Introduction

Our increased understanding of myeloma biology has resulted in significantly improved patient outcomes although, until recently, the major gains have been achieved in patient’s aged < 70 years.

The explanation for this has been attributed to the impact of stem cell transplant but there is evidence suggesting elderly patients have not received no or limited treatment because of concerns around treatment toxicity and quality of life.

Newer agents, however, are not only more efficient at killing malignant plasma cells but are less toxic and so may be used more confidently in elderly patients.

Novel Agents:

Small molecules:

Proteasome inhibitors (PI’s) - Proteasome inhibition affects multiple different pathways. Second (Carfilzamib) and third generation oral (MLN 3124) PI’s are active as single agents and are demonstrating encouraging activity in combination therapy trials in de novopatients and those who relapse or are resistant to Bortezomib.

IMiD’s - IMiD’s demonstrate a spectrum of anti-myeloma mechanisms including anti-angiogenic, anti-proliferative and immunomodulatory effects but different agents that comprise this class of drugs exhibit differential activity patterns. Hence thalidomide demonstrates high anti-angiogenic activity at drug levels achievable in-vivo whilst Pomalidomide is significantly more immunomodulatory than the other 2 agents. Defects in immune surveillance, including functional dendritic cell defects, increased expansion of T-regulatory cells and T-cell dysfunction are well described in myeloma. Exploiting these different mechanisms may be important at different stages in the treatment pathway and influence the choice of agent.

HDACi’s – Histone deacetylase (HDAC) and histone acetyl transferases are enzymes that modulate chromatin conformation rather than by alterations in the primary nucleotide sequence that thereby regulates gene expression. HDAC inhibitors (eg panobinostat, vorinostat, or romidepsin) when used as single agents demonstrate modest activity but combination regimens have shown more promising results in relapsed/refractory disease and phase III studies are ongoing.

Monoclonal antibodies:

An array of antibodies against cell surface receptors, signalling molecules, plasma cell growth factors and mediators of cell adhesion are being used in combination with chemotherapy. Novel agents may enhance antibody activity directly on the tumour cell or by conjugating the antibody with toxins facilitate targeting of the tumour cell.

Lenalidomide, activates NK cells and down-regulates programmed death ligand1 (PDL-1), a ligand for PD-1 responsible for inhibiting T-cell activation and suppressing NK cell activation, providing evidence that these 2 agents may act synergistically. Results of early phase studies with CSI (Elotusimab), CD38 (Daratumumab)and IGF-1 (AVE 1642) are encouraging.

Treatment strategies:

Smouldering myeloma: Two trials have treated patients with high risk smouldering myeloma before signs of progression occur. They suggest early intervention can delay progression but without improved survival.

Furthermore a modest increased risk of acute leukaemia is reported and there is a fear the disease may be driven to evolve into a more aggressive form of the disease secondary to treatment pressure although this has yet to be confirmed.

De novo disease: Once there is evidence of end-organ damage secondary to paraprotein or plasma cell expansion, induction treatment should be initiated to reduce disease bulk with minimal toxicity. The choice of induction agent should be decided on the basis of “risk assessment” based on the disease and the patient’s clinical status. All patients should have their cytogenetic signature analysed.

Similarly, previous thromboses, peripheral neuropathy or co-existent renal impairment, and response to previous treatment favour the use of certain drugs over others. Combination therapy with 2, 3 or 4 drug combinations induce OR’s of 70-90% with CR’s in up to 45% but with increased toxicity with increased numbers of drug.Although prospective trials to validate the effect of cytogenetic risk directed therapy have yet to be reported, there are well described poor risk cytogenetic anomalies such as t(4:14) translocations, 1q gain and del(17p) are associated with significantly poorer outcomes.

Younger patients should be assessed for consolidation with autologous heamopoeitic stem cell transplantation and all patients evaluated for maintenance therapy. Trials are in progress to define the role of early versus late stem cell transplantation.

A Cochrane Review meta-analysis of tandem autologous stem cell transplantation raised uncertainty about the routine use of this approach. The role of allogeneic stem cell transplantation remains unresolved although consideration should be given to high risk patients in first remission and relapsed/refractory patients with a matched related donor.

Relapse/refractory disease: Although novel combination chemotherapy induces higher response rates that are 5-10 fold greater then with conventional chemotherapy the degree of improvement in overall survival has not been nearly as dramatic with almost all patients relapsing with evidence of biochemical progression on serological testing or

clinical deterioration.

Most patients secrete the same paraprotein and carry the same chromosomal aberrations at relapse as at diagnosis suggesting that either the myeloma “stem cell” is protected in an environmental niche or it develops drug resistance secondary to clonal evolution or tiding.

A short progression free survival (PFS) from last treatment and high risk cytogenetics identify a poor risk cohort whilst the choice of salvage agent depends on patient choice, response to prior therapy and the existence of co-morbidities.

Numerous resistance mechanisms have been described. Cereblon protein expression appears to be necessary for IMiD anti-myeloma activity with reduced expression in lenalidomide resistant MM patients at diagnosis making cereblon a potentially new target to improve efficacy.

Patients resistant or refractory to both Bortezomib and Lenalidomide pose a particularly challenging cohort of patients with limited treatment options and short PFS and OS.

Pomalidomide is a 3rd generation IMiD with potent direct anti-myeloma, anti-angiogenic, anti-inflammatory and immunomodulatory activity. In addition, Pomalidomide increases levels of p21 in a p53 independent mechanism, by demethylation and acetylation of H3K9 the p21(WAF-1) promoter, thus modifying the chromatin structure to facilitate enhanced transcription activation.

Early phase 1 and 2 trials of Pomalidomide alone or in combination with dexamethasone showed PR’s or better in 32-40% of relapsed refractory patients. Although prospective randomised data are lacking, efficacy and toxicity is similar at doses of 2 or 4 mgs daily and responses of 70-75% are reported in patients with high risk cytogenetics.

A recent Phase III study compared 302 patients assigned to Pomalidomide+Low dose dexamethasone POM-LoDEX) and 153 to high dose dexamethasone (HiDEX) in patients relapsing or refractory to both Bortezomib and Lenalidimde.

After a median follow-up 10 months 31% had ≥partial response with POM+LoDEX versus 10% with HiDEX (p<0·001). The median duration of response was 7 months with POM+LoDEX with a significant advantage for median PFS (4·0 vs 1·9 months; HR 0·48; p<0.001) and OS (12·7 vs 8·1 months; HR 0·74; p=0·028). On the strength of this study the EMA granted Marketing Authorisation in August 2013.

Conclusions:

For the first time, people are beginning to talk of cure but before we can decide this, we must agree on a definition of cure which for some means dying of causes other than the original disease whilst for others means dying at an age consistent with the remainder of the population without evidence of the original disease.

What is sure is that prolonged survival with good quality of life is now a reality for the majority of patients, something directly attributable to the availability of more active, less toxic drugs.

Better definition of progression events in this genetically heterogeneous disease will improve risk stratification and facilitate more rational treatment combinations with improved outcomes, less toxicity and better quality of life. The future is looking exciting.