1
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.
In this letter, the Thames Valley Cancer Alliance (TVCA) Myeloma 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.
Table 1
Myeloma treatment adaptations in the UK during COVID‐19, challenges to myeloma outcomes
and the measurable outcomes
Myeloma setting
Standard of care
Proposed changes during COVID‐19
Challenges for disease management
Measurable outcomes
TE NDMM
SLiM‐CRAB criteria
Bortezomib‐based
(VCD or VTD)
LenDex
a
as an oral option, or
Bortezomib‐based
b
Effect on depth or duration of response
Bone marrow suppression with LenDex
d
Unknown interaction between SARS‐Cov‐2 and IMiDs
SARS‐CoV‐2 infection incidence rate
Outcome of infection (mild/severe/recovery/death)
Incidence of other infections
Viral infection rates (PIs vs. other Tx)
Rates of deviation from standard of care
ORR, disease progression
Influence of deviation from standard of care on QoL
TNE NDMM
SLiM‐CRAB criteria
Bortezomib‐based (VCD or VMP), or LenDex
Oral option: LenDex
NDMM
SLiM‐only criteria
Bortezomib‐based or LenDex
Watch and wait
b
Risk of end organ damage
Risk of increased disease burden
1st relapse
DVd, or
CarDex, or
LenDex
Oral option
b
: Len‐based, or
PomDex (if received prior Len)
a
Effect on depth or duration of response
Bone marrow suppression with IMiDs
2nd relapse
IxaLenDex
IxaLenDex, or
PomDex (if received prior Len)
a
Effect on depth or duration of response with doublet PomDex compared to triplet IxaLenDex
Bone protection
Monthly IV bisphosphonates for up to 2 years
3‐monthly bisphosphonates in responding NDMM patients
Risk of future skeletal‐related events (SRE)
Incidence of SRE according to strategy (monthly zoledronic acid vs. other)
Biochemical relapse
Consider treatment if >25% increase in paraprotein/ serum FLC
Watch and wait, unless SLiM‐CRAB
b
Risk of end organ damage
Risk of increased disease burden
Rates of disease progression
ASCT
TE NDMM in first remission or selected relapsed MM patients
High dose cyclophosphamide priming
Deferral of ASCT
b
, unless high‐risk patient
c
Filgrastim‐only stem cell collection +/− plerixafor
b
Risk of disease progression
Missing the optimal window for ASCT
Risk of change in the rate of successful collection with filgrastim‐only
Need for hospital visits if plerixafor is required
Rates of ASCT deferrals
Outcomes of deferrals or delay (remission/progression)
Overall success rate of stem cell collection with filgrastim‐only
Plerixafor use rate during collection
Rate of successful collection depending on the choice of induction therapy
AL amyloidosis
VCD 1st‐line therapy
Deferral of treatment if limited organ involvement.
Oral options preferred (CTD, or MelDex, and the use of PO ixazomib instead of SC bortezomib
if possible)e
Risk of ongoing amyloid deposition
Risk of organ failure
Risk of sub‐optimal amyloid response to 1st‐line oral therapy or to treatment attenuation
ORR
Rate of progression or death
Organ failure
Rate of ASCT deferrals
Abbreviations: ASCT, autologous stem cell transplant; CarDex, carfilzomib with dexamethasone;
CTD, cyclophosphamide with thalidomide and dexamethasone; DVd, daratumumab with bortezomib
and dexamethasone; IMiD, immunomodulatory drug; IV, intravenous; IxaLenDex, ixazomib
with lenalidomide and dexamethasone; LenDex, lenalidomide with dexamethasone; MelDex,
melphalan with dexamethasone; ; NDMM, newly diagnosed multiple myeloma; ORR, overall
response rate; PI, proteasome inhibitor; PO, oral; PomDex, pomalidomide and dexamethasone;
QoL, quality of life; RMM, relapsed multiple myeloma; SC, subcutaneous; serum FLCs,
serum free light chains; SLiM‐only and SLiM‐CRAB, criteria for the diagnosis of myeloma;
TE, transplant eligible; TNE, transplant non‐eligible; Tx, treatment; VCD, bortezomib
with cyclophosphamide and dexamethasone; VMP, bortezomib with melphalan and prednisolone;
VTD, bortezomib with thalidomide and dexamethasone.
a
Funded by NHS England during COVID‐19 pandemic;
b
As advised by (
5
);
c
High risk: includes adverse cytogenetics or patients presenting with clinically aggressive
disease, plasma cell leukaemia or extra‐medullary disease;
d
(
20
). e(18)
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
re-use and analysis in any form or by any means with acknowledgement of the original
source, for the duration of the public health emergency.
