Multiple Myeloma: An Incurable B-cell malignancy and A Vicious Cycle of Relapse

Posted on Sep 7, 2020 by Vinita Rakheja

Multiple Myeloma: An Incurable B-cell malignancy and A Vicious Cycle of Relapse

The Multiple Myeloma Market is expected to grow during the study period 2017-30 due to a rich and robust pipeline, increasing incidence, and higher demand for novel therapies.

A cancer of plasma cells, a malignant plasma cell dyscrasia, Multiple Myeloma (MM) is a cancer that accumulates in the bone marrow leading to the number of healthy blood cells to plunge. The condition results in bone fractures (osteolysis) due to an increase in osteoclastic and decreased osteoblastic activity. 

Multiple myeloma usually afflicts people of age 65 and older; however, some patients get diagnosed with bone marrow cancer at the age of 40. It is the second most common form of blood cancer after Non-Hodgkin lymphoma. DelveInsight estimated an overall Multiple myeloma incidence of  85,971 cases in the 8MM (the US, EU5, Japan, and China). The United States accounted for the highest MM incident cases, and DelveInsight estimates the incidence to increase during the forecast period 2020-30 steadily. It has also been reported that men are more likely to get diagnosed with Multiple myeloma than women. However, the pathogenic events giving rise to gender disparity to date remain unclear. 

The complex pathogenesis of Multiple myeloma often renders researchers and scientists in turmoil as there exists no standard of care for cancer. The primary hallmark of the condition is CRAB: C (calcium, elevated), R (renal failure), A (anemia), B (bone lesions), besides the presence of some chromosomal aberrations in several genes. The complexity and variety of pathologies of Multiple myeloma make it challenging to combat therapeutically. 

Nevertheless, recent technological advances have dramatically changed the treatment patterns for treating Multiple myeloma. The entry of novel pharmaceutical entities has substantially progressed, and a lot more are in the pipeline. Looking at the current Multiple myeloma treatment market scenario, the treatment market majorly revolves around chemotherapies in conjunction with proteasome inhibitors, monoclonal antibodies, anti-resorptive agents such as bisphosphonates along with NSAIDs or narcotics, corticosteroids, and bone marrow transplantation. 

Classic conventional chemotherapy has always held its position as indispensable in the Multiple myeloma market. Chemotherapy drugs primarily comprise Melphalan, Vincristine (Oncovin), Cyclophosphamide (Cytoxan), Etoposide (VP-16), Doxorubicin (Adriamycin), among others; and can be given alone or in a combination of other drugs. Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma as they are administered to address the side effects due to chemotherapy such as nausea and vomiting. 

Recent research and trials have shown the positive impact of immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, in patients with multiple myeloma. However, the mechanism on which IMiDs work is still in the dark; and there remains a lot to understand to utilize their potential for anti-myeloma perspective fully. Another way to target myeloma cells is to inhibit the property of Proteasome inhibitors (PIs) to get rid of excess protein (M protein) that builds up in myeloma cells. Here, the characteristic of the myeloma cells is used against them.

At present, the Multiple myeloma treatment market homes three proteasome inhibitors namely Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib). Then, there are Monoclonal antibodies. They need no introduction. The efficacy of Monoclonal antibodies (daratumumab (directed against CD38), Isatuximab (directed against CD38) and elotuzumab (directed against SLAMF7)) in sync with other therapies to treat myeloma suggests an important role mAbs play. No doubt, mAbs will continue to be a part of Multiple myeloma management for years to come. The decades also are a testimony to the rise in biomarker-driven, personalized treatment approaches that aims to minimize the toxic effects. Multiple myeloma is a result of complex genetic aberrations influenced by metabolic endocrine and vascular factors. Thus, targeting molecular pathways to fight cancer is crucial to deliver precision therapy in Multiple myeloma. 

