloma care adaptations in the UK during SARS‐CoV‐2 pandemic: Challenges and measurable outcomes
date: 2020-07-15
journal: Eur J Haematol
DOI: 10.1111/ejh.13479
sha: d9ef2feb54163556f54b8e2e0910dc38e4b9bf10
doc_id: 940533
cord_uid: fz9dl12l

Following the emergence of COVID-19 as a global pandemic, cancer clinicians have been faced with the challenge of continuing to manage patients, with limited data to inform practice (Poortmans et al 2020). Recently, a large prospective cohort study of 800 cancer patients diagnosed with symptomatic COVID-19 demonstrated a mortality rate of 28%, which was largely driven by age, co-morbidities and being a male (Lee et al 2020).

To the Editor, Following the emergence of COVID-19 as a global pandemic, cancer clinicians have been faced with the challenge of continuing to manage patients, with limited data to inform practice. 1 Recently, a largeprospective cohort study of 800 cancer patients diagnosed with symptomatic COVID-19 demonstrated a mortality rate of 28%, which was largely driven by age, co-morbidities and being a male. 2 Patients with plasma cell dyscrasias (PCD), in particular, are known to be at a high risk of infections, in part due to immunoparesis and immunosuppressive therapy. Old age, frailty and co-morbidities add to the complexity of patient management. COVID-19 poses a significant new threat to their health and wellbeing. There is currently little evidence to suggest how myeloma patients will respond to this infection. The UK government recommended that myeloma patients shield for an initial 12-week period, because they fall in the extremely vulnerable group. 3 A UK retrospective real-world audit of 75 myeloma patients with symptomatic COVID-19 demonstrated a high mortality rate especially in patients aged >80 years. 4 At the start of the pandemic, leading professional organisations in malignant haematology have issued key general principles about the management of myeloma patients during the pandemic. [5] [6] [7] [8] Decisions on therapeutic approaches are being made by the multidisciplinary teams (MDTs) on a case-by-case basis, taking into consideration myeloma disease stage, frontline versus relapse, cytogenetics/FISH, age and co-morbidities. 6, 8 All interventions aim to minimise the risk of COVID-19 by reducing hospital visits as well as tailoring immunosuppressive therapy. More recently, the European Myeloma Network published a consensus paper on the management of myeloma during the pandemic. 9

The new norm consists of limiting patients' physical contact with the hospital, conducting telephone consultations and/or virtual visits and using oral therapies wherever possible. 10 However, a number of these proposed changes deviate from the accepted standards of care, which have been built on successive randomised trials. For instance, the UK's National Institute for Health and Care Excellence (NICE) issued a guideline on the delivery of cancer therapies during the pandemic, which includes treatment breaks (possibly for longer than 6 weeks). 11 This enables us, for example, to temporarily withhold treatments for standard-risk myeloma patients who achieved a significant response (≥VGPR: very good partial response) with monitoring and to restart treatment in due course.

A number of indications for oral myeloma therapies have also been funded by NHS England (NHSE) as an interim measure during the pandemic. 12 The final decisions on the choice of therapy (parenteral versus oral), treatment breaks, reduced dose intensity or transplant remain at the discretion of the treating clinician.

We support the significant efforts made to date to limit the spread of this disease and to reduce its impact on myeloma patients, and we hope that all these interventions will help to reduce the risk of transmission. However, we have a limited understanding of how these changes will influence clinical outcomes for PCD patients. Moreover, the decision about the best therapy choice during the pandemic in any myeloma setting is also dependent on drug availabilities, which are different in the UK to other countries.

Group examine the challenges to optimal myeloma outcomes, which may be associated with these new COVID-related adaptations of care in UK routine care, and how clinical outcomes could be measured in the months to come, which we summarise in the accompanying Table 1 .

Patients fulfilling the CRAB criteria should be offered treatment without delay. 5 In the UK, transplant-eligible (TE) NDMM patients typically receive proteasome inhibitor (PI) bortezomib with cyclophosphamide and dexamethasone (VCD) or bortezomib with thalidomide and dexamethasone (VTD) preferably weekly for 6 cycles until a deep response is achieved. 5 Oral immunomodulatory drug (IMiD) lenalidomide in combination with dexamethasone (LenDex) was recently funded by NHSE as an interim measure for use during the pandemic. 12 However, the LenDex doublet combination may potentially be a less preferable induction therapy option compared to bortezomib triplets, particularly in high-risk disease. Although, two previously published studies described certain cytogenetic abnormalities, and immunohistochemical features associated with a poor myeloma response to bortezomib. 13, 14 Oral LenDex remains an established treatment option in the UK in the transplant-non-eligible (TNE) NDMM setting. 

If stem cell harvest cannot be delayed, it should be performed at the end of induction, 5, 9 or after 4 cycles in the case of LenDex, whilst transplant decision is reviewed by the MDT. The filgrastim-only priming strategy can be employed during the pandemic in order to reduce the risk of immunosuppression associated with high dose cyclophosphamide. 5, 9 However, the use of salvage plerixafor may be needed in some cases, 5, 9 which, in turn, will require hospital visits. 

