Bone marrow microenvironment: a valid ally for patients with multiple myeloma

Today I would like to present to you a research, carried out by Dr. Neumeister and colleagues, which talks about bone marrow. (1) The bone marrow is an apparently simple structure: in reality various molecules inside of it interact with each other, creating an environment that could favor the growth and proliferation of myeloma cells. In fact, myeloma cells survive thanks to molecular signals present in the bone marrow.

The role of the bone marrow microenvironment in normal conditions

The bone marrow is organized into small spaces called niches. Each niche is made up of particular cells, such as lymphocytes or cells linked to the functioning of the bone. This complex structure requires a large blood supply: for this reason it is richly vascularized.

The bone marrow microenvironment in patients with myeloma

In the process that leads to the development of myeloma, the bone marrow does not remain unchanged but undergoes various types of changes. It often happens that some cells of the immune system lose their ability to be careful “guardians” of the bone marrow: this results in the marrow no longer functioning as it should. Therefore the myeloma cells will no longer be totally defeated by the immune system, unfortunately becoming free to duplicate themselves!

The bone marrow microenvironment could also play in favor of the myeloma patient

Understanding these mechanisms has made it possible to produce many new drugs that act precisely on the molecular components of the bone marrow. In a certain sense, this allows the activity of the bone marrow to be reprogrammed, no longer against the patient but… in favor of the patient!

An example is given by immunomodulatory drugs, such as Lenalidomide: they not only act by damaging myeloma cells but also by restoring the normal function of the immune system in the bone marrow.

Future challenges

The understanding of the molecular mechanisms that underlie the functioning of the bone marrow microenvironment is advancing ever more rapidly, allowing the development of new therapeutic strategies that can also help patients who have already been heavily treated and have become resistant to previous treatment strategies.

Bibliography
1 – Neumeister P, Schulz E, Pansy K, Szmyra M, Deutsch AJ. Targeting the Microenvironment for Treating Multiple Myeloma. Int J Mol Sci. 2022 Jul 10;23(14):7627. doi: 10.3390/ijms23147627. PMID: 35886976; PMCID: PMC9317002.

Multiple myeloma in Latin America: managing a difficult disease in the absence of resources

Multiple myeloma, despite many advances in recent years, is not an easy disease to manage. Especially in countries like those of Latin America. Today I would like to present to you a scientific article by David Gómez-Almaguer and Vânia Tietsche de Moraes Hungria which describes the unfortunately still backward state of multiple myeloma management in Latin America, in terms of diagnostic procedures and treatment. (1)

Demographic aspects

By Latin America we mean the geographical area including the following countries: Argentina, Brazil, Mexico, Chile, Colombia, Costa Rica, Panama, Ecuador, Peru, Uruguay, and Venezuela. It includes over 600 million inhabitants and many low- and middle-income countries: therefore, unlike Europe and North America, the collection of demographic information is not very accurate and we are often faced with missing data. However, we know that the average age of onset of multiple myeloma is 61 years and that it affects men and women equally. Patients with multiple myeloma in Latin America often also have arterial hypertension and diabetes mellitus, two chronic diseases that are widespread worldwide.

Limited diagnostic tools and late diagnosis

A huge problem in Latin America is access to diagnostic tools that we routinely use. Suffice it to say that only 40% of doctors have access to the evaluation of free light chains in the blood. Not only that… only 80% of hospitals have access to serum protein electrophoresis, an exam that is carried out very easily in Western countries! This leads to a late diagnosis in over 50% of patients.

Outdated staging

The problems increase if we consider more modern methods, such as cytogenetics. In Uruguay it has been noticed that only 23% of patients have access to a cytogenetic evaluation. Under these conditions it is therefore impossible to stage the myeloma on the basis of the r-ISS system, which is widely used today, as information on the patient’s cytogenetics is lacking.

Treatment with limited options

In the area of treatment we find some important problems. Hematopoietic stem cell transplantation is not available in many countries. Furthermore, access to new drugs is difficult due to economic problems of the respective national health systems. The most used standard approach for treatment therefore remains the old chemotherapy, associated with dexamethasone. The situation improves slightly only for patients with higher financial resources, who can receive treatment in better equipped private clinics.

