Multiple myeloma – a rare disease, yet one of the most common blood cancers in the world

Multiple myeloma – a rare disease, yet one of the most common blood cancers in the world

This blog post is also available as a downloadable PDF here: Monocl_MM_blog_11 Jan_2016

Multiple myeloma is the third most common blood cancer, primarily affecting elderly patients. In the last decades, major advances have been made in how the disease is managed using stem cell transplants and novel chemotherapies. However, large unmet medical needs still exist as the disease invariably relapses and patients develop drug resistance. As major brands are about to expire and several exciting pipeline candidates are getting closer to approval, Monocl made a brief indication analysis of the multiple myeloma field and interviewed one of the most exciting startups in this space.

Multiple myeloma is a rare disease, yet one of the most common blood cancers in the world

Multiple myeloma (MM) is an incurable and rare cancer with approximately 103 000 newly diagnosed cases per year worldwide. This makes the disease the third most common blood cancer in the United States (after lymphoma and leukemia). Since 1975, overall myeloma incidence has increased nearly 1 percent annually. Overall mortality rates peaked in the mid-1990s and have fallen in recent years. It has been estimated that approximately 11,000 and 24 300 die from MM in the US and Europe, respectively, per year.


Cytogenetic risk status may affect the prognosis but no universal tests are currently recommended in europe

MM primarily affects elderly individuals with a median age at the time of diagnosis of 70 years of age. In many cases, there may not be many symptoms or other complications in the early stages of the disease. In fact, it is often diagnosed after a routine blood or urine test when patients seek help for persistent bone pain, or by examination following a bone impact fracture, which can be associated with the formation of lytic bone lesions. Diagnosis (and treatment) is typically managed by a hematologist or a hematologist-oncologist. A study of 10 750 MM patients, carried out in 2005, revealed that the median survival of patients in stage I was 62 months, stage II was 44 months and stage III was 29 months using the international staging system. However, this staging system is used for prognosis and disease severity, rather than for determining a treatment strategy. It is well known that myeloma is associated with distinct cytogenetic abnormalities, some of which portend a poor prognosis. Providing a risk-adapted treatment strategy is a key goal in the ongoing research efforts aimed at providing treatment tailored to the individual genetic make-up of a patient, which would avoid unnecessary treatment and toxicity. European guideline opinion leaders have therefore recently concluded that analysis of specific factors to enable a better categorization of patients into different risk groups is valuable but there is a lack of prospective trials supporting a risk-adapted approach. Their recommendation for the time being is therefore to use the most effective treatment regardless of cytogenetic risk status and other risk factors.

Autologous Stem cell transplantation is part of the backbone of MM treatment for eligible patients

The initial evaluation of patients includes an assessment of eligibility for high-dose therapy and autologous stem cell transplantation (ASCT) based on age, performance status, and comorbidities. In Europe, high-dose therapy followed by ASCT represents the standard of care for patients without prohibitive comorbidities, with an age cutoff between 65 and 70 years, depending on the country. A report of more than 20 000 patients in the US and Canada showed that ASCT as upfront therapy has increased over time, as has the age of patients undergoing the procedure, as well as the number of patients with more advanced stages of disease. A typical journey for a patient who is eligible for stem cell transplant thus starts with induction therapy before ASCT is carried out, which is then – based on geography, economy and institutional practices – followed up with consolidation and maintenance therapy. For those patients who are not eligible for ASCT, induction therapy is given to induce remission, which is then in some cases  followed by maintenance treatment.

The introduction of novel agents is the most important advance in the past decade of MM treatment

The most important advance, arguably, in the past decade, however; has been the introduction of the novel agents, thalidomide, bortezomib and lenalidomide, as part of frontline treatment in both transplant and nontransplant eligible patients. These drugs have markedly improved the rate of complete response, without substantially increasing toxicity, and, importantly, time to progression, progression-free survival and overall survival have significantly increased. Analyses show substantial improvements in survival over time following ASCT, with better postrelapse survival when novel agents are incorporated – making the two treatment strategies complementary. A large number of different combinations with these novel agents have been investigated with different outcomes, resulting in a complex treatment algorithm.