The last decade has witnessed instrumental advancements in the development of therapeutic strategies in the Multiple myeloma market. mAbs, iMIDs, and PIs have synergetically added benefits to the existing treatment regimens. The Multiple myeloma therapeutics market in the 8MM  was approximated to be USD 14,111 million in 2017, which is expected to increase during the study period (2017–2030). Several pharma companies, including GlaxoSmithKline, Bristol-Myers Squibb, AbbVie, Roche, Janssen Research & Development, Merck Sharp & Dohme Corp., Pfizer, Takeda, Amgen, AstraZeneca, among others, are investing in strengthening the Multiple myeloma pipeline.

Bristol Myers Squibb and Bluebird bio’s investigational genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy, Ide-cel, a few months ago received Accelerated Assessment status by the EMA. The therapy has received the US FDA’s Breakthrough Therapy Designation and EMA’s PRIME designation for Relapsed and Refractory Multiple Myeloma. The companies have submitted the Biologics License Application for ide-cel to the U.S. Food and Drug Administration to treat adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. Ide-cel is the first CAR T cell therapy submitted for regulatory review to target BCMA and multiple myeloma.

AbbVie and Genentech are investigating Venetoclax (Venclexta, Venclyxto), an oral B-cell lymphoma-2 (BCL-2) inhibitor. The therapy had its significant share of backlash last year amid patients’death during the trial BELLINI in patients with relapsed/refractory multiple myeloma. However, the FDA lifted the partial clinical hold on CANOVA (M13-494), a Phase 3 trial evaluating Venetoclax for the investigational treatment of relapsed/refractory multiple myeloma

On the other hand, Jansenne’s investigational B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy, JNJ-4528 continues to stand strong, improving patient outcomes, shrinking tumors, and emerging out as a durable and reliable option in the Multiple myeloma market. The therapy is in the CARTITUDE-1 Phase 1b/2 trial (NCT03548207) ongoing at several clinical sites across the U.S. and Japan. Janssen has added another third-line blockbuster, Darzalex (daratumumab) cocktail, in the Multiple myeloma market. Darzalex is already approved and has been a backbone therapy Multiple myeloma setting for years. The newly expanded approval of the therapy in combination with Kyprolis (carfilzomib) and dexamethasone (DKd) will enable adult patients with relapsed/refractory multiple myeloma who have received one to three previous lines of therapy to explore the potential of Darzalex for their benefit. 

While every other pharma company is trying its best to come up with standard therapy to cure or at least stop the progression, how can Merck’s wonder drug, Keytruda (pembrolizumab), stay behind for which the fighting tumors are familiar waters? However,  the miracle the drug is doing in other cancers appears to fade a bit when it comes to Multiple myeloma.  The addition of Keytruda to lenalidomide and dexamethasone increased the mortality rates as compared to lenalidomide and dexamethasone alone; as a result, the FDA directed the company to halt the trials KEYNOTE-183 and KEYNOTE-185 years back. 

The Multiple myeloma pipeline is rich, comprising several novel therapies. Other therapies in the Multiple myeloma pipeline are Chidamide (Epidaza) by Chipscreen Biosciences, Felzartamab (MOR202) by MorphoSys and I-Mab, JCARH125, a Juno therapeutics product, among several others. 

Despite the presence of a plethora of treatment approaches,  however highly treatable, Multiple Myeloma, till date, remains incurable. The issue of relapsing of Multiple myeloma remains inevitable and unpredictable. Thus, the future goal of the Multiple myeloma treatment remains to overcome the resistance of the available options and address the issue of relapse of cancer. Nearly all Multiple myeloma patients continue to relapse. Ultimately, they become multi-drug resistant. The remissions periods go on to reduce with an average life expectancy of approximately five to six years after diagnosis. The increasing incidence due to an increase in the geriatric population is further adding to the healthcare burden Multiple myeloma poses.

Nevertheless, a lot is going on in the Multiple myeloma market, and the pharmaceutical companies are exploring the possibility of novel entities in combination or alone to tackle Multiple myeloma. The hope is still there for the standard treatment in the Multiple myeloma pipeline that enables to relieve the disease, prevent the progression/ organ damage, retrieving from resistant drugs, and achieving long-term remission. 

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