Future developments?

Despite a small recent improvement in the diagnosis and treatment of multiple myeloma in Latin America, problems still remain. Greater attention to these issues by national health systems would therefore be desirable.

Bibliography

  1. Full article: Multiple myeloma in Latin America (tandfonline.com)

Curcumin: from the table to the experimental therapeutic use

Today I would like to talk to you about a scientific article dating back to 2012, however very current in terms of future perspectives in the classification of two benign monoclonal gammopathies, monoclonal gammopathy of undetermined significance (known as MGUS) and smoldering myeloma. Terry Golombick and his collaborators carried out a clinical study on the possible benefits of curcumin on MGUS and smoldering myeloma in the period between 2010 and 2012 in the endocrinology department of Sydney (Australia). (1)                               
To date, no pharmacological treatment is routinely applied to these two conditions, and the only strategy is what English scientists call watch and wait.

Curcumin: therapeutic effects already proven

Curcumin is the most active substance extracted from Curcuma longa plants, native to Southeast Asia. Many of its effects on tumors and also on monoclonal gammopathies have already been demonstrated in the past. Curcumin reduces bone loss and also appears to inhibit the proliferation of altered plasma cells present in the bone marrow of patients with MGUS and smoldering myeloma.

The study by Terry Golombick’s team: methods

The study involved 36 patients with monoclonal gammopathy. These were divided into two groups (group A and group B).                                           
Group A received 4g of curcumin daily for three months and a substance with no therapeutic effect (called “placebo”) for another three months.                                                                                   
Group B instead received a placebo for the first three months and curcumin for the following three months.                                                       

Subsequently, only a few patients of the two groups continued their journey with a further phase of the study: it consisted of a daily intake of 8g of curcumin for another 3 months. Curcumin (as well as the placebo) was supplied in the form of tablets that could be taken together with substances rich in fat, such as yogurt, in order to facilitate their absorption.
Periodically the patients underwent blood and urine tests in order to evaluate many clinical parameters, such as hemoglobin, calcium, vitamin D and renal creatinine. Important was the evaluation of the relationship between free light chains (a parameter used at each haematological visit to monitor MGUS and smoldering myeloma) and also of a marker indicative of bone remodeling (known as u-DPYD), detectable in the patients’ urine.

The study by Terry Golombick’s team: results

The results collected at the end of the various phases of the study, and above all at the end of the entire study (after 9 months) were very exciting. In fact, a 36.8% reduction was found in the ratio of free light chains, especially in patients who had altered values of this ratio at the start of the study.

Future prospects

Given the very interesting prospects, new studies on the subject deserve to be conducted even today, in order to understand the obscure points and reinforce the good past results on the use of curcumin, in order to slow down or even block a possible negative evolution of monoclonal gammopathies.

Bibliography
(1) Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study – PubMed (nih.gov)

New Approaches to Smoldering Myeloma in 2022

The topic I would like to talk to you about today gets its ideas from a rather recent review by Iuliana Vaxman and Morie Gertz entitled How I approach smoldering multiple myeloma. (1)

The two authors clarify the current state of knowledge on smoldering myeloma in great detail, in addition to providing their personal approach to the management of this particular clinical condition.

What is Smoldering Multiple Myeloma?

Smoldering myeloma is the condition from which myeloma itself originates. It is not a real disease, but rather a mix of “clinical conditions” without symptoms! In fact, some patients have a very slow progression; it has even been estimated that over 25% of patients with smoldering myeloma will never develop symptomatic myeloma.

High-risk patients: how to identify them?

Alongside the previously mentioned patients, however, we also have patients with very fast progression, with a high risk of evolution into symptomatic myeloma in less than two years. This condition is known as “high risk” smoldering myeloma.

So we understand how important it is to understand what the actual risk is for each patient that their smoldering myeloma could become symptomatic myeloma.

Over the last few years, tools have been validated that allow doctors to identify high-risk patients. One of these is the model developed by the Mayo Clinic in 2018 and takes three parameters into consideration: two detectable on the blood (the M-protein and the ratio of free light chains), one instead on the bone marrow (the percentage of abnormal plasma cells).