Velcade and Revlimid: strong leaders in front line multiple myeloma treatment

Globally, the leading non-alkylating and non-steroidal branded therapies in MM are the proteasome inhibitor (PI) Velcade and the immunomodulatory  (IMiD) drug Revlimid. These two are the most popular brand choices for early chemotherapy regimens that are prescribed in the US and Japan. While this is also true in Europe, cost conservative markets (e.g. Italy, Spain and the UK) consider generic thalidomide as the primary drug or generic melphalan in combination with prednisone (while saving expensive branded products for relapsed and refractory disease). In Europe, the consensus is that a bortezomib-based triple induction regimen with thalidomide, cyclophosphamide, doxorubicin and dexamethasone should be given for four cycles before ASCT. The DNA alkylator melphalan (MEL200) remains the standard conditioning regimen with no standard consolidation or maintenance therapies. In the US, the most common induction regimens are RVd (Revlimid, Velcade, dexamethasone) and Rd (Revlimid & dexamethasone) often with Revlimid containing regimens as consolidation and maintenance (with practices varying across the country). However, the grim truth is that MM remains incurable and a great need remains for new therapies to achieve disease control. In many cases, the choice of therapy can be the same across multiple lines of therapy, as the choice of therapy used is entirely dependent upon the treatments that a patient has received in the past and their own clinical presentation. Many key opinion leaders (KOLs) feel constrained as their choices are limited to different PIs, IMiDs, steroids and DNA alkylators. Clinicians – as well as regulators – thus welcome drugs with novel mechanisms-of-action.

Several innovative drugs approved in the relapse/refractory setting during 2015

Although the introduction of PIs and IMiDs over the last First_relapse2decade has improved survival, MM still invariably leads to relapse (i.e. the disease returns, on or off therapy) and/or refractory disease (resistance to particular drugs). If a patient eligible for ASCT progresses, a second transplant may be possible. Salvage therapy is then applied on further progression or relapse or in the case of those patients who are ineligible for stem cell transplant. The original drug is typically used again to re-challenge the disease, if the relapse has ocurred longer than six moths after the primary therapy. In the US, Celgene’s IMiD drug Pomalyst (pomalidomide) and Onyx’s PI agent Kyprolis (carfilzomib) were both approved under FDA’s accelerated approval program, in 2013 and 2012, respectively, to treat MM patients who have received at least two prior treatments. Pomalidomide was approved shortly afterwards in Europe (known as Imnovid) while the Kyprolis approval took three years. This year, we have seen multiple innovative drug approvals by the FDA in the relapsed/refractory multiple myeloma (RRMM) setting. The first HDAC inhibitor for MM, Farydak (panobinostat), was approved. It was approved after having shown that it doubled the time to disease progression (PFS of 10.6 months vs. 5.8 months) when combined with bortezomib and dexamethasone in patients who had already received at least two prior therapeutics. The first oral PI, Ninlaro (ixazomib), was approved in combination with Rd in patients that have progressed despite treatment with at least one prior therapy. Ixazomib increased PFS by almost 6 months in its phase III trial, which is also what led up to its approval. Darzalex (daratumumab), the first monoclonal antibody targeting CD38, was approved for treating patients whose MM has progressed despite treatment with at least three prior forms of therapy, including a PI and an IMiD, as well as those whose disease is not responsive to either a PI or an IMiD. It was approved based on a phase II study in 106 patients of which 29% had an objective response with a median duration of 7.4 months (a confirmatory study is now required to determine whether it enables longer survival). Two additional phase III studies are also ongoing to competitively position it upstream in combination with Rd and/or Vd. Combination treatment with the market leaders is a general trend for many of the pipeline drugs and because the original drugs from the primary therapy is often used  again upon relapse, the regimens for RRMM can become complex, with treatment choices are entirely dependent on the agents previously received by the patients.

Great unmet clinical needs exist in RRMM settings

In a non-published comprehensive interview analysis with US and European payers, it became very clear that the available MM treatments were considered to be least effective in RRMM patients. This is of course related to the fact that the same drug classes are used in multiple lines, which eventually leads to drug resistance/intolerance. It has recently been shown that patients who are refractory to these novel therapies show a median overall survival (OS) and progression-free survival PFS of 9 months and 5 months, respectively. In a recent investigator led phase III study of Pomalyst (pomalidomide), 75% of the recruited patients (who had failed at least two previous treatments) were double refractory to both bortezomib and lenalidomide. Clearly, there is a great need for innovative drugs to circumvent drug resistance. This is also well correlated with the accelerated approval pathways that FDA has granted to many of the RRMM newcomers. Another case where current therapies don’t respond well is extramedullary melanoma. This occurs in about 13% of myeloma patients and is an extremely aggressive form that is most commonly found in relapsed settings. About 51% of patients with asymptomatic myeloma develop active MM within five years. New treatment strategies are needed for both smoldering and asymptomatic myeloma, as well as high-risk patients where  it is currently unknown how genetic changes ultimately lead to refractory disease.

