Multiple myeloma

Multiple myeloma with renal involvement, bone lesions and Neuropathy
Short Summary

71-year-old-male had been diagnosed as having multiple myeloma (MM), apparently of the IgA-Lambda type, with renal involvement. The disease course is characterized by "ups and downs responding to anti-MM therapy. During the disease course, several problems and complications developed: Renal failure, Bone lesions and Neuropathy.

Patient's Questions
1)    What treatment do you think we should administer at this time?
2)    Centers of excellence in Italy and abroad offering treatment?
Medical Background

71 years old, male

Anamnesis:
Psoriatic Arthritis since 1980, treated over the years with NSAIDs, gold salts, steroids, Methotrexate, cyclosporine.
In 1999 diagnosed with prostatic hypertrophy.
In 2005 discovery of Macular Hole from vitreous-retinic traction.
History:
In January 2006 first evidence of increase in creatinine (1,8 mg/dl) with slight anaemia (11.5 g/dl) and slight proteinuria (30 mg/dl). Despite these counts treatment with methotrexate and cyclosporine was continued.
In September 2006: due to further deterioration of kidney function (creatinine = 3.4 mg/dl) the patient was admitted to the nephrology department in Pisa where numerous tests were performed including a bone biopsy which showed medullary plasma cell infiltration amounting to 40%. A hematology visit was performed by Prof. Boccadoro (Turin) who prescribed the following combined treatment Melphalan-Thalidomide-Dexamethasone-Velcade according to the national GIMEMA protocol; thereafter the patient was transferred to Bologna for logistics purposes.
On October 2006 first visit at the hematology department in Bologna which showed creatininemy 5.3 mg/dl and hemoglobin 8,7 g/dl, these data rendered the patient not eligible for the GIMEMA protocol. The MB (medullary biopsy) showed plasma-cell infiltration of 40-50%, proteinuria was 2 g/24h, skeleton X-Ray was negative.
Treatment was begun with Dex 20mg/die; he was admitted to the Nephrology department at Malpighi Hospital (Prof. Santoro) for a better understanding of the nephrological problem. A biopsy of the kidney was performed which showed vascular nephropathy associated with chronic parenchymal alterations (damage from cyclosporine) with limited aspects of myeloma cast nephropathy. After being discharged, a second cycle of Dex 40 mg/die was given for 4 days; thereafter a high temperature was measured with bronchopneumonial foci; the patient was re-admitted to nephrology dept. due to a further increase in creatinine at 7 mg/dl, reduced once again following appropriate hydration. After discharge (11/2006) treatment with Thalidomide-Dexamethasone was begun, associated with Clexane, which the patient tolerated very well and which progressively led to a reduction in proteinuria to 300 mg/24h, medullary plasma cell infiltration to 10% and in particular creatinine to 2,5-3 mg/dl.
From November 2006 to June 2007 treatment with Thalidomide 100 mg/die + Dexamethasone 40 mg/die for 4 days every 21 days, was continued. The hematological picture always remained stable, creatinine=2.5-2.8 mg/dl, Bence Jones proteinuria=300-500 mg/24 hours. In agreement with Prof. Baccarani it was decided to suspend treatment with Thalidomide and continue only with Dexamethasone and plan a stem cell harvest in view of an autologous transplant.
In October 2007 he was admitted to Istituto Seragnoli, for treatment with growth factor of granulopoiesis; no suitable CD34+ stem cell mobilisation was obtained.
From October 2007 to January 2008 treatment with Dexamethasone was continued. In November proteinuria rose to 759 mg/die, a medullary aspiration was performed which showed a plasma cell infiltration of 5%, and it was decided not to change treatment.
In January 2008, while the other parameters were stable (IgA 222 mg/dl, creatinine 2.5 mg/dl) proteinuria showed a further increase (1260 mg/24 hours) therefore Thalidomide was re-introduced at a dose of 100 mg/die associated with Dexamethasone. At the same time, because the patient was complaining of pain in the vertebral column and ribs, an NMR and a PET scan were performed, both giving negative results.
Treatment continued unchanged until June 2008, Creatininemy and the serum monoclonal component were always stable while proteinuria experienced some oscillation (as per the attached graph).
Another medullary aspiration was performed which showed a plasma cell infiltration of 30-40%.
On August 2008 the cytoreduction treatment was changed with the inclusion of Velcade 1.3 mg/mq on days 1-5-8-12 for August; 25-28-1-4 for September; 9/29 and 2-6-9 for October and lastly the 4th cycle on October 23-27-30 and November 3.
Due to the appearance of more intense pain in the area of the left ribcage and vertebral column a new PET scan was performed on 08/2008, the results are stated here below: “hyperfixation of the indicator is detected in:
