Case 137 – Summary

Thank you for your help in the management of our 53 year old man who presented with all of the CRAB constellation of symptoms of multiple myeloma (hypercalcaemia, renal impairment, anaemia and lytic bone lesions).

We talked a bit about hypercalcaemia where other more common causes include hyperparathyroidism and malignancy of the breast, lung, oesophageal, head and neck, skin, cervix, breast, kidney, and bladder. It can lead to problems including fatigue, confusion, memory problems, depression, nausea, vomiting, abdominal pain, weight loss, thirst, polyuria, constipation, abdominal pain and renal colic, or renal impairment.  It can also lead to a shortened QT interval; prolonged PR interval and cardiac arrhythmias such as ventricular fibrillation which is why if a patient has severe hypercalcaemia of unknown cause (>=3.4mmol/L), emergency hospital admission for management of this should be arranged.

We have already discussed myeloma in previous cases but as myeloma represents approximately 10% of haematological malignancies and patients may remain under follow up for a long period of time, it is always good to revisit. This case went on to develop therapy related MDS which is a very rare complication of treatment. 

Almost all cases of myeloma evolve from MGUS (monoclonal gammopathy of undetermined significance) which progresses to malignancy at approximately 1% per year, depending on the size and type of the paraprotein as well as underlying cytogenetics.

Paraprotein and serum free light chains are used to help diagnose myeloma and to monitor response to treatment, usually monthly during treatment and 3-4 monthly when not on treatment. Approximately 2% of patients have non-secretory disease with no measurable paraprotein or abnormal serum free light chain. 

Diagnosis:

  1. >= 10% clonal plasma cells in bone marrow or plasmacytoma proven on biopsy

+>=1 of the following

  1. Any of the CRAB criteria thought likely related to the plasma cell disorder
  2. bone marrow clonal plasma cells >=60%
  3. SFLC ratio >=100 but involved FLC>=100mg/L
  4. >1 focal lesion on MRI

Staging is with the Revised International Staging System R-ISS

Stage 1

All of:

  1. albumin >=35
  2. Beta 2 microglobulin <3.5
  3. No high risk cytogenetics: t(4;14), t(14;16), del(17p)
  4. Normal LDH

Stage 2

Not stage 1 or 3

Stage 3

  1. Beta 2 microglobulin >5.5

And 1 of

  1. High risk cytogenetics
  2. Raised LDH

Imaging

Low dose whole body CT, PET or MRI are best to detect bone disease

First line treatment for transplant eligible patient

VTD followed by autologous stem cell transplant is the current UK NICE recommendation

VRd followed by autologous stem cell transplant followed by lenalidamide or bortezomib based maintenance may be used elsewhere eg in the US

Supportive management includes aciclovir, co-trimoxazole, prophylactic antibiotics, VTE prophylaxis, zolendronic acid, pain management and input from the MDT, particularly the nurse specialists. 

The increase in therapy‐related MDS and AML in patients with myeloma has long been recognised and again more recently in patients on lenalidomide maintenance therapy, but the risk is low and the benefits outweigh the risk from myeloma by far.

Our patient developed pancytopenia several years after his autologous stem cell transplant and we undertook a bone marrow biopsy.  We looked at some morphological features of MDS in the bone marrow including abnormal myelopoiesis with pseudo Pelger-Huet neutrophils and hypogranular form, abnormal erythropoiesis with intercellular bridging and abnormally shaped nuclei and ringed sideroblasts.  This was in keeping with MDS with multi-lineage dysplasia and ring sideroblasts, but as he had previously had cytotoxic therapy, it was classified as therapy related MDS. 

Risk Stratification in MDS

IPSS‐R prognostic score values

Prognostic variable00·511·5234
CytogeneticsV Good
Good
IntermediatePoorV Poor
BM blast %≤2
>2–<5
5–10>10
Hb (g/l)≥100
80–<100<80


Plts  (×109/l)≥10050–<100<50



Neuts (×109/l)≥0·8<0·8

IPSS‐R cytogenetic prognostic subgroups

Very good−Y, del(11q)
GoodNormal, del(5q), del(12p), del(20q), double including del(5q)
Intermediatedel(7q), +8, +19, i(17q), any other single or double independent clones
Poor−7, inv(3)/t(3q), double including ‐7/del(7q), complex: 3 abnormalities
Very PoorComplex: >3 abnormalities

Therapy-related MDS is associated with higher risk cytogenetic abnormalities and a poorer prognosis. Our patient was young and fit and had mild anaemia and very poor risk cytogenetics giving him an IPSS-R of 5.  As he had high risk disease we discussed him at the MDT where the decision was made to aim for an allogeneic bone marrow transplant.

References

Rajkumar S, Multiple myeloma: 2020 update on diagnosis, risk-stratification and management, American Journal of Haematology, 2020;95:548–567.

NICE Clinical Knowledge Summaries; Hypercalcaemia  https://cks.nice.org.uk/topics/hypercalcaemia/

Killick S et al, Guidelines for the diagnosis and management of adult myelodysplastic syndromes, British Journal of Haematology, 2014; 164;4, 503-525

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