Myeloma market dynamics are likely to change as a result of brand expiries and recent drug approvals

Celgene and Millenium/Takeda currently hold dominating positions on the MM market. Both Revlimid (Celgene) and Velcade (Millenium/Takeda) have gained strong competitive positions by their penetration into all disease settings, resulting in blockbuster sales of $5b and $3b, respectively. But, these market dynamics are likely to change in the coming years as both of these go off patent (Velcade: 2017 in the US & 2019 in Europe; Revlimid: 2019 in the US & 2022 in Europe). Celgene has experienced rapid uptake of its IMiD agent Pomalyst in the RRMM setting but J&J’s recent approval of Darzalex may change this dynamic. Armed with an impressive overall response rate, Darzalex will go head to head and try to undercut Pomalyst by a competitive pricing strategy. Whereas Pomalyst list price is one of the most expensive drugs ($147 302 list price), J&J has communicated that treatment during first full year will run $135 550 on average, with a cost of around
$76 044 for follow-up during the second year. Clinicians on the MM market have long awaited novel drug classes and with monoclonal antibodies and HDAC-inhibitors hitting the market, the anticipations are high.   

Multiple drugs in the MM pipeline target the early RRMM setting as combinations with Velcade and Revlimid

As in most other oncology indications, the competitive strategy of the majority of new agents is to aim for an approval in the relapsed/refractory setting. Clinical needs are higher in the RRMM setting because of the exacerbated status from multiple relapses and increased drug resistance. A common strategy to move upstream to earlier lines of therapy is to perform clinical trials as a combination with novel agents (primarily bortezomib and lenalidomide) to be included among the alternatives in the standard of care armamentarium. Many market analysts believe that the monoclonal antibody Empliciti (elotuzumab) developed by BMS/Abbvie will result in high sales in the RRMM setting. Based on the fact that it has received breakthrough therapy designation in addition to currently being under accelerated assessment and priority review by the EMA and FDA, so do the authorities. Empliciti will challenge Kyprolis, based on its favorable safety profile, in patients who have received ≥1 prior treatments and will be given as a triple combination with Rd. Its approval will likely also mean head to head competition with Darzalex, which is currently being developed in two phase III trials as a combination with Rd and Vd. Another phase III candidate is Masiviera (mastinib), which was refused a European marketing authorization in 2014. Masiviera is an oral tyrosine kinase inhibitor that is developed as a combination treatment with Vd in patients who have received ≥1 prior treatments. According to AB Science’s website, mastinib is currently in 11 additional (non-myeloma focused) phase III trials. In the late stage RRMM setting, only one candidate is currently in phase III trials: Aplidin (plitidepsin). PharmaMar is developing Aplidin in the combination with dexamethasone in a phase III study against single agent dexamethasone. Patients must have received at least three but not more than six prior therapeutic regimens.

Profitable partnering opportunities lie ahead for Innovative pipeline drugs that are able to address unmet needs in multiple myeloma

It is clear that MM is a dynamic and growing space with high profit opportunities, both now and in the future. A competitive battle is ongoing between the current market leaders Celgene (Revlimid, Pomalyst & Thalomid) and Millenium/Takeda (Velcade in the US) & Janssen (Velcade in Europe, Japan & China), and the future market leaders Abbvie/BMS (Empliciti), Janssen (Darzalex), Novartis (Farydak) and Millenium/Takeda (Ixazomib). Market shares will be affected through label extensions (by moving from RRMM to front line therapy, and from novel combinations), pricing strategies (e.g. Pomalyst/Imnovid is no longer reimbursed in England) and convenience factors (e.g. oral formulation). Due to this fierce battle we are likely to see acquisition activity among first-in-class drugs and drugs with novel mechanisms, that may be able to address refractory disease. Drugs showing higher activity in certain high-risk MM patients, as well as those targeting smoldering- or asymptomatic myeloma, are also likely to be well positioned for partnering with one of the market leaders.

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Tobias Thornblad, CEO & Partner, Monocl Strategy Services


CXO and Co-founder of Monocl Software