However, a model of this kind is applied in a single moment in time, and blood and marrow analyzes are done close to the haematological visit. This is in fact called a static approach.

Dynamic approach: a film of the disease

However, the authors of the article advise not to rely only on static models like the one just seen, but rather to evaluate several parameters over time. For example by assessing how much the M protein varies from one medical examination to another. This approach applies to many other parameters, such as hemoglobin or creatinine. The goal would be to “take more snapshots” of smoldering myeloma over time: in other words, a real film! This type of approach is defined as “dynamic”.

From close surveillance to an almost resolutive treatment

Currently, regardless of the risk, the strategy used by the hematologist towards smoldering myeloma is close surveillance; for example every three months. However, there are many researchers who think that, for high-risk patients, a therapeutic approach already in this phase could be useful, slowing down the evolution into symptomatic myeloma or even completely eradicating the altered plasma cells (with a potentially curative effect). Benefits have been demonstrated in the past using the drug lenalidomide, with or without dexamethasone.

Treatment: neither too early nor too late

To date, there are many ongoing clinical trials investigating drugs to treat high-risk patients. On the basis of this, however, a more unanimous definition of a high-risk patient is needed. Finding the moment in which the patient would benefit from a drug treatment has been a real challenge in recent years. The treatment should not be applied too early: every drug has its side effects. But not too late either: early treatment could block the evolution of the disease for a very long time.

Finding this balance represents the recent challenge in scientific research on smoldering myeloma.

Bibliography (1) How I approach smoldering multiple myeloma – PubMed (nih.gov)

Shall we treat smoldering multiple myeloma in the near future?

Smoldering multiple myeloma (SMM) is an asymptomatic precursor of multiple myeloma, currently not treated with drugs. This subject, apparently easy, is actually very complex and debated, due to lack of solid data about this topic. With this article I would like to show you the position of Ola Landgren, an expert in this field (1). The two main questions about this subject are: What is the most appropriate clinical management of patients with SMM? Shall we treat SMM in the near future?

History of SMM

The first description of SMM dates back to 1980, thanks to the studies carried out by Kyle and Greipp. Indeed, they identified a little number of patients with similar characteristics to multiple myeloma in blood and bone marrow, but without clinical symptoms such as bone lesions or renal failure. The authors understood that these patients needed a chemotherapy, but only a periodic observation.

Definition of SMM

In 2003, the International Myeloma Working Group defined this condition better and proposed 2 important criteria for its diagnosis. either there is presence in  the blood of ≥3 g/dL of the so-called monoclonal protein(M-protein) or the presence in the bone marrow of ≥10% of monoclonal plasma cells. Therefore, another crucial criterium, thus the absence of the complications in organ systems, such as bone lesions, hypercalcemia, anemia, renal failure.

SMM management

At the present, the management of SMM consists of monitoring with blood tests every 2 to 3 months for the first year. After that a regular monitoring every 4 to 6 months for 1 year. At this point, if the patient is clinical stable, an evaluation every 6 to 12 months is normally suggested.

Is SMM in truth a homogeneous condition?

Actually, SMM is a really heterogeneous condition. Scientist study it because of the risk for its progression to symptomatic multiple myeloma. Yet in 2007, some studies suggested that patients with SMM could be divided in three risk categories: high-, intermediate-, and low-risk groups for progression. From these important data other researches took place…Indeed, doctors use some criteria to esteem this risk of progression: on one hand the American Mayo Clinic criteria, on the other hand  the Spanish PETHEMA criteria.(2), (3)

You could consider three main SMM groups

On Landgren’s Opinion, you should consider three SMM group. First the multiple myeloma, early detection. In this group the time of progression to symptomatic myeloma is short, about 1 or 2 years. In this case an early treatment with drugs would be necessary to prevent the myeloma symptoms, such as bone fracture or renal injuries. The second group is represented by the indolent multiple myeloma: in this case the progression to symptomatic myeloma could take place, but after 5-10 years. For these patients a periodic observation could be enough. Thirdly another condition called SMM- Monoclonal gammopathy: this situation is similar to the other myeloma precursor called MGUS, and the risk of progression to symptomatic myeloma is really low within 10 years of periodic controls.  

