Blood cancer

IgG Multiple Myeloma
Short Summary

57-year-old male who was found to have back pain and hyperglobulinemia approximately. Marrow biopsy was consistent with IgG myeloma. He was treated with steroids and local radiotherapy with improvement in symptoms and a modest reduction in the M-component. He received melphalan-based autologous stem cell transplantation, which was complicated by reversible respiratory failure. Unfortunately, he relapsed and was treated with bortezomib and steroids for 6 cycles followed by thalidomide. The disease has responded to therapy.

Patient's Questions

The patient is interested in your opinion on:
1) His current treatment?

2) What are the alternatives to this treatment?

3) What are the next steps when Thalidomide will not be effective and the disease will progress?

4) Future treatment ? Experimental therapy ?

5) Is bone narrow transplant from a donor is the next step?

We appreciate your input on the above and any other advice that could help.

Medical Background

male , 57 years old
Diagnosis: Multiple Myeloma

The patient is a 57 year old male. In September 2008, complaints of back ache initiated an investigation that revealed hyperglobulinemia. Imaging studies revealed several vertebral lesions; a vertebroplasty was performed on 10/2008. Bone marrow biopsy showed 30% plasma cells, and a diagnosis of IgG Multiple Myeloma was established.


Additional studies were performed:
Abdominal ultrasound 8/2008 – mildly enlarged spleen
Pulmonary function test 9/2008 – normal
Chest CT (w/o contrast) 10/2008 – Mediastinal lymphadenopathy up to 4c"m in size, vertebra compression fractures in D10, D12 and L1, large sclerotic lesion in D10 and L1
• A multi-acquisition gated (MUGA) scan showed an ejection fraction of 70%.
Serology tests for HBV, HCV, HIV, EBV and HTLV were negative.


Treatment was initiated with high dose dexacort and radiotherapy to the vertebral lesions. After 4 courses (the last administered in 1/2009) a reduction of more than 50% of the monoclonal Ab was noted. Globulin levels dropped from 4.4 to 3.2.
In 4/2009, he underwent Autologus Peripheral Blood Stem Cell transplantation, after induction with 200mg/mm Melfalan (overall 400mg in two days). Post transplantation period was significant for post engraftment, steroid responsive acute respiratory failure, from which he completely recovered.
On 8/2009 , a re-progress of the myeloma was observed ( a rise in globulins, the IG – G and the light chains). Velcade with Dexacort was started with a good response.
After 6 cycles of Velcade, the patient is currently on Thalidomide.
Following is a summary of blood test results.

Expert's Opinion

The patient is interested in your opinion on his current treatment?

Bortezomib is the most active agent currently available for the treatment of myeloma, and the combination of bortezomib and dexamethasone is well-accepted standard therapy. Thalidomide has had a long history in the successful management of myeloma and many people do respond well. However, it tends to be somewhat sedating and constipating. Moreover, it may result in peripheral neuropathy. It is often difficult to use with bortezomib because the combined neuropathic effects of these two drugs can result in serious nerve injury. If the patient is tolerating this regimen, it is certainly fine. To a large extent, many of us now preferentially use lenalidomide (Revlimid), since it is somewhat more potent, less sedating, and not neurotoxic. Lenalidomide may be tougher on the blood counts though, and especially after a stem cell transplantation count depression may be a concern.


What are the alternatives to this treatment?

Effective regimens if the current therapy is not effective are bortezomib, lenalidomide, decadron (VRD); the similar bortezomib, thalidomide, decadron (VTD); melphalan, bortezomib, decadron; or doxil, lenalidomide, decadron. A phase I/II trial has shown significant activity for the 4-drug combination of bortezomib, melphalan, prednisone, and thalidomide (BMPT). The combination of bortezomib, intermediate dose dexamethasone, and continuous low-dose cyclophosphamide is active as well – note that antiviral prophylaxis is necessary with the last regimen. In addition more conventional combination chemotherapy can be used (e.g. VAD).

What are the next steps when Thalidomide will not be effective and the disease will progress?
Commonly, patients who become resistant to thalidomide will respond to lenalidomide. Data are accumulating that long-term maintenance therapy with lenalidomide seems to delay recurrence.

1. Berenson, JR, Yang, HH, Sadler, K, et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 2006; 24:937.

2. Kropff, M, Bisping, G, Schuck, E, et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol 2007; 138:330.

3. Palumbo, A, Ambrosini, MT, Benevolo, G, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood 2007; 109:2767.

4. Pineda-Roman, M, Zangari, M, van Rhee, F, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008; 22:1419.

5. Orlowski, RZ, Nagler, A, Sonneveld, P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007; 25:3892.

6. Ning, YM, He, K, Dagher, R, et al. Liposomal doxorubicin in combination with bortezomib for relapsed or refractory multiple myeloma. Oncology (Williston Park) 2007; 21:1503.