- multiple rib areas, in particular on the right at the II, IV and XI rib at the back and on the left at VII and XII rib at the back;
- left ilium in the parasacral area.
A limited hyper-uptake externally to the left hemisoma of D11-D12 was noted, apparently from osteophyte bridge in active phase. 
Conclusions: The results point to the presence of heteroplastic tissue with elevated glucidic metabolism in the areas described”.
The results of 2 medullary citology fine needle aspirations are also given, performed respectively:
-           062008: “small normal-hypocellulated fragments. Megacariocytes present. Clear excess of plasma cells (approx. 30-40%) mostly of small dimension, rarely of larger dimension, sometimes nucleolated. Reduced erythropoesis and granulopoiesis, normally raping”.
-           11/2008: “Moderate interstitial plasmocytosis (approx. 8%) politi pica on the background of hyporepresented hematopoietic tissue.
(CD138+, K+. LAMBDA+).
Following the appearance of paresthesia in the lower limbs, reduced sensitivity to temperature at the level of the feet and intense pain in the area of the calf muscles, an Electromyography was performed on 1/2009, the relative results are attached:” Sensitive chronic motor polyneuropathy, primarily sensitive and axonopathic in nature, distal and symmetrical, severe in the lower limbs”. For these symptoms, at the hematological check up in Bologna on 112008, treatment was started with Contramal 15 drops 4 times a day; Soldesam drops: 20 drops in the morning for 1 week, 15 drops for 1 week, 10 drops for one week, 5 drops for 1 week, 3 drops until the next check up, always with gastroprotection. The report of this check up by Dr Patrizia Tosiis given here: “…Cenesthesis is disturbed by peripheral neuropathy. In view of the excellent response and the clinical manifestations I would consider suspending treatment for the moment. Every 2 weeks I would assess: hemochrome+platelets, creatinine, azotemia, uricemy, calcemy, potassiemia, blood protein electrophoresis, counts for immunoglobulins, transaminase, glycemia, gamma GT, alkaline phosphatase, Bence Jones proteinuria with urinary electrophoresis and urinary immunofixation, sodium, potassium.
With Dr Santoro, assess the possibility of starting treatment with Mirapexin .18 mg 1 tablet in the evening (for restless legs syndrome)…”.
Further hematological check up with Dr Tosi on 01/2009 with the following report: “..There is a severe peripheral neuropathy; the illness is shown to be well under control, if this continues I would not administer any further treatment nonetheless should the monoclonal component increase again I would also resume treatment with Velcade. I agree with the use of B complex (neural-type, tablets) to try and improve symptoms. For pain management I would prefer contramal to novalgina, which could have a myelotoxic effect. Next consulting room check up on 02/20..”.
The neuropathy symptoms have greatly diminished, the patient has not taken any medication to control them for about 40 days; nonetheless, paresthesia of the lower limbs is still present within acceptable limits, limited sensitivity of the feet and a feeling of discomfort when the toes rub against the bedsheets.
In his current state the patient manifests, over and above the symptoms described previously, a lasting feeling of being cold, with “goose bumps”, even if he is well covered; these feelings alternate with situations of normality and rarely of feeling hot. The patient has suffered from psoriasis for about 35 years, this has clearly almost disappeared during treatment cycles with thalidomide+dexamethasone followed by velcade+dexamethasone, to then re-appear with more virulence at the beginning of December, therefore the patient was forced to start narrowband UVB ray applications at the hospital, these had already been applied in the past with excellent results but this time the same results were late in coming as the psoriasis had extended widely on the calves and appeared quite strongly also on the thighs and less strongly on the rest of the body.
Drugs currently taken by the patient:
- morning:      Lansox 30 mg 1 tablet
                        Folina 1 tablet
                        Calcium carbonate 500mg 1 tablet
- lunch:           Calcium carbonate 500mg 2 tablets
                        Ticlopidina 250 mg 1 tablets
- dinner:          Calcium carbonate 500mg 2 tablets
As the patient was advised to check his blood pressure, which should give a maximum reading below 130 mmHg, Dr X takes Lasix 1 tablet when necessary, i.e. an average of 1 to 2 tablets per day. For insomnia he has been taking Tavor 1 tablet of 1 mg, for some time now, even if recently he has taken even 2 tablets of Tavor per day.