Options of treatment for patients with high-risk SMM

Many alternatives were proposed by study groups lately.  Firstly, drugs used for chemotherapy had lots of secondary effects, thus a treatment of SMM with these heavy drugs could be inconvenient. Other options are available nowadays, less toxic and more efficacious!  Just think of what Mateos and colleagues have evaluated in their quite recent trials. They observed that patients with high-risk SMM had important advantages in the situation using two drugs (Lenalidomide and dexamethasone) rather without medical treatment. Indeed, these drugs would delay the SMM progression to symptomatic myeloma and increase the overall survival of these patients. (4)

Future directions

Many questions are being asked by scientists to understand how to move forward in this field. More and more new and safer drugs are going to arrive to be up against high risk patients. To the starting question “Shall we treat SMM in the near future?”, Ola Landgren answers “yes, but only some of them”. The best would be that all the ideas showed in these review article could be endorsed in a consensus document.

Bibliography

(1) Shall we treat smoldering multiple myeloma in the near future? | Hematology, ASH Education Program | American Society of Hematology (ashpublications.org)

(2) Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111(2):785-789.

(3) Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify ´ risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood. 2007;110(7): 2586-2592. (4) Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus ´ dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(8):1127-1136.

Smoldering myeloma: a heterogeneous condition

Today I would like to summarise the salient point of a review article named “How I treat smouldering multiple myeloma (SMM)” published in 2014 and written by Irene Ghobrial and Ola Landgren. (1)  The main question we can see in this article is the following: Will the treatment of the precursor asymptomatic states of symptomatic myeloma, so the treatment of SMM, lead to the ultimate prevention of progression and cure in MM?
By way of a clinical case of a 42-year-old female patient, the authors start to describe the most important molecular and clinical points that characterise SMM, a precursor state of symptomatic multiple myeloma. 

Molecular mechanisms in SMM                                                                                                                             
Thanks to molecular techniques, such as the so-called Next-generation sequencing, it has been possible to see that in the bone marrow of patients with SMM there are many groups of tumor cells(subclones), that are heterogeneous. Furthermore, abnormalities in some chromosomes could appear in a progressive way by patients with SMM and influence its transformation into the dangerous symptomatic myeloma. 

How to diagnose patients with SMM                                                                                                                              
Although SMM is really heterogeneous, the International Myeloma Working Group established a consensus definition for the diagnosis of SMM in 2003. SMM was defined as either a concentration of M protein ≥3 g/dL in the blood or ≥10% monoclonal plasma cells in the bone marrow.

The role of imaging techniques                                                                                                                                     
To help the diagnosis and the periodic follow-up of patients with SMM, imaging techniques play an important role. For example, MRI is able to exclude the presence of lytic lesion, better than a traditional Rx skeletal survey.

How to estimate the risk of evolution by SMM patients                                                                                        
SMM heterogeneity is also notable in clinical manifestations of this condition. Indeed, you can have SMM very similar to the earlier precursor MGUS, which means a quiet condition.  On the other hand you could find more aggressive situations, that could require a stricter follow-up. Therefore, by a SMM it is really important to always estimate how high the risk to evolve into a symptomatic condition is. To do that, doctors normally use two useful score systems: the American system created by Mayo Clinic and the Spanish PETHEMA. 

Options of management in SMM: observation or early treatment?                                                                        
In 1990 the question “To treat or not to treat” early myeloma conditions, such as the state known as SMM at the present, appeared for the first time. The answer was negative first. (2)                                 
However, more efficient drugs are disposable nowadays, so that the treatment of SMM could be possible for types classified as “high risk” inside clinical trials. Obviously with interesting advantages. (3)

New sceneries in the near future                                                                                                                                       
It is very important to consider that SMM is a really heterogeneous condition and more studies are required before adopting new strategies in clinical practice. However, thanks to more and more accurate definitions of the risk of transformation into symptomatic myeloma and the knowledge of new drugs characteristics, it will be possible to reach other important goals by the prevention of symptomatic myeloma in the near future.

