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).

The US has given fast-track approval to a surprising new cancer drug


“Even when it’s killing cells, you feel great.”

A new cancer drug called Venetoclax is causing quite a stir in the medical community, with the announcement that the US FDA has given it fast-track approval for the treatment of patients with chronic lymphocytic leukemia (CLL).

CLL is one of the most common types of leukemia in adults, and during a recent clinical trial, 80 percent of patients treated with Venetoclax experienced complete or partial remission of their cancer.

Developed in Australia over several decades, Venetoclax is taken in pill-form, and of the small sample of patients who have been treated with it so far, some reported no adverse side-effects at all.

“It causes no side-effects. Nothing, absolutely nothing,” Robert Oblak, who had recurring CLL when he was selected to participate in the trial in 2013, told the ABC. “Quite amazing. So even when it’s killing cells, you feel great.”

Oblak estimates that he was just the 11th person in the world to be treated with Venetoclax, and within a year of treatment, he went into remission.

The phase II trial involved 107 patients aged 18 or older with CLL, who had undergone at least one type of treatment already.

The patients also had to have a particular chromosome abnormality in their leukemia cells called 17p deletion, which means they’re lacking a portion of the chromosome that acts to suppress cancer growth.

They were asked to take one Venetoclax pill per day for five weeks straight, with doses starting at 20 mg and gradually increasing to 400 mg.

At the end of the trial, which involved patients and researchers from 31 centres in the US, Canada, the UK, Germany, Poland, and Australia, four out of five patients experienced a positive result, with complete remission reported for one in five.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumour cells alive,” Richard Pazdur from the FDA’s Centre for Drug Evaluation and Research, announced back in April. 

“For certain patients with CLL who have not had favourable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The results of the trial, which were published in The Lancet in June, informed the FDA’s decision to fast-track approval of the drug and make it available to patients in the US.

Despite being developed by researchers at Australia’s Walter and Eliza Hall Institute of Medical Research, it’s not yet been approved for use by Australian patients, but an application has been made.

So, how does the drug work? Venetoclax is one of a new generation of immunotherapy cancer drugs that are designed to address certain failings of a person’s own immune system – such as missing portions of chromosomes that inhibit the cells’ ability to fight the spread of cancer.

In CLL patients with 17p deletion, malignant cells don’t proliferate all that much, but they don’t die, because the body’s immune response has been hindered, and abundant levels of a protein called BCL2 helps keep them alive.

“Cells, when they are born, are destined to die and cancer cells and particularly leukaemia cells delay that death by using a protein called BCL2 that stops the normal time of death,” John Seymour from the Peter MacCallum Cancer Centre in Melbourne, who helped oversee the trial, told the ABC.

“Venetoclax works by specifically blocking the action of that BCL2, and allows the cells to die in the way that they were destined to.”

venetoclax-actionVenetoclax

So rather than killing off the cancer cells – and a bunch of healthy cells in the vicinity – like current treatments like chemo and radiotherapy do, the drug reestablishes the balance of the body’s immune system, and effectively allows the cancer cells to die on their own.

This explains why some patients, like Oblak can undergo treatment with no discernible side-effects. But let’s be clear – Oblak was very lucky.

The FDA reports that, depending on the patient, side-effects from Venetoclax include low white blood cell count, diarrhoea, nausea, anaemia, upper respiratory tract infection, low platelet count, and fatigue. Serious complications can include pneumonia, fever, and death.

During the Venetoclax trial, of the 107 patients, 11 ended up dying, seven because of the progression of their cancer, and four from adverse side-effects.

Similar results were seen in a separate trial of a similar immunotherapy cancer drug, Ipilimumab, which has recently been approved for the Australian market.

While Australian patient Greg Lawson was declared free from melanomas 12 months after treatment, and reportedly suffered “virtually no side-effects”, his wife, who was treated with a different melanoma immunotherapy drug at the same time, died when her body could not tolerate the treatment.

“She had two sets of the treatment, but was so ill from the side-effects that the decision was made to take her off it,” Lawson told the ABC.

But with immunotherapy drugs seeing “extraordinary” results in other trials this year, and with the possibility of a ‘universal cancer vaccine’ hanging in the air, this is just the beginning for the next generation of cancer treatment.