Multiple myeloma .The management of the newly diagnosed patient Dr Denis O’Keeffe

Lymph node Bone Marrow Germinal Center SWITCH RECOMBINATION V(D)J Lymphoplasmacyte IgM Lymph node Germinal Center SOMATIC Lymphoblast HYPERMUTATION Plasma blast SWITCH RECOMBINATION In order to characterize the translocations in MM we need first to determine when they are occuring, during VDJ recombination, or isotype switching. This slide shows a summary of B cell differentiation. In the BM a pre-B cell undergoes VDJ recombination to make a functional Ig gene. An error resulting in a translocation to bcl-1 can result in mantle zone lymphoma, to bcl-2 in indolent lymphoma, and to c-myc to Burkitt’s lymphoma. This cell can enter the bloodstream, and the secondary lymphoid tissue where if it encounters antigen directly as part of the primary immun response, it can differentiate into a short lived plasma cell, that live about 3 days. Alternatively if it encounters antigen in the context of an antigen presenting cell it can enter a germinal center where it undergoes multiple rounds of division and somatic hypermutation of its immunoglobulin genes. The cells who Ig genes have retained or increased their affinity for antigen exit the germinal center, and they may undergo isotype switching and home to the BM where they can differentiate into long lived plasma cells with a lifespan of about 30 days. It is this cell that is the counterpart of the malignant plasma cell in myeloma. It has switched isotype, and its Ig genes have undergone extensive somatic hypermutation indicaing passage throuh the germinal center. Based on this analysis we postulated that the translocations in MM would occur at this stage, after passing through the germinal, during the process of isotype switch recombination Virgin B cell V(D)J RECOMBINATION Bone Marrow Plasma cell G,A,E Pre-B cell

Basic immunoglobulin structure

Complications Bone destruction –Pain,fractures,spinal cord compression Hypercalcemia- N&V Renal failure Anaemia- tiredness, shortness of breath Infection

Multiple myeloma Presenting factors: bone pain (70%) anaemia (66%) symptoms of hypercalcaemia (20%) fever and infection (15%) renal failure (10%) bleeding (10%) chance finding (10%) symptomatic hyper viscosity (4%)

Myeloma bone pathology

Cell proliferation and factors secreted by tumour cells Bone destruction Bone pain and breakage Hypercalcaemia

Cell proliferation and factors secreted by tumour cells Paraprotein (monoclonal protein in blood/urine) Amyloid Renal failure

Multiple myeloma Diagnosis: SPEP Bone marrow Skeletal survey/MRI scans 24 hour urine collection FBC/U&E B2Microgloulin/CRP

Challenges of the new patient 1. Pain and symptoms related to myeloma 2. Psychological shock of diagnosis 3. Social circumstances and social support 4. Stopping work and financial impact

Considering initial treatment 1. Age 2. Performance status 3. other illnesses 4. Social support structure

Specific consideration Transplant versus no transplant Fit versus intermediate versus frail

Choice of treatment – Fit young patient Aim – Achieve as deep a response as possible Complete remission - associated with longer disease free time

What is a persons prognosis at the outset ? Staging Cytogenetics Depth of initial response

Staging at diagnosis The International Staging System This system divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels. Stage I Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is 3.5 (g/dL) or greater Stage II Neither stage I or III, meaning that either: The beta-2 microglobulin level is between 3.5 and 5.5 (with any albumin level), OR The albumin is below 3.5 while the beta-2 microglobulin is less than 3.5 Stage III Serum beta-2 microglobulin is 5.5 or greater.

Durie-Salmon staging The amount of abnormal monoclonal immunoglobulin in the blood or urine: Large amounts of monoclonal immunoglobulin indicate that many malignant plasma cells are present and are producing that abnormal protein. The amount of calcium in the blood: High blood calcium levels can be related to advanced bone damage. Because bone normally contains lots of calcium, bone destruction releases calcium into the blood. The severity of bone damage based on x-rays: Multiple areas of bone damage seen on x-rays indicate an advanced stage of multiple myeloma. The amount of hemoglobin in the blood: Haemoglobin carries oxygen in red blood cells. Low haemoglobin levels mean you are anaemic and can indicate that the myeloma cells occupy much of the bone marrow and that not enough space is left for the normal marrow cells to make enough red blood cells.