Bibliography

(1) How I treat smoldering multiple myeloma | Blood | American Society of Hematology (ashpublications.org)

(2) Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J; Myeloma Group of Western Sweden. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Eur J Haematol. 1993; 50(2):95-102.

(3) Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013; 369(5):438-447.

A mysterious gammopathy of underexplored significance

Today I would like to present a review article of Madhav V. Dhodapkar (1)about the monoclonal gammopathy of undetermined significance, condition known also as MGUS, that is the asymptomatic precursor state of a multiple myeloma.

This condition was first called essential hypergammaglobulinemia by Jan Gosta Waldenström in 1960. Because of its possible evolution to multiple myeloma, in 1978 Kyle and colleagues introduced the current term monoclonal gammopathy of undetermined significance (MGUS). (2), (3)

The diagnosis

Blood and bone marrow examinations are necessary to confirm the diagnosis. You should look for the presence of a monoclonal protein in blood: in case of MGUS, its value is <3 g/ dL. After that, the percentage of altered plasma cells should be <10% in  the bone marrow. 

Precursor states

It is known that most human cancers are preceded by precursor states: these conditions are even more common than the cancer itself! One of the precursor states of multiple myeloma is the MGUS. Myeloma is characterized by a strong resemblance to its precursor states. But be careful! The evolution of MGUS to multiple myeloma is possible… but not obligated! Therefore, the fact that MGUS is a blood condition offers many advantages for the periodic follow up of the patient. Indeed, both tumor cells and normal cells from the bone marrow can be readily and repeatedly isolated.

From genetics to the microenvironment

From genetics perspective, myeloma and its precursor MGUS are really similar. Both of these conditions are very heterogeneous: this heterogeneity is established early, starting with MGUS.   Although many MGUS are genetically complex and with a high risk of transformation in myeloma, other MGUS show no evolution. In fact, you should consider that a malignant transformation of MGUS to myeloma may depend also on interactions of tumor cells with the surrounding microenvironment. For example with the bone cells. A characteristic of multiple myeloma is the so-called lytic bone disease, that is absent in MGUS. However, in some patients with MGUS you should find little alterationsin skeletal architecture, so an increased risk of fractures even in MGUS. (4) Some scientific studies suggest that acting on both genetics and surrounding microenvironment already in this MGUS phase will be possible in the future to develop new approaches for a real efficacious prevention of the dramatic evolution of MGUS to multiple myeloma.

From chronic inflammatory states to pre-MGUS

An increase of bioactive lipids in the body may cause a chronic inflammatory statethat represents an augmented risk of evolution from MGUS to myeloma. (5) This inflammatory state is known as pre-MGUS and needs to be better evaluated with further studies. But you can already understand that obesity is a dangerous factor also for an MGUS patient. Therefore, simple lifestyle modifications targeting obesity could even stop the malignant evolution of MGUS, allowing its stability in the future. 

Advantages of an early diagnosis

Development of simple approaches to diagnose and intervene early could be very useful to study the biology of MGUS cells and other related factors, allowing the best conditions to prevent a dramatic evolution. I would like to cite a famous quote from Winston Churchill,  reported in the article, and really adaptable to MGUS:  It is a riddle, wrapped in a mystery, inside an enigma; but perhaps there is the key.

Bibliography

(1) MGUS to myeloma: a mysterious gammopathy of underexplored significance | Blood | American Society of Hematology (ashpublications.org)

(2) Waldenstrom J. Studies on conditions associated with disturbed gamma globulin formation (gammopathies). Harvey Lect. 1960-1961;56:211-231.

(3) Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64(5):814-826.

(4) Ng AC, Khosla S, Charatcharoenwitthaya N, et al. Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1a levels in patients with MGUS. Blood. 2011;118(25):6529-6534.

(5) Frohn C, Höppner M, Schlenke P, Kirchner H, Koritke P, Luhm J. Anti-myeloma activity of natural killer lymphocytes. Br J Haematol. 2002; 119(3):660-664.

