**4. Newly diagnosed multiple myeloma**

Current treatment strategies for newly diagnosed patients are always aiming to reach deepest complete remission - molecular or immunophenotypic in [15,16]. In the first decade of this century, therapeutic regimens with one novel agent as backbone together with glucocorticoids and alkylating cytostatics were used as high standard based on randomized trials (Tab. 1). Modern protocols of second decade use intensive treatment strategies in the clinical trials called "Multi Agent Sequential Therapy Targeting Different Clones" with at least two novel agens based on the strong evidence of curative potential of such approaches such as Total Therapy trials pioneered by Bart Barlogie in the Little Rock in [14].

M – melfalan, P – prednison, T – thalidomide, V – Velcade (bortezomib); R – Revlimid (lenalidomide)

**Table 1.** Better PFS on randomized trials with one novel agent based regimen vs. melphalan prednisolon (MP)


transplantation is always one of the most effective treatment options during the relapse setting and can be very safely used based on the individual history of the patient in [24]. There is a reduced chance to achieve complete remission if compared to first line therapy. However, combinative regimens using two novel agents (carfilzomib or bortezomib with lenalidomide or thalidomide) are able to induce even higher proportions of remission including complete remission than older types of therapy without the use of imunomodulatory drugs and proteasome inhibitors in newly diagnosed patients (personal experience with lenalidomide and carfilzomib). Generalized benefits for patients in further relapses from a similar number of treatment cycles using one novel agent (IMiD or proteasome inhibitor) is in median at least 1 year in [25]. Thus, the main benefit is not due to overcoming the natural course of the disease but rather to the possibility of using other novel agents in the next relapse. In the advanced disease stage, the treatment is very individualized and reaches a state of stability for a longer period of time (> 6 months) is considered to be acceptable treatment outcome. Long term survival of more than 10 years is currently reached for more than one third of multiple myeloma patients; this has been achieved due to new efficient drugs that can be offered to patients in relapse. It is important to create long-term treatment strategies so that the patient is offered efficient treatment even in third, fourth and further relapses of the disease. The patients who have relapsed after at least two new drugs have a very poor outcome if no other

**Agent Dose level 0 Dose level -1 Dose level -2**

Prednisone 50 mg qod 25 mg qod 12.5 mg qod

Thalidomide 100 mg/d 50 mg/d 50 mg qod

20 mg/d d 1,8,15,22 / 4 wk

Strategies for the Treatment of Multiple Myeloma in 2013: Moving Toward the Cure

0.18 mg/kg d 1-4 / 4-6 wks

50 mg/d d 1-21 / 4 wks

1.3 mg/m2 once/wk d 1,8,15,22 / 5 wks

> 15 mg/d d 1-21 / 4 wks

10 mg/d d 1,8,15,22 / 4 wk

http://dx.doi.org/10.5772/55366

5

0.13 mg/kg d 1-4 / 4-6 wks

50 mg qod d 1-21 / 4 wks

1.0 mg/m2 once/wk d 1,8,15,22 / 5 wks

> 10 mg/d d 1-21 / 4 wks

Dexamethasone 40 mg/d

Melphalan 0.25 mg/kg

Cyclophosphamide 100 mg/d

Lenalidomide 25 mg/d

Adopted from Palumbo & Anderson, New Engl J Med 2011

**Table 2.** Dose reductions algorithm for frail patients

Wk, week; d, day; qod, every other day

Bortezomib 1.3 mg/m2 twice/wk

d 1,8,15,22 / 4 wk

d 1-4 / 4-6 wks

d 1-21 / 4 wks

d 1,4,8,11 / 3 wks

d 1-21 / 4 wks

new drug is available, and they should receive the best palliative care in [26].

A similar course without myeloablative regimen but with extension of the induction phase of therapy should be evaluated for seniors not indicated for a myeloablative regimen. Unfortu‐ nately, in this group of patients, proof of curability is still anecdotal; treatment is less intensive and more modified based on status of the patient. It is important to treat the patient and not the disease. Adequate intensity of therapies in fragile patients is one of the more important aspects for a final positive outcome (Tab. 2) in [22]. Novel combinative fully peroral regimens with two novel agens will further improve prognosis in patients not indicated for myeloabla‐ tive treatment.