Cytogenetics

CR represents an early index of potential long survival in multiple myeloma On the basis of the response status after a 2-year landmark, the subsequent median survival was 9.7 years for patients with CR, 4.4 years for those with PR and 2.7 years for patients with NR (P<0.001).1. Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. 2. August 2016 – New criteria based on imaging, bone marrow blood protein analysis CR represents an early index of potential long survival in multiple myeloma M Wang1, K Delasalle1, L Feng1, S Thomas1, S Giralt1, M Qazilbash1, B Handy1, J J Lee1 and R Alexanian1 Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. Kim JS1, Kim K, Cheong JW, Min YH, Suh C, Kim H, Jo DY, Ryoo HM, Yoon SS, Lee JH; Korean Multiple Myeloma Working Party.

Transplant eligible Bortezumab Lenalidomide Cyclophosphamide Pomilidomide Dexamethasone

Standard treatment Cyclophosphamide/Bortezumab/Dexamethasone Vs Lenalidomide/Bortezumab/Dexamethasone

Autologous transplant Stem cells are

Crude but it works PETHEMA trial – Increased CR rates from 37 to 57% in group treated with VTD Palumbo trial 2014 – Improved DFS and OS with transplant.

Maintenance Lenalidomide – CALGB study 58% vs 37% at 37 months had progressed myeloma requiring treatment . Secondary cancers occurred in 8 vs. 3 % . Weigh up risks versus benefit.

Non transplant but fit patients Bortezumab Lenalidomide Cyclophosphamide Thalidomide Dexamethasone Plus melphalen.

Different issues Performance status Co-morbidities Social support structures.

Standard regimens in Ireland Melphalen/bortezumab/Prednisolone Cyclophosphamide/bortezumab/prednisolone Lenalidomide/Dexamethasone (Low dose)

Supportive treatments Bisphosphonate

Standard treatment 2 years of monthly treatment Side effects – osteonecrosis Must have dental assessment and treatment before starting

Other supportive- Prevent infection Valaciclovir Septrin Immunoglobulin

The future- Proteosome inhibitors / Immunomodulators Carfilzomib – New proteosome inhibitor Ixazomib (is the first orally-available proteosome inhibitor approved by the FDA on November 20, 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy  

Antibody treatment Elotuzumab is a humanized recombinant monoclonal IgG1 antibody targeting signalling lymphocyte activation molecule (SLAMF7), also known as CS1 (CD2-subset-1) . More recently, a phase III study, ELOQUENT-2, compared the combination of elotuzumab, lenalidomide, and dexamethasone to lenalidomide and dexamethasone in patients with relapsed disease The elotuzumab-containing arm had superior progression-free survival (19.4 months vs. 14.9 months in the control group; p<0.001), and the overall response rate was also higher (79% vs. 66%; p<0.001).

Daratumumab Daratumumab is a human IgG1κ monoclonal antibody that targets CD38, a transmembrane glycoprotein found at low levels on lymphoid and myeloid cells, and is involved with calcium flux and signal transduction. In a cohort of 42 patients receiving 16 mg/kg, 64 percent of patients were refractory to both bortezomib and lenalidomide, 17 percent were refractory to carfilzomib, and 36 percent were refractory to pomalidomide. The overall response rate in this group was 36 percent, including two patients who had a complete response and two patients with a very good partial response.

Summary 1. Initial therapy is evolving for myeloma 2. Assess the patient based on age, co-morbidities and performance status 3. Decide if transplant is an option. 4. Aim for the best response with initial therapy 5. Consider induction / transplant/ maintenance for fit patients 6. For non-transplant patients consider the most powerful treatment that is tolerable. 7. New treatments especially antibody treatment is coming rapidly