2
THE NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM) SETTING
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.
In either setting (TE or TNE), the set‐up of a home self‐administration option for
eligible patients can enable the delivery of bortezomib‐based regimen (if more appropriate
than oral therapies) whilst reducing hospital attendance.
Remote regular monitoring is recommended to manage new myeloma diagnoses presenting
with the SLiM‐only part of the SLiM‐CRAB criteria.
5
However, without systemic therapy, there is a risk of end organ damage during monitoring.
3
STEM CELL COLLECTION
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.
4
THE RELAPSED MULTIPLE MYELOMA (RMM) SETTING
Daratumumab with bortezomib and dexamethasone (DVd) is widely used as a first relapse
therapy in the UK. Oral doublet options LenDex, or pomalidomide with dexamethasone
(PomDex, which is recently funded by NHSE as an interim measure during the pandemic
for patients previously treated with lenalidomide),
12
may be less efficacious than standard of care triplet DVd.
A network meta‐analysis across the whole relapsed population demonstrated that daratumumab‐based
triplets DVd and DRd (daratumumab with lenalidomide and dexamethasone; not currently
approved in the UK) had a higher probability of providing the longest progression‐free
survival (PFS) than their respective comparators, in patients who received only 1
prior therapy.
15
With the recent approval of subcutaneous (SC) daratumumab by the European Medicines
Agency,
16
which has since also been approved for funding by NHSE under the Cancer Drugs Fund
(CDF), it may be possible in the future to deliver the triplet combination DVd at
home to eligible patients in subsequent cycles, if a home administration service is
set up, provided that patients did not experience infusion‐related reactions during
their first few doses of SC daratumumab. It would be challenging for patients to self‐administer
SC daratumumab given that the final volume of the syringe is 15mls, but support from
the community nursing home administration team can help overcome this challenge.
For patients treated with carfilzomib plus dexamethasone (CarDex) at first relapse
and are tolerating it well, reducing dose intensity from twice‐weekly to once‐weekly
prior to achieving a significant response will reduce hospital visits, but could result
in a reduced depth of response.
17
The all‐oral triplet ixazomib with lenalidomide and dexamethasone (IxaLenDex) remains
the UK's established treatment option of choice at 2nd relapse in preference to doublet
PomDex (recently funded by NHSE in this setting as an interim measure during the pandemic,
for patients previously treated with lenalidomide), because there are no head to head
trial data comparing these two options .
Patient fitness or frailty, disease presentation and the history of prior therapies,
which all determined the aims of myeloma care prior to the pandemic, should continue
to be the basis for treatment decisions during the pandemic whilst taking proactive
steps to reduce the risk of COVID‐19 transmission. Treatment modifications as suggested
by expert bodies should be employed according to clinical judgement in individual
circumstances.
5
AUTOLOGOUS STEM CELL TRANSPLANT
Unless myeloma has a higher risk of progression post‐induction therapy such as adverse
cytogenetics, or has a clinically aggressive presentation (eg plasma cell leukaemia
or extra‐medullary disease), an MDT decision based on risk versus benefit can be made
to defer autologous stem cell transplant (ASCT) if possible,
5
,
6
,
8
and best haematological response 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
6
AL AMYLOIDOSIS PATIENTS
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‐by‐case 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.
7
SUPPORTIVE CARE
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.
Monthly SC denosumab is an alternative strategy. However, it is not currently approved
in the UK to treat myeloma patients. When it becomes available, it can prevent hospital
visits if home administration facilities are available or where patients are educated
about self‐administration.
9
8
AUDITABLE OUTCOMES
The measurable outcomes of the proposed changes in each PCD setting are described
in the Table 1. In addition to COVID‐19 outcomes, it would be important to establish
the extent to which a myeloma patient receiving treatment responds differently to
this viral infection compared to a myeloma patient off treatment, or to someone without
myeloma. So far, the largest cohort study of cancer patients diagnosed with symptomatic
COVID‐19 published in Lancet did not identify any evidence that cancer patients on
cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality
from COVID‐19 disease compared with those not on active treatment.
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.
9
FUTURE QUESTIONS
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.
CONFLICTS OF INTEREST
None.
AUTHOR CONTRIBUTIONS
FD and KR conceived the article. FD wrote the manuscript, which all authors contributed
to, critically reviewed and approved.