#### **5. Relapse of multiple myeloma**

Aims of treatment for patients with relapsed/progressed disease are more limited. Key targets of intensive therapeutic strategies regarding the first and second relapse should be to make the disease chronic again for several years. Balance between efficacy and toxicity as well as long-term toxicity (peripheral polyneuropathy) are main issues in this setting in [23]. ReStrategies for the Treatment of Multiple Myeloma in 2013: Moving Toward the Cure http://dx.doi.org/10.5772/55366 5


Adopted from Palumbo & Anderson, New Engl J Med 2011

**Table 2.** Dose reductions algorithm for frail patients

Modern protocols of second decade use intensive treatment strategies in the clinical trials called "Multi Agent Sequential Therapy Targeting Different Clones" with at least two novel agens based on the strong evidence of curative potential of such approaches such as Total

MPT > MP Randomized trial 6

MPV > MP Randomized trial 1

MPR - R > MP Randomized trial 1

VMPT - VT > MP Randomized trial 1

**Table 1.** Better PFS on randomized trials with one novel agent based regimen vs. melphalan prednisolon (MP)

**3.** Consolidation therapy (3-4 cycles of combined treatment, if possible different from entry

**4.** Maintenance therapy by lenalidomide and possible combination of drugs should ensure maintenance of remission due to probable immunomodulatory effect in [20,21].

A similar course without myeloablative regimen but with extension of the induction phase of therapy should be evaluated for seniors not indicated for a myeloablative regimen. Unfortu‐ nately, in this group of patients, proof of curability is still anecdotal; treatment is less intensive and more modified based on status of the patient. It is important to treat the patient and not the disease. Adequate intensity of therapies in fragile patients is one of the more important aspects for a final positive outcome (Tab. 2) in [22]. Novel combinative fully peroral regimens with two novel agens will further improve prognosis in patients not indicated for myeloabla‐

Aims of treatment for patients with relapsed/progressed disease are more limited. Key targets of intensive therapeutic strategies regarding the first and second relapse should be to make the disease chronic again for several years. Balance between efficacy and toxicity as well as long-term toxicity (peripheral polyneuropathy) are main issues in this setting in [23]. Re-

M – melfalan, P – prednison, T – thalidomide, V – Velcade (bortezomib); R – Revlimid (lenalidomide)

**1.** Induction therapy (2-6 lines of combined therapy) in [17] **2.** Myeloablative treatment (1-2 autologous transplantation)

induction therapy) in [18,19]

**5. Relapse of multiple myeloma**

tive treatment.

Therapy trials pioneered by Bart Barlogie in the Little Rock in [14].

4 Multiple Myeloma - A Quick Reflection on the Fast Progress

transplantation is always one of the most effective treatment options during the relapse setting and can be very safely used based on the individual history of the patient in [24]. There is a reduced chance to achieve complete remission if compared to first line therapy. However, combinative regimens using two novel agents (carfilzomib or bortezomib with lenalidomide or thalidomide) are able to induce even higher proportions of remission including complete remission than older types of therapy without the use of imunomodulatory drugs and proteasome inhibitors in newly diagnosed patients (personal experience with lenalidomide and carfilzomib). Generalized benefits for patients in further relapses from a similar number of treatment cycles using one novel agent (IMiD or proteasome inhibitor) is in median at least 1 year in [25]. Thus, the main benefit is not due to overcoming the natural course of the disease but rather to the possibility of using other novel agents in the next relapse. In the advanced disease stage, the treatment is very individualized and reaches a state of stability for a longer period of time (> 6 months) is considered to be acceptable treatment outcome. Long term survival of more than 10 years is currently reached for more than one third of multiple myeloma patients; this has been achieved due to new efficient drugs that can be offered to patients in relapse. It is important to create long-term treatment strategies so that the patient is offered efficient treatment even in third, fourth and further relapses of the disease. The patients who have relapsed after at least two new drugs have a very poor outcome if no other new drug is available, and they should receive the best palliative care in [26].