Waldenström macroglobulinemia in 2020

It is incredible that DNA modifications in our genome cancorrelate with clinical presentation of an illness and can also be helpful to choose the best treatment against the illness. This is the case of Waldenstöm macroglobulinemia, as Jorge J. Castillo and Steven P. Treon explained in their review article published in 2020. (1)
The authors showed  simultaneously with a classical clinical description the story of a real patient, who discovered his complicated situation only by alterations in his laboratory exams: a high protein level in blood, without physical symptoms.

How to confirm the diagnosis

Given an elevation of protein level in blood it is important to be referred to a hematologist/oncologist for more deepened exams. Firstly blood tests, as the antibody levels in the blood: an augmentation of a specific antibody, called IgM, can let you suspect an illness called Waldenström macroglobulinemia (WM). However, to confirm this diagnosis you  also need a bone marrow biopsy. This biopsy is useful to show you the appearance of the bone marrow, that in case of WM is invaded by lymphoplasmacytoid cells. But it is necessary to study the DNA of these cells, in order to identify the presence of two mutations in some genes that compose your DNA: these are the so called  MYD88 L265P mutation  and CXCR4 mutation.

Other important investigations after the diagnosis

Once the diagnosis is established, you need further investigations in order to define  the illness and its consequences better. The Computed tomography (CT) is very important to see in chest, abdomen, and pelvis if some lymph nodes or alternatively the spleen or the liver are involved by the cells that characterised the WM.  A characteristic of this disease is also that the blood acquires a viscous consistence. This situation, called hyperviscosity, can generate problems in the eyes. Although this is not obligatory, it could happen: so an ophthalmologic control with funduscopic examination is required after the hematologist has established the diagnosis. These exams should be repeated yearly to control if vision problems appear. 

To treat or not to treat?

Not all patients with WM should be treated, but only some patients. For example a patient with anemia that produces physical symptoms, as chronic fatigue. Or patients who involved lymph nodes in the body, e.g. in the chest or in the abdomen. Or patients with really viscous blood.

Drugs used for the first treatment

A careful and accuratediscussion between doctors and patients should take place on the positive and negative aspects of each treatment option. It is so important to define a personalised therapy, taking into account patient‘s specific symptoms and other diseases(diabetes…), DNA exams previously accomplished and, last but not least, side effects of the different drugs and the personal preference of the patients. A drug used for the first treatment of a WM could be Rituximab, but it is less effective in patients with very elevated levels of IgM in the blood. To solve that, other drugs could be combined with Rituximab, for example Ibrutinib.

When MW come back

Despite good results of a therapy, there is always the risk that the WM could appear again. In this context it is important to choose a drug on the basis of the clinical story of each patient. An interesting and promising option is represented by Ibrutinib. In the USA this drug has been approved for the treatment of patients with symptomatic WM in April of 2015, because in other studies Ibrutinib has given important advantages in terms of clinical response and patients survival without illness progression. (2)  

However, Ibrutinib has effects on platelet aggregation in the blood, increasing the risk of bleeding with surgical procedures. Therefore, this drug can increase the risk of arrhythmia, especially atrial fibrillation. So a patient that takes Ibrutinib should be under the care of a cardiologist with experience with this complication. (3)  It is important to say that about 20% of WM patients who discontinue ibrutinib temporarily might experience the so called withdrawal symptoms, like fever, night sweats, and fatigue. These symptoms could be fortunately be managed with low doses of steroids.

Future treatment options

Other drugs can be used to treat a WM and new treatment options have appeared in recent years. The choice is based increasingly on the knowledge of typical DNA alterations of the disease and many new drugs aim to apport more favourable and durable clinical responses (remission)  and lower toxicity rates.

Bibliography

(1) Management of Waldenström macroglobulinemia in 2020 (nih.gov)

(2) Treon SP, Meid K, Gustine J, et al. Ibrutinib monotherapy produces longterm disease control in previously treated Waldenstrom’s macroglobulinemia. Final report of the PIVOTAL Trial (NCT01614821). Hematol Oncol. 2019;37(S2):184-185.

(3) Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4(12):1491-1500.

Smouldering multiple myeloma: a heterogeneous precursor

Today I am going to introduce the last part of Doctors Rajkumar and Kumar‘s article. (1)
It’s an interesting description of smouldering multiple myeloma and its treatment possibilities.