7. Reece, DE, Rodriguez, GP, Chen, C, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 2008; 26:4777.

8. Terpos, E, Kastritis, E, Roussou, M, et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia 2008; 22:2247.

9. Popat, R, Oakervee, H, Williams, C, et al. Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma. Br J Haematol 2009; 144:887.

10. Richardson, PG, Sonneveld, P, Schuster, M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110:3557.

11. Sonneveld, P, Hajek, R, Nagler, A, et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer 2008; 112:1529.


Future treatment ? Experimental therapy?
Alternatives for the future might include an investigational study or clinical trial. Some drugs that are currently in development include the proteasome inhibitors carfilzomib or salinosporamide; the new IMID, pomalidomide; histone deacetylase inhibitors such as LAQ824 and LBH589 as well as tubacin, and vorinostat; the PI3K/AKT inhibitor perifosine; and the heat shock protein inhibitor 17-AAG. Most of these are available only on clinical trials now. A good resource to find them is http://clinicaltrials.gov

12. Mitsiades CS, Hideshima T, Chauhan D, McMillin DW, Klippel S, Laubach JP, Munshi NC, Anderson KC, Richardson PG. Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib. Semin Hematol. 2009;46:166-75.

Is bone narrow transplant from a donor the next step?
Allogeneic hematopoietic cell transplantation (HSCT) may be a curative treatment for some patients with multiple myeloma. Its use is limited by the toxicity of the procedure – especially infections and graft-versus-host disease. Moreover, a donor must be available – either a family member or a matched unrelated donor. There are two types of allogeneic HSCT – myeloablative and reduced intensity. Since the patient has already had an autologous HSCT, the myeloablative option is not viable—the toxicity would be too high. Thus reduced intensity would be required.

Reduced intensity conditioning (RIC) regimens use less intensive chemotherapy or irradiation prior to the infusion of donor stem cells. This approach relies on the immunologic attack of the donor immune cells on the myeloma. Several reports have looked at RIC transplantation following autologous HSCT.

One analysis studied patients with previously treated myeloma up to 70 years of age enrolled in 1 of 4 prospective trials that included auto-HCT and followed by allo-HSCT. After a median follow-up of 6.3 years, the 5-year non-relapse mortality rate was 18% primarily due to graft-versus-host disease. Median time to progression was 5 years while median overall survival had not been reached. A larger study evaluated patients with newly diagnosed myeloma who were =65 years of age and had at least one sibling. All patients were initially treated with chemotherapy and patients with an HLA-identical sibling were scheduled to receive an autologous HSCT followed by a RIC allogeneic HCT using a sibling donor. At a median follow-up of 46 months, median overall survival had not been reached in the patients getting RIC HSCT following autologous HSCT, but these patients received their allogeneic transplants as primary therapy – not after relapse, so the data may not completely apply. Nevertheless, these results suggest that in patients with responsive disease allogeneic HSCT has a role.

A more relevant study performed by the Spanish group compared the use of autologous or reduced-intensity allogeneic HSCT in patients with myeloma who failed to achieve a complete or near complete remission after an initial autologous HSCT (ref 17). At a median follow-up after second transplantation of 5.2 years, patients who received an allogeneic HSCT had higher rates of complete remission (40 vs 11%) and a trend toward longer progression free survival (31 months vs not yet reached), but a higher rate of transplant-related mortality (16 vs 5%, respectively). There was no measurable improvement in survival though.

13. Kroger, N, Schwerdtfeger, R, Kiehl, M, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100:755.

14. Maloney, DG, Molina, AJ, Sahebi, F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102:3447.

15. Bruno, B, Rotta, M, Patriarca, F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356:1110.

16. Stewart, AK. Reduced-intensity allogeneic transplantation for myeloma: reality bites. Blood 2009; 113:3135.

17. Rosinol, L, Perez-Simon, JA, Sureda, A, et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112:3591.

18. Einsele, H, Schafer, HJ, Hebart, H, et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121:411.

19. Majolino, I, Davoli, M, Carnevalli, E, et al. Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma. Leuk Lymphoma 2007; 48:759.

20. de Lavallade, H, El-Cheikh, J, Faucher, C, et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008; 41:953.


Summary:
1. The patient is a relatively young man with disease that has been responsive to therapy and is currently responding to therapy. This is encouraging regarding the likelihood of responding to alternate treatments.

2. There are a number of combination regimens that may be clinically useful, although they are not curative.

3. Experimental studies are ongoing in a number of academic centers. The new drugs are showing good signs of activity. It might be difficult to decide what experimental therapy to try, but that decision is often determined by the clinical trial protocol per se.

4. Allogeneic transplantation is potentially curative therapy in a proportion of patients, although the risks are substantial due to transplant-related toxicity. Moreover a donor must be available (either a sibling or an unrelated donor is acceptable). I would recommend undertaking the transplantation before the disease becomes completely resistant to therapy. The smaller the disease burden and the better medical condition of the patient, the better the transplant outcome is likely to be.

""