Multiple Myeloma


For me, the top story for multiple myeloma in 2018, is venetoclax. Venetoclax represents the culmination of efforts to develop a therapeutic agent tailored to work in certain genetic subtypes of the disease. How did we get here? How can this development be the most important one for 2018, when everyone is talking about CAR T-cell therapies and bispecific antibodies? How can this development be so important given that we have the results of phase III trials showing improvement in disease control with daratumumab-based combinations? How could this be the story of the year when we have the possible addition of new drugs such as selinexor? The answer is simple. This is the first time that a truly targeted therapeutic has been developed for multiple myeloma. Let me explain.

Myeloma has been, for several years, one of the best understood tumors when it comes down to disease biology and genetic changes. Description of the major subtypes of the disease and secondary genetic changes dates back now close to 15 years. Although we have had important refinements to this knowledge framework, the basic genetic groups are the same. The addition of novel tools, such as gene-expression profiling and mutation analysis with next-generation sequencing, has increased the depth of our understanding of the genetic nature of the disease. Myeloma is divided into two broad subgroups, the hyperdiploid and the non-hyperdiploid variants.

One of the hallmarks of myeloma is that the non-hyperdiploid variant is enriched for chromosome translocations involving the immunoglobulin heavy-chain locus. Although the translocation t(11;14) could be detected through cytogenetic analysis, it was not until molecular genetic studies performed by Bergsagel, Kuehl, and Chesi identified the presence of the translocations t(4;14) and t(14;16). Despite having this detailed knowledge of the disease, genetics had been predominantly used to stratify patients into risk categories and to propose different treatment pathways. However, none of these treatments has directly targeted the consequence of genetic aberrations. Previous efforts to target the FGFR3 gene, associated with t(4;14), have failed. Genetic understanding did not provide to myeloma the opportunity that was fully realized in chronic myelogenous leukemia.

Nevertheless, genetics in myeloma did help with a better understanding of the prognostic categories of disease. This has allowed for a more tailored conversation with patients regarding the likelihood of better outcomes. Furthermore, the knowledge about high-risk genetic features changed the paradigm upon which we recommend maintenance therapy in the post–stem cell transplant setting. Knowing that patients with high-risk genetic features derive greater benefit from the use of proteasome inhibitors became important practical knowledge. Arguably, the natural history of patients with t(4;14) was changed because of the addition of bortezomib to treatment. At the same time, great strides were made in the fight against multiple myeloma by the incorporation of medications that target “normal plasma cell differentiation” and protein metabolism. The introduction of proteasome inhibitors and IMIDs, followed by the introduction of monoclonal antibodies, greatly improved the survival for myeloma patients. Nevertheless, genetics have not augmented our treatment armamentarium. However, that will change with venetoclax!

Although there is still significant room for a better understanding of the mechanism of action of venetoclax in multiple myeloma, it is now very clear that this drug seems particularly effective for patients with the translocation t(11;14). Even if better biomarkers are developed for the selection of the right patients, venetoclax provides options for patients with this translocation and for whom no treatments have been available. We are all hoping that venetoclax will be approved by the FDA soon. Patients have been treated with venetoclax, often in combination with steroids or with proteasome inhibitors, off-label when no further treatment options were available to them. Several clinical trials have now demonstrated a very high rate of response to combination strategies that use venetoclax, particularly in patients with t(11;14). We have seen patients who have been heavily pretreated and who have achieved a complete response with venetoclax and dexamethasone alone.

The obvious corollary questions are as follows. Should venetoclax be used as maintenance therapy in patients who have the translocation t(11;14)? What is the role of venetoclax in patients who have light-chain amyloidosis (50% have this translocation) and in patients with primary plasma cell leukemia (50% also have this translocation)? Should venetoclax be used earlier in the course of the disease in patients with this genetic abnormality as a part of combination strategies? If venetoclax can treat effectively the 15% of patients with this genetic abnormality, what about MCL-1 inhibitors?

Recent data from the Mayo Clinic has shown that, although survival for most myeloma patients has improved over the past 15 years, these improvements have lagged among patients with the translocation t(11;14). Perhaps this has been because t(11;14) plasma tends to be more lymphoid and their cytoplasm contains fewer proteins. Accordingly, the protein stress associated with the use of proteasome inhibitors and IMIDs is lessened in patients with t(11;14).

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Breakthrough Therapies in Cancer: CAR T-Cell Therapies


With each passing day, we inch closer to curing cancer.

Until now, the cancer treatment universe was limited to 4 modalities, namely Surgery, Radiation, Chemotherapy and Targeted Drug Treatments. Recently, we have witnessed the addition of a fifth front in the battle against cancer, called Immunotherapy.

In Immunotherapy, scientists have been trying to develop ways to train the human immune system to fight and kill cancer-cells, just like they kill germs in trivial disorders such as the common cold. This technique of harnessing the immune system, is called “Adaptive Cell Transfer” or ACT.