What is a smouldering multiple myeloma?
Smouldering multiple myeloma is a precursor of a symptomatic myeloma. Sure enough in smouldering myeloma your plasma cells in the bone marrow produce an amount of abnormal protein (the so-called Monoclonal protein) of ≥3 g/dl, so the same quantity of symptomatic myeloma.
However in smouldering myeloma you don’t have any myeloma defining events (MDE), so the following conditions are always absent in smouldering myeloma:

  • end-organ damage (hypercalcemia, renal insufficiency, anaemia, or bone lesions),
  • bone marrow clonal plasma cells ≥60%,
  • serum involved to uninvolved free light chain (FLC) ratio ≥100
  • more than one focal lesion (5 mm or more in size) on magnetic resonance imaging (MRI). (2)

Smouldering myeloma is a heterogeneous entity

Nowadays scientific knowledge shows us that smouldering myeloma is not a uniform condition. Indeed the authors divided smouldering myeloma in three separated groups:

  • a low-risk smouldering myeloma, so a situation that presents a low risk to become a symptomatic myeloma
  • a high-risk smouldering myeloma, which presents indeed a high-risk to develop a symptomatic myeloma
  • an intermediate-risk smouldering myeloma. (3)

To understand the right group for each patient, doctors use three parameters:                   

  • Monoclonal protein in the blood >2 g/dL
  • Serum free light-chain ratio in the blood >20
  • Plasma cells in the bone marrow >20%

Low-risk smouldering myeloma: watch and wait                                                                 
If you have a low-risk smouldering myeloma, a periodical medical examination by your haematologist with some routinary blood tests is enough.

High-risk smouldering myeloma: an untimely but useful treatment                                
In this situation the authors recommend to start the therapy. A possibility is represented by the use of Lenalidomide or the couple Lenalidomide and dexamethasone (that is also called Rd).  
Lenalidomide (Revlimid®) is a drug, that is similar to Thalidomide. It is powerful and offers many advantages, such as the death of tumoral cells and the inhibition of new vessels development. But be also careful, because Lenalidomide can cause deep vein thrombosis and pulmonary embolism; to avoid it, a good prophylaxis is therefore necessary, for example with aspirin.
A Spanish and an American scientific study has proven good advantages for the couple Lenalidomide-dexamethasone for patients in rapport to the simply and periodic medical observation. Lenalidomide is able to slow down the progression of smouldering myeloma in symptomatic myeloma, by slowing down the appearance of myeloma symptoms, the so-called Myeloma Defining Events (see above). (4),(5)

Many challenges await us                                                                                                       
This overview has shown the great evolution of medical knowledge in term of this watershed condition. However, there is still a long way to go, and many other scientific studies are necessary.

Bibliography

(1) Multiple myeloma current treatment algorithms – PubMed (nih.gov)

(2) Kyle, R. A. et al. Clinical course and prognosis of smoldering (Asymptomatic) multiple myeloma. N. Engl. J. Med. 356, 2582–2590 (2007).

(3) Rajkumar, S. V., Landgren, O. & Mateos, M. V. Smoldering multiple myeloma. Blood 125, 3069–3075 (2015).

(4) Mateos, M.-V. et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N. Engl. J. Med. 369, 438–447 (2013).

(5) Lonial, S. et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J. Clin. Oncol. 38, 1126–1137 (2020).

What can you do if multiple myeloma exacerbate again?

Multiple myeloma is characterised by quiet and unquiet periods. After a treatment at the moment of the diagnosis, myeloma becomes stable: this stability is called remission. Unfortunately this quiet phase does not last forever, thus a recrudescence of the illness can occur on average after 3 or 4 years from the diagnosis. In this situation, the so-called relapse, a new treatment is necessary for the patients. The choice of a treatment for each relapse depends on many factors: the timing of relapse, the aggressiveness of the relapse, the response to prior therapy and the general conditions of the patient.                                        
Today I am going to explain you the second part of the article written by Doctors Rajkumar and Kumar, so the treatment of relapsed multiple myeloma. (1)

The first relapse: if a new transplantation is possible                                                                
A new Autologous Stem Cell Transplantation (ASCT) can be a good option for patients:                     

  • Who have never had a transplant before,
  • Who had a prolonged remission with the first transplantation.