Expert's Opinion

During the disease course, several problems and complications developed: 
  • Renal failure: It is difficult to determine from the documents I have reviewed, what is the role of cyclosporine, previously administered to the patient for his psoriasis (see below), and what is due to MM involvement. Biopsy was more consistent with cyclosporine nephrotoxicity. However, the response to anti-MM therapy with decreasing creatinine, support the conclusion, that we are facing a myeloma kidney, at least partially. Another possibility, that apparently is not the case, is amyloidosis with kidney involvement, but the absence of significant proteinuria, as well as the findings in the renal biopsy, almost exclude it.
  • Bone lesions which appear to be symptomatic (bone pain). This appears to be an integral part of MM.
  • Neuropathy: The neurological symptoms are considered to be adverse effects of both Velcade and thalidomide. They are currently well treated by neurologists, as well as an attempt to avoid the potential offending drugs.  
 Other medical problems:
  • Psoriasis: Recovered with anti-MM therapy (a known phenomenon) but recently recurred.
  • Psoriatic arthritis: Treated over the years with NSAIDs, gold,steroids, methotrexate, cyclosporine.
  • Renal failure: Related partially to cyclosporine toxicity (see above). I believe that at least part of the problem is related to MM. 
 
Comments and suggestions:
Before one can address the questions raised, unfortunately, some information is still missing, which makes it difficult to draw definite conclusions and provide particular recommendations.
The still open questions that might help me to evaluate the situation are as follows:
  • The protein profile of the patient, at diagnosis, and during the course. This includes the findings of the immunofixation and beta-2 microglobulin (although with renal failure it is not accurate), as well as the recent tests for free light chains.
  • Prognostic parameters, such as cytogenetics.
  • I still do not understand well the level of response to treatment.
  • Most important, I need to know what the patient suffers from now. If the symptoms are mostly related to the psoriasis – then one should not be too aggressive with this particular patient.

In the absence of the information, I would like to specify several comments and suggestions:
  •  I tend to be quite conservative with a 71 year old gentleman. Thus, I agree with the general approach that has been taken. I tend not to submit such patients to autologous stem cell transplantation, but rather treat them with a relative conservative anti-MM therapy.
  • If the patient has responded fairly, and this appears to be the case (unless I still miss information), and he is currently, relatively asymptomatic, then very mild approach can be taken at the present time. This means either no anti-MM treatment till we have to (see below), or a mid maintenance. Such maintenance can include dexamethasone, with or without melphalan or only melphalan.
  • Only if the protein profile increases significantly (the monoclonal peak) or clinical symptoms or complications appear, that will be related to the hematological disease, this will force us to renew the more active aggressive anti-MM therapy. If this is the case, we might take several possible therapeutic approaches:
    • Renew thalidomide-dexamethasone combination, with continued treatment for the neuropathy.
    • Velcade also has not received its full chance, but I would avoid it because of the neuropathy.
    • Since the patient is not a candidate for stem cell transplantation, melphalan, as a single agent, or probably better as a combination with steroids – can also be administered.
    • Lenalidomide (Revlimid), as a single agent, or better in a combination, usually with dexamethasone, is a very attractive possibility for the future. I do not know the patient' health insurance status, since it is very expensive (about E 6500 per month) agent, but indeed very effective, with minimal adverse effects.
    • Other therapeutic regimens that can be considered are a combination of doxorubicin (adriamycin) or Doxil with other agents (the old VAD), and cyclophosphamide based combinations.   
  • Supportive treatment is very important in MM:
    • If the patient is anemic – erythropoietin is very effective
    • If bone pain is significant – local radiation therapy might help
  • The renal failure should be treated in parallel, and also as a separate problem. I suppose that together with the nephrologists one will have to take into consideration a dialysis strategy.
  • There are several excellent medical centers in Italy and Italian very professional leading doctors experts in MM. Most of them I know personally:
    • Prof. Antonio Palumbo – Turino
    • Prof. Mario Boccadoro (Has seen the patient in the past)
    • Prof. Michel Cavo

""