CAR T-Cell Therapies have emerged as the most promising form of Immunotherapy.

What are CAR T-cell Therapies?

When we get sick with the common cold, our immune system attacks the infectious germs and kills them, effectively curing us. What is at work here are a type of cells present in our blood called T-cells. T-cells have the unique ability to identify affected cells, latch on to them and kill them.For a long time, cancer researchers have wondered if it’s possible to train our immune system to kill cancer cells the same way, and effectively become cancer-free. This field of study, titled ‘Immunotherapy’ has been widely researched, and Chimeric Antigen Receptor (CAR) T-Cell Therapies are one of the most exciting advancements in this field.

In a CAR T-cell therapy, a patient’s T-cells are genetically engineered, so that they attach themselves to cancer cells and kill them. More specifically, such T-cells are extracted from the patient’s own blood. These cells are then engineered in a lab to identify specific proteins (or antigens) present within cancer cells, and then these cells are injected back into the patient’s bloodstream.

Many scientists refer to CAR T-Cell Therapies as ‘Living Drugs’ because they constantly attach cancer cells, thereby reducing the rates of recurrence/relapse significantly.

The National Cancer Institute recently issued a simple graphical representation of such therapies on their Twitter feed:
Additionally, the Dana-Farber Cancer Institute has published a video explaining how CAR T-Cell Therapies work:

Current Status of Car T-Cell Therapies

The use of Car T-cell therapies has been limited to clinical trials so far. In these trials, many patients in advanced stages of cancer have experienced positive effects. Many such trials involved patients suffering from advanced ALL (Acute Lymphoblastic Leukemia) with limited treatment options. Most patients experienced 100% remission, and many of them remained in remission for prolonged periods of time.Similar promising results have been observed in the case of lymphoma patients. For patients with ALL, the first line of treatment is usually chemotherapy, followed by a bone marrow transplant. But if the cancer relapses, the treatment options get increasingly thin, close to none. CAR T-cell Therapies act as breakthrough treatments in such cases. So far, the clinical trials have shown positive results. In a trial conducted at the Children’s hospital of Philadelphia (CHOP), 27 out of 30 patients, showed all signs of cancer disappear completely.

Latest Developments

  • The United States FDA has recently approved CAR T-cell therapies for a subtype of ‘B’ cell Acute Leukemias in children (Kymriah) and another one for refractory ‘B’ cell Lymphomas in adults (Yescarta).
  • In another trial conducted on ALL patients at the Memorial Sloan Kettering Cancer center, 14 out of 16 patients demonstrated total recovery, some of them as early as 2 weeks into the treatment.

Potential Side Effects, Toxicity and Management

While the side-effects of such treatments can be life-threatening, the medical fraternity has developed sustainable safeguards against such effects, with supportive treatments. Some of these side effects are listed below:

  1. Cytokine Release Syndrome (CRS) – CRS may cause high fevers, low blood pressure or poor lung oxygenation. Some patients experience delirium, confusion and seizure while undergoing treatment. Such symptoms typically appear within the first week of treatment, and are usually reversible.
  2. Tumour Lysis Syndrome (TLS) – TLS includes a group of metabolic complications that can occur due to the breakdown of dying cells, usually at the onset of toxic cancer treatments. However, TLS can occur a month or more after CAR T-cell therapy. TLS can be a life-threatening complication arising from any treatment that causes cancer cells to break down, including CAR T-cells. This complication has been managed by standard supportive therapy.
  3. B-cell Aplasia – Since T-cells are targeted against surface receptors of B-cells, the normal B-cells also get dystroyed by them. However, no significant or long term side effects have been recorded.

In addition to these side effects, ScienceDirect.com has published a summary of various clinical trials conducted in the field, highlighting their effectiveness in hematologic disorders as compared to results in cases of solid tumors.

For solid tumours, there are a few challenges such as higher risk of major complications and a difficult tumour microenvironment for these cells to be effective. But these hurdles are surmountable, and we will eventually witness better results with this revolutionary approach.
-Dr Amit Jotwani (Co-founder, Onco.com and Senior Consultant Oncologist)

What’s Next in CAR T-cell Therapies?

CAR T-cell therapies seem to have a lot of potential, but further research is needed to make them mainstream and available to patients globally. Many labs around the world are currently testing these therapies, not just for blood cancer but also for solid tumors such as pancreatic and brain cancers. Given the amount of interest the field has generated among researchers worldwide, it is likely that the next decade will be transformative in defining the cancer treatment paradigm.

Watch the video. URL:https://youtu.be/OadAW99s4Ik

References:

1. LLS.org – Article on Chimeric Antigen Receptor T-Cell Therapies
2. ESMO.org – The Evolving Field Of CAR T-Cell Therapies
3. Nature.com – CAR T-Cell Therapies Journal
4. Cancer.gov – The National Cancer Institute’s take on CAR T-Cell Therapies
4. ScienceDirect.com – Toxicity & Management in CAR T-Cell Therapy