The first relapse: if a new transplantation is impossible                                                       
If a new transplantation is impossible, the authors have proposed an interesting algorithm in order to decide the best treatment. First we have to consider the role of Lenalidomide as treatment at the moment of the diagnosis. Lenalidomide (Revlimid®) is a drug, similar to Thalidomide, which can be used as a treatment at the moment of the diagnosis. It is powerful and offers many advantages, such as the death of tumoral cells and the inhibition of new vessels development. But pay attention, because Lenalidomide can cause deep vein thrombosis and pulmonary embolism; to avoid it, a good prophylaxis is therefore necessary, for example with aspirin.              
In this context, two important questions are the following: Did the patient obtain good results with the use of Lenalidomide as first treatment? Or was the patient resistant to the Lenalidomide? 
On the basis of these questions, the authors have distinguished two groups of patients: patients who were not resistant to Lenalidomide and patients who were resistant to Lenalidomide.

If the patient was not resistant to Lenalidomide

The triplet Daratumumab, Lenalidomide (Revlimid®) and dexamethasone, often indicated as DRd, is the best option for the authors in this situation. This triplet has done an important reduction in risk of progression, compared to the couple Lenalidomide and dexamethasone, the so-called Rd. Furthermore, this triplet presents a better tolerability: sure enough Daratumumab is used in a subcutaneous formulation, that reduces the infusion-related side effects and the time for the administration of this drug.

If the patient was resistant to Lenalidomide

For patients who were resistant to Lenalidomide, the authors suggest therapies using Pomalidomide or Bortezomib (Velcade®). (2), (3)                                                                                           
The triplet based on Daratumumab, Bortezomib and dexamethasone (called DVd) is the preferred choice for the authors.                                                                                                          
However, if patients have been previously treated with daratumumab, the authors suggest a therapy based on Carfilzomib (Kyprolis®), for example the triplet Carfilzomib, Pomalidomide and dexamethasone, often indicated as KPd .                                                                                   
Bortezomib and Carfilzomib have brought many advantages to patients affected by myeloma. However, they are drugs to be used carefully, because they can cause also secondary effects. Bortezomib can cause a significant risk of peripheral neuropathy. Two strategies were proposed to minimize the risk: the subcutaneous administration of Bortezomib and its use in a once-weekly schedule. The authors recommend also for these patients a prophylaxis against Herpes zoster infections. Carfilzomib has a lower risk to develop neurologic problems (low neurotoxicity) than bortezomib, however some patients (approximatively 5%) have developed serious cardiac side effects. (4), (5)

Treatment of second and subsequent relapses

For a subsequent relapse you can use the same therapeutic schemas validated for the first relapse. But the treatment of each patient must be personalised and the patient should use:

  • at least two new drugs that he is not resistant to
  • preferably the drugs should be part of a different group from those that the patient used for the first relapse.

Other options are in progress: some examples

The use of Venetoclax has been investigated in patients who present a particular anomaly in their DNA by the cytogenetic evaluation: this is the translocation t(11;14). (6)                      
Allogeneic transplantation can be considered in selected young patients with relapsed multiple myeloma, if suitable donor cells are available. (7)                                                              
Therefore, several promising treatments are under investigation for myeloma, offering a chance for a more and more accurate and personalised therapy for each patients.

Bibliography

(1) Multiple myeloma current treatment algorithms – PubMed (nih.gov)

(2) Attal, M. et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet 394, 2096–2107 (2019).

(3) Chari, A. et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 130, 974–981 (2017).

(4) Siegel, D. S. et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120, 2817–2825 (2012).

(5) Bringhen, S. et al. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies. Haematologica 104, 1640–1647 (2019).

(6) Kumar, S. et al. Efficacy of venetoclax as targeted therapy for relapsed/ refractory t(11;14) multiple myeloma. Blood 130, 2401–2409 (2017).

(7) Laubach, J. et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia 30, 1005–1017 (2016).