Unless myeloma has a higher risk of progression post-induction therapy such as adverse cytogenetics, or has a clinically aggressive presentation should be maintained with the continuation of induction therapy, or maintenance lenalidomide. 8 The challenges here include the risk of progressive disease and/or loss of the optimal time window for ASCT.

If an MDT decision is made to proceed with ASCT, exclusion of COVID-19 infection by PCR for SARS-CoV-2 is required, along with strict precautions to prevent COVID-19 transmission. 9

The decision to initiate therapy should be made by the MDT on case-by-case basis, assessing the extent and severity of organ involvement, and balancing risk vs. benefit of deferring treatment. 18 If treatment is required, the International Society of Amyloidosis (ISA) recommends to reduce steroid dose, and to use oral chemotherapy combinations wherever possible such as melphalan with dexamethasone (MelDex), cyclophosphamide with thalidomide and dexamethasone (CTD), in addition to switching from SC bortezomib to oral ixazomib if possible. 18 ASCT can be deferred following a case-bycase MDT discussion, if a deep haematological response is reached with stem cell-sparing chemotherapy. 18 The risks associated with these strategies in amyloidosis management are ongoing amyloid deposition with the risk of progressive organ failure, 19 in addition to the risk of sub-optimal response to oral treatment options or to dose attenuation.

The optimal uses of prophylactic antivirals, pneumocystis jirovecii (PCP) prophylaxis, antibacterial prophylaxis with levofloxacin (for 12 weeks in NDMM) and anti-thrombotic agents (with IMiDs) are recommended during the pandemic, in addition to prophylactic filgrastim in patients with a history of recurrent neutropenia, and erythropoiesis-stimulating agents in anaemic patients in order to prevent the need for blood transfusions and the associated hospital visits. 5, 9 Frequency reduction of bisphosphonates (eg, zoledronic) from monthly to 3 monthly 5,9 especially in NDMM patients who achieved a significant myeloma response, will reduce hospital visits and the associated risk of COVID-19 transmission. However, this strategy may not provide patients with optimal protection from future skeletal-related events (SREs) compared to those who received monthly antiresorptive therapy for a minimum of 2 years. 2 We can also investigate whether there is a proven association between the use of PIs and increased risk of viral infections, which was an initial concern at the start of the pandemic.

In the context of deviations from standard of care during the pandemic, disease-related outcomes for PCD patients should be compared to data about standards of care reported in clinical trials or similar real-world studies. It would also be useful to assess the impact of reduced dose intensity, therapy suspension, and SREs following frequency reduction of bisphosphonates.

As an exploratory outcome, we could investigate whether the COVID-19 pandemic benefited myeloma patients in any way, such as individualising myeloma care whilst maintaining optimal clinical outcomes. This pandemic placed healthcare care resources under significant strain, but it would also be important to evaluate the extent of improvements in the delivery of myeloma care, and the resultant impact on patients' quality of life, from measures such as home or self-administration of injectable therapies.

The COVID-19 pandemic is proving to be a period of great uncertainty and PCD patients require close monitoring to study outcomes of COVID-19-related treatment adaptations. Deviation from standard of care for these patients is not a long-term sustainable strategy.

It is unclear how to deal with PCD patients recovering from COVID-19 particularly optimal timing to resume treatment, and the choice of treatment. Issues of prolonged viral shedding as reported with other respiratory viruses, risk of further transmission in healthcare facilities and durability of COVID-19 immunity in patients with immunoparesis require prospective evaluation. Patient-reported outcome measures (PROMs) during the outbreak and the effect of the pandemic on myeloma trial participation also warrant investigation.

COVID-19, infection, myeloma, outcome, SARS-CoV-2, therapy

None.

Cancer and COVID-19: what do we really know?

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study

Guidance on shielding and protecting people who are clinically extremely vulnerable from COVID-19

Real-world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID-19 disease) in patients with multiple myeloma receiving systemic anti-cancer therapy

UK Myeloma Forum guidance to support medical decision-making in the management of myeloma patients during the COVID-19 (Coronavirus) outbreak. 2020

ESMO management and treatment adapted recommendations in the COVID-19 era: Multiple myeloma

European Society for Blood and Marrow Transplantation (EBMT)

International Myeloma Society Recommendations for the Management of Myeloma Patients During the COVID-19 Pandemic

Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN)

Care of haematology patients in a COVID-19 epidemic

COVID-19 rapid guideline: delivery of systemic anticancer treatments

Interim treatment change options during the COVID-19 pandemic, endorsed by NHS England

Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value

Clinical and immunohistochemical features associated with a response to bortezomib in patients with multiple myeloma

Comparative efficacy of treatments for previously treated multiple myeloma: a systematic literature review and network meta-analysis

Summary of Products Characteristics. DARZALEX 1,800 mg solution for injection

Carfilzomib therapy for relapsed myeloma: results of a UK multicentre experience

International Society of Amyloidosis. International Society of Amyloidosis recommendations on the management of patients with systemic amyloidosis during the COVID-19 pandemic

Update on diagnosis, prognosis, and treatment

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma